Low-dose melphalan in elderly acute myeloid leukaemia: complete remissions but resistant relapse with therapy-related karyotypes.
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Acute Disease↗
Biomedical subjects
R Kerr
Publications and source records attributed to R Kerr.
Transfusion-associated graft vs. host disease in a patient with high-grade B-cell lymphoma. Should cellular products for patients with non-Hodgkin's lymphoma be irradiated?
We present the case of a 64-year-old man who died from transfusion-associated graft vs. host disease (TA-GVHD) having been treated 2 years earlier for a high-grade, non-Hodgkin's lymphoma (NHL). We suggest that he was at increased risk of developing TA-GVHD as a result of the NHL and its subsequent treatment, and propose that patients with NHL should be added to those 'at risk' groups who receive irradiated cellular blood components.
Antineoplastic Combined Chemotherapy Protocols↗
Direct antiglobulin test negative, non spherocytic autoimmune haemolytic anaemia.
We report a case of direct antiglobulin test (DAT) negative warm autoimmune haemolytic anaemia (AIHA). At initial presentation our patient had compensated haemolysis and was DAT positive for complement only. Severe haemolytic anaemia developed some years later with a negative DAT. Spherocytes were not a feature of the blood film and osmotic fragility studies were negative. Immune mediated haemolysis was confirmed by fluorescent activated cell sorter (FACS) analysis using antihuman IgG immunoglobulin. Response to immunosuppression was transient but a good response was achieved following splenectomy. Repeat FACS analysis post splenectomy demonstrated a marked rise in IgG coated red cells. Techniques used in establishing the diagnosis and possible mechanisms for this presentation are discussed.
Aged↗
Magnetic resonance imaging of the foot and ankle.
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Ankle Injuries↗
A paraxial exclusion zone creates patterned cranial neural crest cell outgrowth adjacent to rhombomeres 3 and 5.
Cranial neural crest cell migration is patterned, with neural crest cell-free zones adjacent to rhombomere (R) 3 and R5. These zones have been suggested to result from death of premigratory neural crest cells via upregulation of BMP-4 and Msx-2 in R3 and R5, consequent to R2-, R4-, and R6-derived signals. We reinvestigated this model and found that cell death detected by acridine orange staining in avian embryos varied widely numerically and in pattern, but with a tendency for an elevated zone centered at the R2/3 boundary. In situ hybridization of BMP-4 mRNA resolved to centers at R3 and R5 but Msx-2 resolved to the R2/3 border with only a faint smear from R5 to R6. Outgrowth of neural crest cells was less in isolated R3 cultures than in R1+2, R2, and R4 cultures, but R3 showed neither a decrease in outgrowth of neural crest cells nor an increase in cell death when cocultured with R1+2, R2, or R4. In addition, in serum-free culture, exogenous BMP-4 strikingly reduced neural crest cell outgrowth from R1+2 and R4 as well as R3. Thus we cannot confirm the role of intraneural cell death in patterning rhombomeric neural crest outgrowth. However, grafting quail R2 or R4 adjacent to the chick hindbrain demonstrated a neural crest cell exclusion zone next to R3 and R5. We suggest that one important pattern determinant for rhombomeric neural crest cell migration involves the microenvironment next to the neural tube.
Animals↗
Phase I trial of interferon gamma retroviral vector administered intratumorally with multiple courses in patients with metastatic melanoma.
The purpose of this study was to determine the safety and antitumor activity of IFN-gamma retroviral vector in patients with advanced melanoma. Seventeen patients (9 single courses, 8 multiple courses) received a total of 363 intratumor injections of IFN-gamma retroviral vector (1 x 10(7) PFU/ml administered at 0.3, 0.5, and 1.0 ml per cohort). No grade III/IV adverse events were attributed to study medication. Replication-competent retrovirus was not detected in any of the 17 patients by polymerase chain reaction studies. Eight patients showed elevated anti-tumor antibody responses in comparison with baseline by ELISA. One of nine patients treated with a single course had an optimal response of stable disease, compared with eight of eight multiple-injected patients. Median survival of single-injected patients was 150 days, and patients who received multiple injections have still not achieved median survival duration, with four of eight still living (p = 0.0462, Wilcoxon; p = 0.0273, log rank). We conclude that intratumor injection of IFN-gamma is safe and well tolerated. Evidence of antitumor activity is suggested in patients with advanced malignancy that received multiple injections.
Adult↗
Differential expression of the muscarinic m2 acetylcholine receptor by small and large motoneurons of the rat spinal cord.
The purpose of this study was to determine if motoneurons in the spinal ventral horn express the muscarinic m2 acetylcholine receptor. Motoneurons were retrogradely labelled in adult rats by intramuscular injection of Fluorogold and examined with confocal microscopy for evidence of immunoreactivity for the receptor. The cells were also double-labelled for choline acetyltransferase to determine if they were contacted by cholinergic axons. Almost all large motoneurons (diameters greater than 35 microm) displayed intense immunoreactivity for the receptor which was evenly distributed along the plasma membrane. Small cells were immunonegative for the receptor or weakly labelled. As large cells probably correspond to alpha-motoneurons and receive many cholinergic contacts, it is concluded that acetylcholine can influence this type of motoneuron by acting through the m2 receptor.
Animals↗
International Subarachnoid Aneurysm Trial.
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Age Factors↗
Endovascular aneurysm treatment and the incidence of vasospasm.
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Embolization, Therapeutic↗
Glutamate receptor subunits associated with rat sympathetic preganglionic neurons.
The purpose of this study was to determine what subunits of the glutamate (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)) receptor are expressed by sympathetic preganglionic neurons in the spinal cord of adult rats. Preganglionic neurons were retrogradely labelled with Fluorogold, double-labelled with choline acetyltransferase immunofluorescence, and examined with confocal microscopy for evidence of immunoreactivity for GluR1, GluR2, GluR2/3 and GluR4 subunits. Quantitative analysis revealed that 92, 63 and 85% of preganglionic cells in the T8 segment express GluR1, GluR2 and GluR2/3 subunits, respectively. Cells were not immunoreactive for the GluR4 subunit. This evidence is consistent with the idea that most sympathetic preganglionic neurons form heteromeric AMPA receptors. Cells with GluR2 subunits will assemble receptors which are impermeable to calcium ions and may be resistant to excitotoxic cell death.
Animals↗
Computer simulation to estimate the effectiveness of carotid endarterectomy.
OBJECTIVES: To investigate the benefit of carotid endarterectomy relative to medical treatment, by comparing the outcome for different groups of patients following transient ischaemic attacks. METHODS: A Markov model was used to describe the survival and quality of life of patients treated for a transient ischaemic attack. The benefit is measured in terms of quality adjusted life months (QALMs). The outcome was estimated using a computer simulation with parameters based on published studies on the probability of events following treatment. The benefit of carotid endarterectomy was explored using a baseline set of parameters and a sensitivity analysis. RESULTS: The baseline scenario of a 65-year-old male patient with the model factors set at an intermediate level showed a benefit for surgery of 3 QALMs compared with medical treatment alone. The sensitivity analysis showed that the most favourable combination of factors had a benefit of 13.4 QALMs and the least favourable a loss of 2 QALMs. Of all 128 factor combinations, 79.9% showed a benefit for surgery, 5.5% showed equal benefit, and 15.6% showed a benefit for medical treatment. CONCLUSIONS: Computer simulations have the potential for deriving estimates of benefit for different patient groups from the results of clinical trials. Combined with reliable information on costs, the technique could also demonstrate variations in cost-effectiveness for these groups. For patients following a transient ischaemic attack, the results from this simulation and limited cost information suggest that carotid endarterectomy is unlikely to be a cost-effective intervention in the UK for many patient groups despite a reduction in the risk of stroke.
Aged↗
An immunocytochemical investigation of the relationship between substance P and the neurokinin-1 receptor in the lateral horn of the rat thoracic spinal cord.
The relationship between substance P-containing axons and sympathetic preganglionic neurons possessing the neurokinin-1 receptor was investigated in the lateral horn of the rat thoracic spinal cord. Sympathetic preganglionic neurons were labelled retrogradely with Fluorogold. Sections containing labelled cells were reacted with antibodies against choline acetyltransferase, substance P and the neurokinin-1 receptor and examined with three-colour confocal laser scanning microscopy. In all, 95 sympathetic preganglionic neurons were examined and 79% of these were immunoreactive for the neurokinin-1 receptor. Substance P-immunoreactive axons not only made contacts with preganglionic neurons which were immunoreactive for the receptor but also made contacts with cells which did not express the receptor. Dendrites, labelled with immunoreactivity for choline actyltransferase, also received contacts from substance P-immunoreactive varicosities but this was not related to the presence or the absence of receptor. An electron microscopic analysis was performed to investigate the relationship between substance P-containing boutons and dendrites possessing the neurokinin-1 receptor. Immunoreactivity for substance P was detected with peroxidase immunocytochemistry and immunoreactivity for the receptor was detected with the silver-intensified gold method. Substance P-containing boutons made synapses with dendrites which were positively and negatively labelled for the receptor. Receptor immunoreactivity was not usually present at synapses formed by substance P boutons with neurokinin-1-immunoreactive dendrites. It is concluded that substance P may modulate much of the activity of sympathetic preganglionic neurons through an indirect non-synaptic mechanism.
Animals↗
Synaptic connections of dorsal horn group II spinal interneurons: synapses formed with the interneurons and by their axon collaterals.
Five dorsal horn interneurons with monosynaptic input from group II primary afferent fibres were physiologically characterized and intracellularly labelled with horseradish peroxidase. The cells were prepared for combined light and electron microscopy, and synaptic arrangements formed by axon collaterals of interneurons and synapses formed with their dendrites and somata were examined with the electron microscope. Immunogold reactions for gamma-aminobutyric acid, glycine and glutamate were performed to determine if these synapses were excitatory or inhibitory. Axon collaterals in lamina VI formed synapses with somata and dendrites of other neurons, and collaterals of one cell also formed axoaxonic synapses. It was concluded that one cell from the sample was inhibitory, whereas the remainder were probably excitatory. Dendrites and cell bodies of interneurons were contacted by several types of synaptic bouton. The first type of bouton displayed immunoreactivity for glutamate, the second type contained both gamma-aminobutyric acid and glycine, the third type contained glycine alone, and the fourth type contained gamma-aminobutyric acid alone. Some large glutamatergic boutons were postsynaptic to other boutons. Presynaptic boutons at these axoaxonic synapses always contained gamma-aminobutyric acid but a minority also contained glycine. The results of this study demonstrate the heterogeneity of dorsal horn group II interneurons and provide evidence that they include inhibitory and probably also excitatory neurons. Boutons originating from several chemically different classes of neuron are responsible for postsynaptic inhibition of these interneurons, and the presence of axoaxonic synapses indicates that their excitatory input is also controlled presynaptically.
Animals↗
Absence of co-localized glutamic acid decarboxylase and neuropeptides in noradrenergic axons of the rat spinal cord.
Patterns of co-localization of immunoreactivity for dopamine beta-hydroxylase (the synthetic enzyme for noradrenaline) and glutamic acid decarboxylase (the synthetic enzyme for GABA) or each one of six neuropeptides (neuropeptide Y, substance P, met-enkephalin, galanin, dynorphin A and somatostatin) were investigated with dual-colour confocal laser scanning microscopy in axons of cervical, thoracic and lumbar spinal segments of six adult rats. Four regions of the grey matter were studied (laminae I-II, V, IX and X) and, in thoracic segments, the intermediolateral cell column was also examined. The extent of co-localization was estimated by direct assessment of merged pairs of optical sections and by automated image analysis. Significant co-localization was found for neuropeptide Y in axons of the intermediolateral cell column of thoracic segments and in lamina X of cervical and thoracic segments. None of the other peptides or glutamic acid decarboxylase were found to coexist at significant levels with dopamine beta-hydroxylase and hence it is likely that this group of neuropeptides and GABA are not co-transmitters of bulbospinal noradrenergic axons in the rat.
Animals↗
Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology and clinical biology. I. The intramedullary cartilage tumors.
We reviewed 845 cases of benign and 356 cases of malignant cartilaginous tumors from a total of 3067 primary bone tumors in our database. Benign cartilaginous lesions are unique because the epiphyseal plate has been implicated in the etiology of osteochondroma, enchondroma (single or multiple), periosteal chondromas and chondroblastoma. In the first part of this paper, we will review important clinical, radiologic and histologic features of intramedullary cartilaginous lesions in an attempt to support theories related to anatomic considerations and pathogenesis.
Adolescent↗
Microcirculatory compensation to progressive atherosclerotic disease.
The precapillary resistance in the skin of the foot increases with standing. This mechanism, termed the venoarterial reflex (VAR) restricts arterial inflow, and avoids an excessive rise in capillary pressure. This study tests the hypothesis that there is microcirculatory compensation to atherosclerotic disease of increasing severity. Foot skin perfusion (FSP) was measured in 100 limbs with a laser Doppler placed on the plantar aspect of the great toe. Limbs were categorized as normal (n = 31) with an ankle brackial index (ABI) > or = 0.96, claudicants (n = 42) ABI 0.5-0.86, and critical ischemia (n = 27) with an ABI < or = 0.49 or a pulse volume recording consistent with severe peripheral vascular disease and symptoms of rest pain or tissue loss. Segmental Doppler pressures and pulse volume recordings were performed prior to laser Doppler measurements. Subjects with clinical signs or symptoms of chronic venous insufficiency were excluded. The resting foot skin perfusion was measured in the horizontal and dependent position, with the patient supine and sitting. Comparisons within categories were done using Wilcoxon matched pairs signed rank test and between groups with Mann-Whitney U test for unpaired data. Differences were considered significant if they exceeded the 95% confidence level (p value < or = 0.05). Resting supine skin perfusion was similar between nondiabetic normals and claudicants and diabetic normals and claudicants. There was a significant decrease in the foot skin perfusion (mean FSP +/- SEM) in the normal limb with a change from the supine (7.8 +/- 2.2 ml/min/100 g) to the dependent (2.8 +/- 0.6 ml/min/100 g) position indicating an intact VAR. This was absent in 33% of the limbs with claudication. Limbs with critical ischemia demonstrated an increase in FSP with dependency (supine 4.0 +/- 1.0 ml/min/100 g) versus dependent (8.4 +/- 1.8 ml/min/100 g) and was present in both diabetic and nondiabetic limbs. Microcirculatory compensation occurs early in atherosclerotic limbs. Although supine FSP is similar in normals and claudicants, a greater percentage of claudicants demonstrate a loss of the VAR. Critically ischemic limbs have increased FSP in the dependent position. These observations indicate that there are microcirculatory alterations in limbs with claudication and assist in explaining why patients with ischemic rest pain obtain relief and develop edema with dependency.
Arteriosclerosis↗
Comparison of a once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain.
Kadian/Kapanol (K) is a capsule formulation of morphine designed for 12- or 24-hourly dosing. This double-blind study compared the efficacy and safety of K every 24 hr to K every 12 hr and MS Contin tablets (MSC) every 12 hr. One hundred fifty-two patients with cancer pain were titrated to adequate analgesia with immediate-release morphine (IRM) solution. Stabilized patients were randonized to one of the three treatments for 7 +/- 1 days. Rescue medication was IRM tablets. Efficacy and safety were assessed by time to first remedication and total dose of rescue medication, pain scores, global assessments, and incidence of morphine-related side effects. Fifty-four patients were treated with K every 24 hr. 45 with K every 12 hr. and 53 with MSC every 12 hr. Mean age was 61 years and mean total daily dose of morphine was 138 mg. Forty-six percent of the K every 24 hr patients, 51% of the K every 12 hr patients, and 55% of the MSC every 12 hr patients required rescue medication on the final day. Time to remedication was 16.0 hr for K every 24 hr, 9.1 hr for K every 12 hr and 8.7 hr for MSC every 12 hr (P = 0.0010). Patient global assessment significantly favored K every 24 hr over MSC every 12 hr (P = 0.018). There were no statistically significant differences among the treatments for any morphine-related side effects when adjusted for baseline. K had efficacy and safety profiles similar to MSC every 12 hr but had the advantage of 12- or 24-hourly administration.
Administration, Oral↗
Evidence for the presence of neurokinin-1 receptors on dorsal horn spinocerebellar tract cells in the rat.
Dorsal horn spinocerebellar tract cells of adult rats were labelled by retrograde axonal transport with the B subunit of cholera toxin. Sections were prepared from lumbar and thoracic spinal segments and incubated with antisera which specifically recognise neurokinin-1 receptor protein and substance P. Labelled cells and immunoreactivity for the receptor and substance P were identified by using three different fluorophores and the relationships between them were assessed in single optical sections with three-colour confocal laser scanning microscopy. Forty-eight cells were examined and 23 of them displayed immunoreactivity for the receptor. Many substance P-immunoreactive profiles were present in lamina V and some formed contacts with spinocerebellar tract cells possessing neurokinin-1 receptor immunoreactivity. The evidence suggests that substance P may influence the activity of a subpopulation of dorsal horn spinocerebellar tract cells by acting through neurokinin-1 receptors.
Animals↗