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Biomedical subjects

R A Jones

Publications and source records attributed to R A Jones.

At least 163 records · Page 9Linked to original sources

MHC class I and class I-like gene product expression by malignant T cells: relationships between CD1a, HLA-ABC and beta 2-microglobulin.

Beta 2-microglobulin (beta 2m) forms the invariant light chain of the MHC-encoded HLA-ABC and the non-MHC-encoded CD1 molecules. While HLA-ABC (MHC Class I) molecules are virtually ubiquitous in tissue distribution, CD1 determinants by contrast are more restricted. We have assessed, by indirect immunoenzymeassay, the relative membrane densities of these molecules on malignant thymic and post-thymic T cells. It was found that the T cells of mature post-thymic proliferations expressed significantly more beta 2m-associated protein, predominantly HLA-ABC in nature, than thymic-ALL blasts. This parallels the situation found in normal peripheral T cells and thymocytes. In contrast to post-thymic T cells, thymic-ALL blasts showed considerable case to case variation with respect to non-HLA-associated beta 2m and, of particular interest, not all of this excess beta 2m could be accounted for by CD1a. We therefore conclude that other beta 2m-containing molecules may be expressed on thymic-ALL blasts and possibly also on post-thymic leukaemic T cells. In addition, it was found that T cells from CD4+ cases of post-thymic proliferations expressed more beta 2m-associated determinants than other T cells, whether of either normal or malignant origin, and that certain post-thymic malignancies express significantly increased levels of beta 2m-associated protein relative to normal peripheral T-cells. This is in direct contrast to the situation seen in many solid malignancies.

Antigens, Differentiation↗

Vertebral fractures without neurological deficit. A long-term follow-up study.

Twenty-five patients, who did not have osteoporosis and who were between the ages of seventeen and sixty years, were treated for one or more stable compression fractures of a vertebra with compaction of less than 50 per cent and without an associated neurological deficit. The patients were followed for a minimum of nine years. Associated vertebral fractures (12 per cent) were identified during the first three months after the injury, but no deformity progressed after three months. Radiographic changes of degenerative disc disease were evident in eight patients, but the changes did not correlate with symptoms or with level of activity. With one exception, all patients functioned as well as uninjured subjects of comparable age. Patients who have a compression fracture of a vertebra should have serial radiographs made for at least three months to ensure that all fractured vertebrae are identified and to document any progression of deformity.

Adolescent↗

Cell surface expression of beta 2-microglobulin (beta 2m) correlates with stages of differentiation in B cell tumours.

Cell surface beta 2-microglobulin (beta 2m) densities of malignant B cells were determined by enzyme immunoassay in 97 cases of immunologically defined lymphoproliferative disease. Absolute beta 2m densities were found to depend on disease category with the lowest levels found on cells from chronic lymphocytic leukaemia (mean = 5.6 ng/10(6) cells, n = 27); atypical chronic lymphocytic leukaemia (mean = 5.9 ng/10(6) cells, n = 8); and prolymphocytoid chronic lymphocytic leukaemia variant (mean = 6.0 ng/10(6) cells, n = 16). beta 2m densities for B non-Hodgkin's lymphoma (n = 14) and B prolymphocytic leukaemia (n = 17) cases were 8.1 and 10.0 ng/10(6) cells, respectively, and the highest densities were found on cells from "late-B cell" tumours (mean = 14.3 ng/10(6) cells). Plasma cells from cases of Ig secreting tumours expressed unexpectedly low beta 2m densities (mean = 9.3 ng/10(6) cells; n = 6).

B-Lymphocytes↗

Effectiveness of three field treatments for induced mild (33.0 degrees C) hypothermia.

Three field applicable treatments for hypothermia were compared. Subjects were cooled in stirred cold water (8.0 degrees C) to a core temperature (Tco) as low as 33 degrees C and rewarmed in a random order by each of three techniques: shivering, external heat, and treadmill exercise. Tco was monitored with an esophageal thermistor probe at the level of the heart. Treatment effectiveness was determined by calculating the amount of Tco afterdrop, length of afterdrop period, rate of Tco increase, and total recovery time. Rate of Tco increase for exercise (4.9 degrees C/h) was significantly higher (P less than 0.05) than shivering (3.5 degrees C/h) but not external heat (3.7 degrees C/h). Exercise afterdrop amount and afterdrop length values (0.95 degrees C and 24 min, respectively) were significantly higher (P less than 0.05) than both shivering (0.33 degrees C, 15 min) and external heat (0.32 degrees C, 14 min). Therefore, although rate of Tco increase during recovery for exercise was faster than for shivering or external heat, as it was preceded by a greater afterdrop length and amount, total recovery time did not differ among the three treatments.

Adult↗

Cigarettes, respiratory rate, and the relaxation paradox.

Recent research indicates that individuals differ in their physiological reactions to nicotine, some showing strong increases in heart rate within 1 min of beginning to smoke and others showing little or no heart rate change with smoking. In the present research, monitoring of the respiratory rates of these two types of smokers before, during, and after smoking revealed that the former show an increase in respiratory rate while smoking, whereas the latter show a decrease. It is suggested that these changes in respiratory rate, a relatively easily monitored bodily function, may provide the cues used by smokers for inferring the effect that smoking has on them, that is, stimulating versus relaxing.

Adult↗

Childhood systemic-pulmonary shunts: subsequent suitability for Fontan operation.

We investigated whether or not a systemic arteriopulmonary shunt (SAPS) after 1 year of age affects a child's chances for a successful Fontan procedure. From 1967 to 1986, 50 patients more than 1 year old with tricuspid atresia or other complex lesions amenable to a Fontan operation received a SAPS. Follow-up was incomplete in six patients. Two patients died within 1 week of surgery, and two died within 9 months for a total mortality of 8%. Each of the 40 remaining patients was catheterized 6 months to 10.8 years (mean 4.9 years) after placement of a SAPS. By the criteria of Choussat and Fontan, there were one or more adverse SAPS-induced changes in nine patients (23%). Three developed pulmonary hypertension, one with associated elevation of pulmonary arteriolar resistance and pulmonary artery distortion, and one in conjunction with severe congestive heart failure. Six additional patients developed isolated distortion of the ipsilateral pulmonary artery. Of these nine patients, three had successful Fontan operations (33%), two died after the Fontan operation, and four are no longer candidates. In contrast, of 31 patients without documented SAPS-induced complications, 27 have undergone Fontan operations, 23 successfully (74%). Palliation with a SAPS after 1 year of age can place children at increased risk for a subsequent Fontan operation.

Age Factors↗

Use of maximal bicycle exercise testing with respiratory gas analysis to assess exercise performance in patients with congestive heart failure secondary to coronary artery disease or to idiopathic dilated cardiomyopathy.

Analysis of respiratory gases during maximal treadmill exercise testing has been used in patients with congestive heart failure (CHF) to detect the lactate threshold, presumed to reflect the onset of skeletal muscle underperfusion, and maximal oxygen consumption (VO2), the point at which VO2 plateaus with increasing work due to exhaustion of peripheral oxygen delivery capacity. To determine if this approach is also useful during maximal bicycle exercise testing, ventilatory, hemodynamic and systemic lactate responses to bicycle exercise were measured in 48 patients with CHF. Ventilatory responses also were assessed in 12 normal subjects. Exercise increased VO2 to 24.8 +/- 3.9 ml/min/kg in normal subjects and 13.9 +/- 3.7 ml/min/kg in patients with CHF (p less than 0.001). In all but 1 patient the VO2 increment over the last 3 minutes of exercise was comparable to that in normal subjects exercising over identical work times, suggesting that maximal VO2 was not achieved. Moreover, in patients who exercised for less than 6 minutes, a ventilatory lactate threshold could not be identified. In the 33 patients who exercised longer, a ventilatory lactate threshold was identified in 31 and correlated well (r = 0.81) with blood lactate threshold, as defined by the VO2 at which lactate increased 5 mg/dl over rest levels. However, the 95% confidence limit for predicting blood lactate threshold from ventilatory data was +/- 200 ml/min, a large range relative to the measured ventilatory threshold (570 +/- 132 ml/min). These data suggest that in patients with CHF, respiratory gas analysis during maximal bicycle exercise cannot be used to measure maximal VO2 and provides only a general index of blood lactate behavior.

Cardiac Output↗

Covalent carcinogenic O6-methylguanosine lesions in DNA. Structural studies of the O6 meG X A and O6meG X G interactions in dodecanucleotide duplexes.

High-resolution proton and phosphorus nuclear magnetic resonance studies are reported on the self-complementary d(C1-G2-N3-G4-A5-A6-T7-T8-C9-O6meG10-C11-G12) duplexes (henceforth called O6meG X A 12-mer when N3 = A3 and O6meG X G 12-mer when N3 = G3), which contain symmetry-related A3 X O6meG10 and G3 X O6meG10 interactions in the interior of the helices. We observe inter-base-pair nuclear Overhauser effects (NOE) between the base protons at the N3 X O6meG10 modification site and protons of flanking G2 X C11 and G4 X C9 base-pairs, indicative of the stacking of N3 and O6meG10 bases in both O6meG X A 12-mer and O6meG X G 12-mer duplexes. We have assigned all the base and a majority of the sugar protons from two-dimensional proton-correlated and nuclear Overhauser effect experiments on the O6meG X A 12-mer duplex and O6meG X G 12-mer duplex in solution. The observed NOEs establish that the A3 and O6meG10 at the modification site and all other residues adopt the anti configuration about the glycosidic bond, and that the O6meG X A 12-mer forms a right-handed duplex. The interaction between the bulky purine A3 and O6meG10 residues in the anti orientation results in large proton chemical shift perturbations at the (G2-A3-G4) X (C9-O6meG10-C11) segments of the helix. By contrast, we demonstrate that the O6meG10 residue adopts a syn configuration, while all other bases adopt an anti configuration about the glycosidic bond in the right-handed O6meG X G 12-mer duplex. This results in altered NOE patterns between the base protons of O6meG10 and the base and sugar protons of flanking C9 and C11 residues in the O6meG X G 12-mer duplex. The phosphorus backbone is perturbed at the modification site in both duplexes, since the phosphorus resonances are dispersed over 2 parts per million in the O6meG X A 12-mer and over 1 part per million in the O6meG X G 12-mer compared to a 0.5 part per million dispersion for an unperturbed DNA helix. We propose tentative pairing schemes for the A3 X O6meG10 and G3 X O6meG10 interactions in the above dodecanucleotide duplexes.

Base Composition↗

Structural studies of the O6meG.C interaction in the d(C-G-C-G-A-A-T-T-C-O6meG-C-G) duplex.

One- and two-dimensional nuclear magnetic resonance (NMR) experiments have been undertaken to investigate the conformation of the d(C1-G2-C3-G4-A5-A6-T7-T8-C9-O6meG10-C11-G12) self-complementary dodecanucleotide (henceforth called O6meG.C 12-mer), which contains C3.O6meG10 interactions in the interior of the helix. We observe intact base pairs at G2.C11 and G4.C9 on either side of the modification site at low temperature though these base pairs are kinetically destabilized in the O6meG.C 12-mer duplex compared to the G.C 12-mer duplex. One-dimensional nuclear Overhauser effects (NOEs) on the exchangeable imino protons demonstrate that the C3 and O6meG10 bases are stacked into the helix and act as spacers between the flanking G2.C11 and G4.C9 base pairs. The nonexchangeable base and H1', H2', H2'', H3', and H4' protons have been completely assigned in the O6meG.C 12-mer duplex at 25 degrees C by two-dimensional correlated (COSY) and nuclear Overhauser effect (NOESY) experiments. The observed NOEs and their directionality demonstrate that the O6meG.C 12-mer is a right-handed helix in which the O6meG10 and C3 bases maintain their anti conformation about the glycosidic bond at the modification site. The NOEs between the H8 of O6meG10 and the sugar protons of O6meG10 and adjacent C9 exhibit an altered pattern indicative of a small conformational change from a regular duplex in the C9-O6meG10 step of the O6meG.C 12-mer duplex. We propose a pairing scheme for the C3.O6meG10 interaction at the modification site. Three phosphorus resonances are shifted to low field of the normal spectral dispersion in the O6meG.C 12-mer phosphorus spectrum at low temperature, indicative of an altered phosphodiester backbone at the modification site. These NMR results are compared with the corresponding parameters in the G.C 12-mer, which contains Watson-Crick base pairs at the same position in the helix.

Base Composition↗

Structural studies of the O6meG.T interaction in the d(C-G-T-G-A-A-T-T-C-O6meG-C-G) duplex.

High-resolution proton and phosphorus NMR studies are reported on the self-complementary d(C1-G2-T3-G4-A5-A6-T7-T8-C9-O6meG10-C11-G12) duplex (henceforth called O6meG.T 12-mer), which contains T3.O6meG10 interactions in the interior of the helix. The imino proton of T3 is observed at 9.0 ppm, exhibits a temperature-independent chemical shift in the premelting transition range, and broadens out at the same temperature as the imino proton of the adjacent G2.C11 toward the end of the helix at pH 6.8. We observed inter base pair nuclear Overhauser effects (NOEs) between the base protons at the T3.O6meG10 modification site and the protons of flanking G2.C11 and G4.C9 base pairs, indicative of the stacking of the T3 and O6meG10 bases into the helix. Two-dimensional correlated (COSY) and nuclear Overhauser effect (NOESY) studies have permitted assignment of the base and sugar H1', H2', and H2'' nonexchangeable protons in the O6meG.T 12-mer duplex. The observed NOEs demonstrate an anti conformation about all the glycosidic bonds, and their directionality supports formation of a right-handed helix in solution. The observed NOEs between the T3.O6meG10 interaction and the adjacent G2.C11 and G4.C9 base pairs at the modification site exhibit small departures from patterns for a regular helix in the O6.meG.T 12-mer duplex. The phosphorus resonances exhibit a 0.5 ppm spectral dispersion indicative of an unperturbed phosphodiester backbone for the O6meG.T 12-mer duplex. We propose a model for pairing of T3 and O6meG10 at the modification site in the O6meG.T 12-mer duplex.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Composition↗

Prolymphocytoid transformation of CLL: a clinical and immunological study of 22 cases.

The clinical, morphological and immunological features of 22 cases of chronic lymphocytic leukaemia in 'prolymphocytoid' transformation (CLL-Pro) are reported. Immunophenotypic patterns in CLL-Pro differ from CLL by the appearance of significant (greater than 15%) FMC7-positive components and/or increased SIg densities in most cases. Membrane TU1 and MRBC receptor expression was similar to that found in typical CLL. Morphologically, all cases showed a mixture of small lymphocytes and larger nucleolated 'prolymphocytes' although the degree of prolymphocytoid change was unrelated to immunological patterns. Clinically, the cases behaved in a very heterogeneous fashion, with some patients dying rapidly following transformation despite treatment, while others even if untreated had a long, stable and relatively benign course. It was not possible to predict which patients would do badly from immunological or morphological features but the presence of more than one involved lymph node site and the occurrence of B-symptoms appeared to identify a group that did badly. Immunological assessments were however important in therapeutic terms, drawing distinction between CLL-Pro variants and prolymphocytic leukaemia (PLL).

Humans↗

Individual differences in nicotine sensitivity.

It is suggested that individual differences in sensitivity to nicotine may help account for a number of anomalous findings uncovered in research on nicotine regulation. However, an examination of the literature reveals very little pertinent evidence. To demonstrate the existence of such differences, 124 male and female subjects were screened for responsiveness to nicotine by smoking a standard cigarette while their heart rates were continuously monitored for 5 minutes before, during, and after smoking. Puff analyses were also conducted to determine the amount of nicotine subjects obtained from cigarettes. Based on increases in heart rate of more than 10 or less than 8 beats per minute from baseline to smoking periods, subjects were categorized as responsive or nonresponsive. To assess stability of responsiveness over time, 20 responsive and 20 nonresponsive subjects were called back for a second session 1 week to 4 months later. At the second session, heart rates were again monitored before, during, and after smoking a standard cigarette. The data indicate that subjects maintained their relative degree of sensitivity to nicotine over time. The results are discussed in terms of Solomon's opponent process model and it is suggested that not all smokers are addicted to nicotine.

Female↗

Repair of oligodeoxynucleotides containing O6-methylguanine by O6-alkylguanine-DNA-alkyltransferase.

O6-Alkylguanine-DNA-alkyltransferase is a DNA repair protein known to carry out the transfer of alkyl groups from the O6-position of guanine in alkylated DNA to a cysteine acceptor site contained within its own protein sequence. We have examined the ability of this protein isolated from either E. coli or mammalian cells to perform this repair reaction in short oligodeoxynucleotides. Dodecadeoxynucleotides of the sequence 5'-dCGNGAATTCm6GCG-3' where N is any one of the normal four bases were all repaired very rapidly by the protein with 50% repair in less than 15 s at 0 degree C. The hexadeoxynucleotide 5'-dCGCm6GCG-3' was repaired slightly more slowly with 50% removal taking 7 min at 0 degree C and 1.5 min at 37 degrees C. The tetradeoxynucleotide 5'-dTm6GCA-3' was also a substrate but was repaired much more slowly requiring 45 min for 50% repair at 37 degrees C. These results indicate that (a) the AGT has a strong but not absolute preference for double-stranded DNA substrates; (b) the repair of O6-methylguanine is independent of the base opposite the lesion; and (c) that oligodeoxynucleotides as short as tetramers are substrates for repair by this protein.

DNA Repair↗

Small for dates babies: are they really a problem?

One hundred and sixty four infants less than 5th centile for gestation specific birth weight were born at gestations greater than or equal to 37 weeks in the Cambridge Maternity Hospital in 1982. Of these, 60 were less than 2-3rd centile--that is, greater than 2 standard deviations below mean birth weight. Serious disease was rare: only six (4%) had recognisable malformations. There was only one neonatal death, a baby less than 2-3rd centile with the Neu-Laxova syndrome. Nine (5%) became hypoglycaemic but with no serious symptoms: one of these was already on the neonatal unit with respiratory distress syndrome and was given intravenous dextrose, and the remaining eight all responded to milk feeds. Only 13 out of the 164 patients (8%) were admitted to the neonatal unit, eight of the 12 survivors for 48 hours or less. Small for dates babies of 37 weeks' gestation or more pose few neonatal problems and can be safely cared for on a postnatal ward.

Birth Weight↗