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Biomedical subjects

T Jones

Publications and source records attributed to T Jones.

At least 253 records · Page 14Linked to original sources
PubMed1995

The small cell lung cancer antigen cluster-4 and the leukocyte antigen CD24 are allelic isoforms of the same gene (CD24) on chromosome band 6q21.

Cluster-4 and CD24 cDNA's have recently been cloned from the small cell lung carcinoma (SCLC) cell line SW2 and from the erythroleukemia cell line K562, respectively. The only difference in the coding sequence, between cluster-4 and CD24 antigens is the substitution of a single base pair leading to a substitution of Val by Ala near the putative glycosylphosphatidylinositol (GPI) anchorage sites of the mature protein. Here we demonstrate that the nucleotide substitution which distinguishes the cluster-4 and CD24 antigen genes is due to an allelic polymorphism on chromosome band 6q21. In addition, we identified by Southern blotting and PCR of DNA from somatic human x hamster hybrid cell lines homologues of cluster-4/CD24 on the Y chromosome and chromosome 15. We suggest, however, that the gene on 6q21 is the active locus since the mRNA of cell lines always represents the allelic variants found on chromosome 6. The distribution pattern of this allelic polymorphism in SCLC cell lines and leukocytes of healthy donors did not reveal any obvious relationship with disease. However, it is noteworthy that homozygosity for cluster-4 was found in only one case whereas heterozygosity and homozygosity for CD24 both contribute up to 50% of the samples examined.

Alleles↗
PubMed1995

Demonstration of thalamic activation during typical absence seizures using H2(15)O and PET.

BACKGROUND: The EEG correlate of absence seizures is 3-Hz, generalized spike-wave activity. Depth electrode recordings in animal models suggest that spike-wave activity oscillates within thalamocortical circuits, but the site of the primary abnormality is uncertain. The aim of the present study was to determine whether there is a selective increase in blood flow in the thalamus during absence seizures and, if so, whether it precedes the appearance of spike-wave activity on scalp EEG. METHODS: Using PET, regional cerebral blood flow (rCBF) was measured in eight patients with idiopathic generalized epilepsy in whom typical absence seizures were induced by voluntary hyperventilation. Each patient was studied up to 12 times, with an intravenous bolus injection of H2(15)O followed by a 90-second scan. The distribution of rCBF during absence seizures and in the 30 seconds before an absence seizure were compared with the distribution of rCBF when absence seizures did not occur. RESULTS: There was a mean global 14.9% increase in blood flow in association with typical absence seizures and, on top of the global increase, a focal increase in thalamic blood flow of 3.9 to 7.8%. There were no significant focal changes in rCBF in the 30 seconds before the onset of spike-wave activity on the EEG. CONCLUSION: This study provides evidence for the key role of the thalamus in the pathogenesis of absence seizures but was unable to show that it is the site of initiation of the seizures.

Adult↗
PubMed1995

Disposition of inhaled 1,1,1,2-tetrafluoroethane (HFA134A) in healthy subjects and in patients with chronic airflow limitation. Measurement by 18F-labeling and whole-body gamma-counting.

HFA134a (1,1,1,2-tetrafluoroethane) is a nonozone-depleting candidate to replace the chlorofluorocarbons used as propellants in metered-dose inhalers (MDIs) for pharmaceuticals that are widely used in the treatment of respiratory tract disease. As a means for ensuring the safety of such a compound for human use, it is necessary to establish that there is no excessive or unexpected accumulation in the body and in selected regions. A sensitive whole-body gamma-counting technique has been used with 18F-labeled HFA134a to measure the whole-body and regional absorption, distribution, and retention of HFA134a after administration in humans by single-breath inhalation. In seven healthy subjects, labeled HFA134a was rapidly eliminated by ventilation during the first few minutes, with an average of 9.6% of the radioactivity retained in the body at 5 min. This radioactivity cleared with an apparent terminal half-life of 1.5-4.2 hr to leave, on average, < 1% of the administered dose (< 750 micrograms, approximately 0.2 microCi) retained in the body at 5.8 hr. Disposition of radioactivity was independent of the position of label. Thus, there was no evidence of any significant degradative metabolism. On average, only 0.0056% of the administered dose appeared in the urine within the first 2 hr. Later samples contained no significant radioactivity. Inhaled HFA134a first distributed to all regions of the body and then cleared without evident accumulation in any specific region.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1995

Deletion mutants in human cytomegalovirus glycoprotein US9 are impaired in cell-cell transmission and in altering tight junctions of polarized human retinal pigment epithelial cells.

Retinal cytomegalovirus (CMV) disease is one of the major manifestations of viral pathogenesis in immunosuppressed patients with the acquired immunodeficiency syndrome (AIDS). CMV infection of the retina causes directional destruction which begins at the optic nerve head adjacent to the retinal capillaries and progresses, if untreated, to retinal detachment and blindness. Infection does not occur across the basal membrane of the retinal pigment epithelium (RPE), adjacent to the highly vascularized choroid. CMV replicates in polarized RPE cells, and progeny virions cross apical and lateral membranes of RPE cells grown on permeable filter supports, but not basal membranes. Cell-cell junctions of CMV-infected RPE cells are permeabilized, and the tight junction protein zonula occludens (ZO-1) is disassembled; progeny virions then spread to neighboring cells through the lateral cell membranes, which in polarized cells differ significantly in lipid and protein composition from the apical cell membranes. We found that CMV mutants with deletions in US9 and US8/US9 failed to spread from cell to cell, exhibiting a small-plaque phenotype in polarized RPE cells. Immunofluorescence confocal microscopy staining of ZO-1 protein revealed that RPE cells infected with CMV deletion mutants RV35, RV80, and RV61 did not exhibit altered tight junctions, in contrast to RPE cells infected with wild-type strain AD169 virus. Our findings indicate that US9, which is an accessory glycoprotein in infected foreskin fibroblasts, is required for transmission of virus across cell-cell junctions of polarized RPE cells. The relationship between US9 expression and virus transmission across cell-cell boundaries suggests that US9 may directly or indirectly permeabilize tight junction complexes of polarized RPE cells.

Cytomegalovirus↗
PubMed1994

Central nervous pathways mediating angina pectoris.

The central nervous pathways of angina pectoris have never been identified in vivo in man. We used positron emission tomography to examine the changes in regional cerebral blood flow associated with angina pectoris. Dynamic positron emission tomography with 15O-labelled water was used in 12 patients with angina and angiographically proven coronary artery disease to measure regional cerebral blood flow changes during angina induced by intravenous dobutamine. All subjects had typical retrosternal chest pain accompanied by ischaemic electrocardiographic changes during dobutamine infusion. Compared to the resting state, angina was associated with increased regional cerebral blood flow in the hypothalamus (percentage change in regional cerebral blood flow +6.5 and Z score 7.2) periaquaductal grey (+2.6 and 4.0), bilaterally in the thalamus (left: +2.7 and 4.3; right +3.7 and 4.7) and lateral prefrontal cortex (left +11.5 and 7.6; right +8.5 and 7.8) and left inferior anterocaudal cingulate cortex (+9.4 and 6.6). In contrast, it was reduced bilaterally in the mid-rostrocaudal cingulate cortex (left -3.7 and 6.3; right -4.7 and 4.6) and fusiform gyrus (left -3.2 and 4.0; right -3.3 and 3.7), right posterior cingulate (-3.9 and 5.8) and left parietal cortices (-4.8 and 6.3). Several minutes after stopping dobutamine infusion, when the patients no longer experienced angina and the electrocardiographic changes had resolved, thalamic, but not cortical activation could be seen. We propose that the central structures activated constitute the pathways for perception of anginal pain and that the thalamus may act as a gate to afferent pain signals, with cortical activation being necessary for the sensation of pain. This method of investigation may form a basis for research into anomalies of visceral pain perception such as silent myocardial ischaemia.

Adult↗
PubMed1994

Performance comparison of a state-of-the-art neuro-SPET scanner and a dedicated neuro-PET scanner.

The physical performances of two current state-of-the-art scanners dedicated to functional imaging of the brain, one a single-photon emission tomography (SPET) scanner and the other a positron emission tomography (PET) scanner, have been compared under identical conditions. The aim of the study was to compare the capabilities of the devices under conditions resembling the routine clinical environment, as well as to consider other issues such as radiation burden for some common investigations. Both systems have slightly less than 11-cm axial fields of view. The PET system can be operated in a septa-less (3D) mode as well as conventionally with septa (2D). The spatial resolution of both devices was less than 8 mm in all dimensions in scattering media. On average, the PET scanner's resolution was approximately 10%-15% better than the SPET system. Energy resolution on the SPET system was superior due the scintillator used [NaI(Tl)]. Sensitivity in air with a line source on the PET system was found to be approximately 150 times greater in 3D and approximately 25 times greater in 2D than with the SPET system. A normal subject was studied on each system in an attempt to obtain the highest quality data possible for a subjective comparison. It is clear that, while PET retains the advantages of more desirable radiopharmaceuticals and higher sensitivity, the quality obtainable from SPET devices has improved markedly. SPET may prove as useful for many clinical investigations.

Brain↗
PubMed1994

Dosimetry of intravenously administered oxygen-15 labelled water in man: a model based on experimental human data from 21 subjects.

Models based on uniform distribution of tracer in total body water underestimate the absorbed dose from H2(15)O because of the short half-life (2.04 min) of 15O, which leads to non-uniform distribution of absorbed dose and also complicates the direct measurement of organ retention curves. However, organ absorbed doses can be predicted by the present kinetic model based on the convolution technique. The measured time course of arterial H2(15)O concentration following intravenous administration represents the input function to organs. The impulse response of a given organ is its transit time function determined by blood flow and the partition of water between tissue and blood. Values of these two parameters were taken from the literature. Integrals of the arterial input function and organ transit time functions were used to derive integrals of organ retention functions (organ residence times). The latter were used with absorbed dose calculation software (MIRDOSE-2) to obtain estimates for 24 organs. From the mean values of organ absorbed doses, the effective dose equivalent (EDE) and effective dose (ED) were calculated. From measurements on 21 subjects, the average value for both EDE and ED was calculated to be 1.2 microSv.MBq-1 compared with a value of about 0.5 microSv.MBq-1 predicted by uniform water distribution models. Based on the human data, a method of approximating H2(15)O absorbed dose values from body surface area is described.

Adult↗
PubMed1994

Fluorine-18 deoxyglucose uptake in sarcoidosis measured with positron emission tomography.

Regional pulmonary glucose metabolism (MRglu; mumol h-1 g-1), extravascular lung density (D(EV); g cm-3) and vascular volume (VB; ml cm-3) were measured in a single midthoracic transaxial slice (approximately 2 cm thick) using position emission tomography (PET) in seven patients with histologically proven sarcoidosis. The measurements were repeated 1-7 months later after steroid therapy (in two cases, no treatment) in order to assess MRglu as an index of inflammation and relate it to routine pulmonary function tests, chest radiography and serum angiotensin converting enzyme (SACE) levels. MRglu was computed from serial lung scans and peripheral venous blood samples for 60 min following an i.v. injection of 18F-2-fluoro-2-deoxy-D-glucose (18FDG). Both MRglu (which was increased in six of seven patients) and elevated SACE levels returned to normal in those patients treated with high-dose steroids. Regional vascular volume was normal in six of seven cases and did not change significantly with therapy. The high tissue density measured in all patients decreased significantly in two of three patients treated with 40 mg prednisolone daily. The abnormal MRglu observed in active sarcoidosis becomes normal pari passu with SACE levels during high-dose steroid therapy. We conclude that MRglu measured with 18FDG and PET may reflect "disease activity" in sarcoidosis in quantitative terms (per gram lung tissue) and in respect of disease distribution.

Adult↗
PubMed1994

Potential role of granulocyte-macrophage colony-stimulating factor as vaccine adjuvant.

The uses of GM-CSF as an immunomodulator and vaccine adjuvant are reviewed. GM-CSF has a variety of effects on immune responses: it induces class II major histocompatibility complex antigen expression on the surface of macrophages; it enhances dendritic cell maturation and migration; it results in a localized inflammation at the injection site; and it has marked effects on maturation of haematopoietic progenitor cells in the bone marrow. Animal and human studies suggest that administration of GM-CSF can increase antibody titres to foreign antigens. Monkeys injected with human interleukin (IL)-3 plus GM-CSF, at a different injection site, developed peak antibody titres which were 8- to 30-fold higher than those in monkeys injected with IL-3 alone. In a study of ovarian cancer patients receiving GM-CSF to prevent chemotherapy-induced neutropenia, two patients who had demonstrated a low titre of antithyroid antibodies prior to the study showed an increase in antibody titre and transient thyroiditis after administration of GM-CSF. Recently a GM-CSF/antigen fusion protein has been tested. An antibody corresponding to a specific idiotype expressed on B-cell lymphomas was fused to GM-CSF and injected into mice with B-cell lymphoma xenografts. The mice developed antibodies to the lymphoma and there was a protective effect against disease progression. Preliminary results of clinical trials using GM-CSF in humans suggest that it enhances antibody responses to hepatitis B vaccine. On the basis of these preliminary results, several clinical trials are being planned and it would appear that GM-CSF has potential as a vaccine adjuvant.

Adjuvants, Immunologic↗
PubMed1994

Quantitation of [11C]diprenorphine cerebral kinetics in man acquired by PET using presaturation, pulse-chase and tracer-only protocols.

The quantitation of regional cerebral in vivo opioid receptor rate constants using [11C]diprenorphine and positron emission tomography (PET) using 3 types of protocol (presaturation, pulse-chase naloxone displacement and tracer-only protocols) together with measurements of regional cerebral blood flow is described in normal volunteers. Arterial blood was sampled continuously for radioactivity and was corrected for metabolites and plasma/blood partition of radioactivity to provide a continuous plasma input function. A compartmental model involving 3 tissue compartments was used to describe the regional cerebral pharmacokinetics of the tracer. The compartments comprised: (1) free plus rapidly exchanging non-specifically bound ligand, (2) specifically bound, naloxone displaceable ligand, and (3) a kinetically distinguishable non-specifically bound pool. Regional estimates of fractional rate constants relating to specific binding were obtained using naloxone in a pulse-chase design of tracer displacement. Less precise estimates of these rate constraints were obtained from single-tracer-only studies, but when binding was expressed as the tissue total volume of distribution relative to plasma there was good correlation with regional values obtained from pulse-chase studies performed in the same individuals. The application of these protocols to the measurement of indices of regional-specific opioid receptor binding in the human brain is discussed.

Adult↗
PubMed1994

Imaging transient, randomly occurring neuropsychological events in single subjects with positron emission tomography: an event-related count rate correlational analysis.

Many neuropsychiatric symptom states are idiosyncratic, involuntary, randomly occurring, subjective, and transient. The brain states associated with these clinically important mental states cannot be imaged directly with existing positron emission tomography (PET) techniques. A new PET method that brings such mental/brain states under experimental control for analysis in single subjects is described. It utilizes a slow bolus H2 15O three-dimensional (3D) regional CBF imaging technique. The analysis focuses upon natural or experimentally induced variance in the temporal distribution of specific neuropsychological events over the course of a study session. For each scan, the amount of radioactivity entering the brain during these events is calculated to derive a score reflecting the contribution of the events to the image. A statistical analysis is then performed to identify those pixels in which the intensity covaries with the scan scores over the subject's scans. This permits the identification of the brain areas associated with the mental state of interest. The method is validated using an auditory sentence-monitoring task. The detection in single subjects of cerebral activations associated with recurrent events as brief as 2 s in duration is demonstrated. This method may be used as a means of imaging ephemeral neurologic or neuropsychiatric symptom states or as an alternative to a subtraction design for activation studies.

Adult↗
PubMed1994

Expression and activity of p40MO15, the catalytic subunit of cdk-activating kinase, during Xenopus oogenesis and embryogenesis.

Threonine 161 phosphorylation of p34cdc2 and its equivalent threonine 160 in p33cdk2 by cdk-activating kinase (CAK) is essential for the activation of these cyclin-dependent kinases. We have studied the expression and associated kinase activity of p40MO15, the catalytic subunit of CAK, during Xenopus oogenesis, meiotic maturation, and early development to understand in more detail how cdk kinases are regulated during these events. We find that p40MO15 is a stable protein with a half-life > 16 h that is accumulated during oogenesis. p40MO15 protein and its associated CAK activity are localized predominantly to the germinal vesicle; however, a small but significant proportion is found in the cytoplasm. The amount of p40MO15 detected in stage VI oocytes remains unchanged through meiotic maturation, fertilization, and early embryogenesis. Significantly, p40MO15 was found to be constitutively active during oogenesis, meiotic maturation, and the rapid mitotic cycles of early development. This suggests that regulation of p34cdc2 and p33cdk2 activity during cell cycle progression does not involve changes in the level or activity of p40MO15/CAK.

Animals↗
PubMed1994

Changes in central opioid receptor binding in relation to inflammation and pain in patients with rheumatoid arthritis.

A group of four patients with RA were examined to test the hypothesis that there is a change in the endogenous opioid system in the brain during inflammatory pain. Regional cerebral opioid receptor binding was quantified using the opioid receptor antagonist [11C] diprenorphine and positron emission tomography (PET). In the four patients studied in and out of pain, significant increases in [11C]diprenorphine binding were seen in association with a reduction in pain. Increases were seen in most of the areas of the brain that were sampled apart from the occipital cortex. Significant region-specific increases over and above the more generalized changes were also seen in the frontal, cingulate and temporal cortices in addition to the straight gyrus. These findings are consistent with the hypothesis that there are substantial increases in occupancy by endogenous opioid peptides during inflammatory pain.

Arthritis, Rheumatoid↗
PubMed1994

Blood concentrations of dopexamine in patients during and after orthotopic liver transplantation.

Blood concentrations of dopexamine were measured in five female patients during and after orthotopic liver transplantation. Each patient received a continuous infusion of the drug (2 micrograms kg-1 min-1), starting at induction of anaesthesia and finishing 48 h afterwards. Blood concentrations of dopexamine increased rapidly at the start of the infusion, to a mean (range) value of 64 (40-150) ng ml-1 after 20 min. Blood concentrations of dopexamine increased further during the anhepatic period of surgery, to 236 (180-410) ng ml-1. On reperfusion of the donor liver, concentrations of dopexamine decreased rapidly, reaching similar values to the maximum seen during the dissection period. Steady-state was not reached during either the dissection or anhepatic periods. From 1-2 h after revascularisation the mean (range) steady-state concentration was 85 (69-102) ng ml-1 corresponding to a mean (range) clearance of 24 (20-29) ml min-1 kg -1. These results suggest that the liver plays a significant role in the clearance of dopexamine.

Adult↗
PubMed1994

Conventional and cross-correlation brain-stem auditory evoked responses in the white leghorn chick: rate manipulations.

Rate-dependent changes in the chick brain-stem auditory evoked response (BAER) using conventional averaging and a cross-correlation technique were investigated. Five 15- to 19-day-old white leghorn chicks were anesthetized with Chloropent. In each chick, the left ear was acoustically stimulated. Electrical pulses of 0.1-ms duration were shaped, attenuated, and passed through a current driver to an Etymotic ER-2 which was sealed in the ear canal. Electrical activity from stainless-steel electrodes was amplified, filtered (300-3000 Hz) and digitized at 20 kHz. Click levels included 70 and 90 dB peSPL. In each animal, conventional BAERs were obtained at rates ranging from 5 to 90 Hz. BAERs were also obtained using a cross-correlation technique involving pseudorandom pulse sequences called maximum length sequences (MLSs). The minimum time between pulses, called the minimum pulse interval (MPI), ranged from 0.5 to 6 ms. Two BAERs were obtained for each condition. Dependent variables included the latency and amplitude of the cochlear microphonic (CM), wave 2 and wave 3. BAERs were observed in all chicks, for all level by rate combinations for both conventional and MLS BAERs. There was no effect of click level or rate on the latency of the CM. The latency of waves 2 and 3 increased with decreasing click level and increasing rate. CM amplitude decreased with decreasing click level, but was not influenced by click rate for the 70 dB peSPL condition. For the 90 dB peSPL click, CM amplitude was uninfluenced by click rate for conventional averaging. For MLS BAERs, CM amplitude was similar to conventional averaging for longer MPIs.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1994

Relationships between regional ventilation and vascular and extravascular volume in supine humans.

With the use of positron emission tomography, alveolar ventilation (VA), lung density, and pulmonary blood volume (VB) were measured regionally in eight nonsmokers in the supine posture and one nonsmoker in the prone posture during quiet breathing in a transaxial thoracic section at midheart level. Regional values of alveolar volume (VA) and extravascular tissue volume (VEV) were derived from the inherent relationships between different compartments in the lung. Ratios proportional to gas volume (VA/VEV) and ventilation (VA/VEV) per alveolar unit, respectively, were calculated. No differences between right and left lung were found. Variations in the vertical direction could explain approximately 65% of the total within-group variation in VA, VB, and ln (VA), whereas the corresponding value for horizontal variation was only 3-9% (right lung, supine subjects). Similar gravitational gradients were found in the single prone subject. There was a significant linear correlation between VA and ln (VA). When VA and VA are related to a given number of alveolar units (VEV), the data are consistent with a linear relationship between VA/VEV and VA/VEV, indicating that ventilation might be explained by the elastic properties of lung tissue according to Salazar and Knowles (J. Appl. Physiol. 19: 97-104, 1964). Regional VB was closely associated with the gradient of regional alveolar volume (VA/VEV) (by virtue of weight of blood and competition for space) and therefore, indirectly, closely associated with the vertical gradient of ventilation.

Adult↗