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Biomedical subjects

J J Wright

Publications and source records attributed to J J Wright.

At least 91 records · Page 5Linked to original sources
PubMed1987

T cell receptor alpha-, beta-, and gamma-genes in T cell and pre-B cell acute lymphoblastic leukemia.

We examined alpha-, beta-, and gamma-T cell receptor (TCR) gene activation within acute lymphoblastic leukemias (ALLs) that represent early stages of B and T cell development. We wished to determine if TCR rearrangement and expression was lineage restricted, showed any developmental hierarchy, or could identify new subsets of T cells. Rearrangement of gamma and beta TCR genes occurred early in development but in no set order, and most T-ALLs (22/26) were of sufficient maturity to have rearranged both genes. T-ALLs preferentially rearranged C gamma 2 versus the C gamma 1 complex; no preference within the beta locus was apparent. Once rearranged, the beta TCR continued to be expressed (11/13), whereas the gamma TCR was rarely expressed (3/14). The alpha TCR was expressed only in more mature T-ALLs (8/14) that usually displayed T3. The 3A-1 T cell associated antigen appeared earliest in development followed by T11 and T3. Within pre-B cell ALL a higher incidence of lineage spillover was noted for gamma TCR rearrangements (8/17) than for beta rearrangements (3/17). This also contrasts with the only occasional rearrangement of immunoglobulin (Ig) heavy chains (3/25) in T-ALL. However, in pre-B ALL the pattern of gamma TCR usage was distinct from that of T cells, with the C gamma 1 complex utilized more frequently. Almost all ALLs could be classified as pre-B or T cell in type by combining Ig and TCR genes with monoclonal antibodies recognizing surface antigens, although examples of lineage duality were noted. Unique subpopulations of cells were discovered including two genetically uncommitted ALLs that failed to rearrange either Ig or TCR loci. Moreover, two T lymphoblasts were identified that possessed the T3 molecule but failed to express alpha plus beta TCR genes. These T-ALLs may represent a fortuitous transformation of T cell subsets with alternative T3-Ti complexes.

B-Lymphocytes↗
PubMed1987

Gene rearrangements as markers of clonal variation and minimal residual disease in acute lymphoblastic leukemia.

Immunoglobulin (Ig) heavy (H) and light (L) chain gene rearrangements were used as molecular markers of clonal evolution and minimal residual disease in B cell precursor acute lymphoblastic leukemia (ALL). All leukemic episodes within individual patients shared at least one identical Ig rearrangement and thus arose from a common clonal progenitor cell. Nine of 11 patients displayed completely identical patterns between leukemic episodes, while two of 11 patients demonstrated genetic progression between diagnosis and relapse as evidenced by additional rearrangements. These genetic changes marked the emergence of leukemic subclones. Ig gene rearrangements were also used as sensitive markers to identify clonal cell populations in ALL patients following induction or reinduction therapy and to search for residual bone marrow disease in patients in clinical remission or with isolated extramedullary relapse. DNA rearrangements provide tumor-specific markers to follow the genetic variation of ALL and may facilitate the early detection of recurrent disease.

B-Lymphocytes↗
PubMed1987

Gross electrocortical activity as a linear wave phenomenon with variable temporal damping, regulated by ascending catecholamine neurones.

We report critical tests for a theory of electrocortical wave processes, in which telencephalic dendritic potentials reflect the mass action of coupled oscillatory circuits exhibiting complicated and unspecified non-linearities, the whole system being driven by active cell firing. Specific assumptions were: stochastic independence for instantaneous coupling parameters in the system, an individual central tendency to the cycle time for each circuit, and the maintenance of steady state conditions. Application of the central limit theorem to the state transition matrix shows that the gross electrocortical waves should be linear waves, exhibiting a multitude of invariant resonant modes, with the natural frequencies of all the modes being clustered about a smaller number of center values. Ascending brain-stem neurones of at least the dopaminergic and noradrenergic classes should regulate both the power of noise-like signals driving the telencephalic resonant patterns, and the temporal damping of each resonance. We devised tests which involved between hemisphere comparisons of electrocortical spectra, before and after unilateral lesion of transhypothalamic ascending fibres, thus obtaining ratio power changes attributable to post lesion asymmetry of damping and driving, in modes of equivalent left-right center-frequencies. These ratio spectra were curve-fitted to an approximate theoretical expression, and the parameters obtained enabled tests of several specific predictions. Estimates of the center values for resonant mode frequencies, comparison of the relative changes in left/right phase with that expected from the ratio changes in power, and estimates of the surface-to-signal transformation of left and right signals made by a back-calculation, all conform to expectation from the theory, and are consistent across lesion of different types of ascending neurone.

Animals↗
PubMed1987

Refinement of lymphoma cytogenetics by the chromosome 18q21 major breakpoint region.

A small (2.8-kilobase, kb) major breakpoint region localized to segment 18q21 rearranges in greater than 70% of t(14;18)(q32;q21) lymphomas. This rearrangement interrupts the Bcl-2 gene and introduces it into the Ig locus at 14q32. The rearrangement between the joining region (JH) of Ig on chromosome 14 and the 18q21 region creates a translocation-specific DNA rearrangement. We generated probes that distinguish the 14;18 juncture on the derivative (der) 14 and der (18) chromosomes, providing a molecular approach to t(14;18) identification. Approximately 60% of unselected follicular lymphomas, 20% of diffuse large cell lymphomas, and 50% of adult undifferentiated non-Burkitt lymphomas demonstrated 14;18 rearrangements within the major breakpoint region. Examination of DNA for 14;18 rearrangements resolved the identity of 14q+ chromosomes in two patient's cells that lacked an obvious reciprocal partner. Identification of the exact restriction fragments that mediate translocations complements routine cytogenetics. The detection of DNA rearrangements does not require dividing cells or the presence of an identifiable reciprocal partner and can detect clonal translocation rearrangements when the neoplastic cells are only a minority of all cells present.

Chromosome Banding↗
PubMed1987

Immunoglobulin and T cell receptor gene configuration in acute lymphoblastic leukemia of infancy.

We examined immunoglobulin (Ig) heavy chain, K light chain, and T cell receptor (TCR) gamma and beta gene configuration in the leukemic cells from a series of infants aged less than 1 year with acute lymphoblastic leukemia (ALL). Each of these 11 cases demonstrated leukemic cell surface antigens that have been correlated with a B cell precursor phenotype. Of the 11, lymphoblasts of 4 retained the germline configuration of both Ig and TCR loci, whereas 7 had rearranged the Ig heavy chain gene. Two of these seven showed light chain gene rearrangement. TCB beta chain rearrangement had occurred in only one of the 11 patients' tumors. No TCR gamma chain rearrangements were identified. These results are in contrast to earlier studies of B cell precursor ALL in children in which Ig heavy chain gene rearrangements were evident in every case and approximately 40% showed Ig light chain rearrangement as well. In addition, 45% of cases of B cell precursor ALL of children had rearranged their gamma TCR genes, and 20% had rearranged beta. These data suggest that ALL in infancy represents an earlier stage of B cell development than is found in B cell precursor ALL of children. ALL in the infant age group has been associated with the worst prognosis of all patients with ALL. This study suggests that the disease in infants differs not only clinically, but also at the molecular genetic level, from the disease in children.

Acute Disease↗
PubMed1986

Lymphoblastic transformation of myelodysplastic syndrome.

Acute myeloblastic leukemia occurs as a complication of myelodysplastic syndromes, but the appearance of an acute lymphoblastic leukemia (ALL) has only been reported once. We describe a case in which lymphoblastic transformation occurred in the setting of a dysmyelopoietic syndrome. This leukemia was characterized by lymphoid morphology, terminal deoxynucleotidyl transferase (TdT) positivity, cytogenetic abnormalities, and immunoglobulin gene rearrangements. The patient responded to conventional therapy for this leukemia (vincristine and prednisone). Our case supports the hypothesis of a common lymphohemopoietic progenitor and suggests that in vitro tests may help identify a subset of these patients and be important in selecting appropriate therapy.

Aged↗
PubMed1986

Immunoglobulin chain gene rearrangements in a t(4;11) acute leukaemia with monocytoid blasts.

We report a case of acute leukaemia with the t(4;11) chromosomal translocation which, at initial diagnosis, had L-1 lymphoblasts that were positive for terminal deoxynucleotidyl transferase (TdT) and HLA-DR but negative for myeloid cytochemical markers. At last relapse the patient had mostly monocytoid blasts which were not TdT negative but were positive for HLA-DR, weakly positive for Sudan Black B (SB), periodic acid Schiff's (PAS), naphthol AS-D acetate esterase (NSE), chloroacetate esterase (CAE) and negative for acid phosphatase (AP) and nitroblue tetrazolium (NBT) reduction. Treatment with 12-o-tetradecanoylphorbol-13-acetate (TPA) in vitro induced differentiation to macrophage-like cells that were strongly positive for SB, PAS, NSE, AP, CAE and NBT reduction, indicating a latent monocyte-like phenotype. Thus the leukaemic cell clone or a precursor clone with the t(4;11) translocation manifested a lymphoid phenotype at initial diagnosis and a monocytoid phenotype at relapse. Immunoglobulin gene analysis of the monocytoid relapse blasts revealed rearrangements of the heavy chain gene alleles and germline light chain genes. Thus, the leukaemia clone with the t(4;11) chromosomal translocation could be a bipotential cell with heavy chain gene rearrangements occurring in a primitive cell which may retain the ability to differentiate along the myeloid-monocytoid lineage in response to the appropriate stimulus. Alternatively, these characteristics may result from a transformation associated event.

Cell Differentiation↗
PubMed1986

Mental phenomena as changes of state in a finite-state machine.

This paper examines the classical functions of the psyche--cognition, affection and conation--from a phenomenological viewpoint and finds them to be defined each in terms of the other. It is held that this circularity of definition reflects the fundamental unity of conscious experience and, as a consequence, that the search for the biological substrate underlying individual functions too readily degenerates into a morphological and biochemical phrenology. An alternative approach, based on considerations from the field of artificial intelligence, is discussed. This approach provides a description of mental phenomena as changes of state in a finite-state machine, the next state being determined by both previous states and current inputs. This concept is shown to be compatible with the descriptions of conscious experience outlined in the phenomenology of Karl Jaspers. It is suggested that neurobiological investigations should be directed towards defining the processes by which state changes occur and further seeking to define mental pathology as aberrations of these dynamic processes.

Affect↗
PubMed1986

Schizophrenia as a disorder of cerebral state transition.

This paper offers a speculative consideration of the schizophrenic process in the light of recent findings concerning the wave nature of electrocortical activity. These findings indicate that changes of brain state can be described in the terminology of finite-state machines, and both the instantaneous states and the state transitions can be specified. It is suggested that the mental phenomena of schizophrenia may be reducible to events (some specific type of instability) which could be observed by appropriate analytic techniques applied to EEG. Present empirical EEG findings in schizophrenics are reviewed in this light, and the role of dopamine blockade in treatment is also considered.

Arousal↗
PubMed1985

State-changes in the brain viewed as linear steady-states and non-linear transitions between steady-states.

Preceding papers concern a linear theory of electrocortical waves and their regulation by brain-stem neurones, in conditions of steady-state. The present paper reconsiders the theory, and generalizes beyond the effects of the fibre systems so far studied. Relaxation and unification of the assumptions upon which the initial model was based is undertaken. It is shown that the generalised model may render state changes within the brain accessible to systematic description, using the EEG as dependent variable. It is proposed that a multitude of stable states are possible within the brain, each characterised by a set of damping parameters for separate linear resonant modes. Within each stable state, the set of sums of resonant modes characterises a sub-space of the total state-space. Transition between stable regions can occur with either perturbation by external signals, or by internal controls. Tentative consideration is given to the role of plastic changes leading to adaptive learning as an attribute of a system of this type.

Cerebral Cortex↗
PubMed1985

Quantitation of a mass action of dopaminergic neurones regulating temporal damping of linear electrocortical waves.

We have previously proposed that electrocortical waves are linear waves, subject to regulation by mesotelencephalic dopaminergic neurones. As a further means to test this theory, selective unilateral lesions of varying extent were made in the nucleii of origin of the dopaminergic mesotelencephalic tract. Changes in the electrocortical power spectrum were assessed by a repeated measure, between hemispheres comparison of ratio changes in power. With increasing unilateral dopamine cell damage, the animals showed increasing contralateral sensorimotor neglect. Curve fitting the ratio changes in power attributable to lesion, showed that estimates of the power of driving signals and the temporal damping moved in reverse directions with increasing extent of lesion, as expected from the theory. A further test was undertaken, to determine whether equal estimates for a transformation of surface signals were obtained from each side. Equality would not be expected if the equation for relative power were invalid. Left and right equality was found for three grades of unilateral lesion.

Animals↗
PubMed1985

Relationship between sensorimotor neglect and the specificity, degree and locus of mesotelencephalic dopaminergic cell loss following 6-hydroxydopamine.

The involvement of cell groups within the dopaminergic mesotelencephalic system in the development of the sensorimotor neglect syndrome was re-evaluated in two ways. Firstly, dopaminergic specificity of the neglect was further established by studying the relationship between nomifensine protection of dopamine cells against 6-hydroxydopamine damage and the degree of neglect which resulted. The sensorimotor neglect syndrome which developed following injection of 6-hydroxydopamine was diminished by concomitant treatment with nomifensine in parallel with the degree of protection afforded the dopaminergic cells. Non-specific damage produced by 6-hydroxydopamine was unaltered by nomifensine. Secondly, the role in sensorimotor neglect of both total cell damage, and damage to regional sub-classes of dopaminergic cells was considered. It was found that the extent of the resulting neglect was correlated with the overall damage to the substantia nigra and ventral tegmental area, rather than to any individual region within this dopaminergic system. There was a threshold, involving destruction of approximately one third of the system, below which no neglect syndrome developed. Certain regions, including the ventral tegmental area (VTA), showed a higher partial correlation with the extent of neglect than other regions. While specific lesioning of the A8 or A10 dopaminergic neurons is probably insufficient to produce a neglect syndrome, damage to these areas potentiates the severity of the neglect produced by nigrostriatal lesions. It appears that the involvement of the individual subclasses of the mesotelencephalic dopaminergic neurons in the neglect syndrome is more widespread than previously thought.

Animals↗
PubMed1985

Contributions of noradrenergic neurones of the locus coeruleus to the temporal damping of linear electrocortical waves.

The preceeding paper (Wright et al. 1985a) gives evidence that mesotelencephalic dopaminergic neurones regulate gross electrocortical waves with linear properties, by influencing the strength of their driving signals and temporal damping. The present study further generalises the findings to ascending noradrenergic neurones, which have different fields of termination to dopaminergic fibres. It is shown that: Estimates of the major groups of natural frequencies for the telencephalic system obtained from curve-fitting the ratio changes in the power spectrum attributable to unilateral noradrenergic neurone lesion, are again centered about the frequencies of the major cerebral rhythms. Estimates of electrode transfer characteristics, using parameters obtained from curve fitting ratio changes in power, in conjunction with the raw left and right power spectra, are again found to be equal left and right, as required by the theoretical derivation. Changes in relative amplitude of electrocortical waves and their relative phase are significantly in accord with the relationship expected from theory.

Animals↗
PubMed1985

Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18.

Specific chromosomal translocations found in distinct neoplasms suggest that genes that flank such breakpoints play a critical role in transformation. We have characterized the t(14;18)(q32;q21) chromosomal translocation present in over 60% of human follicular lymphomas. We exploited an unexpected rearrangement of an Ig heavy-chain gene to clone the chromosomal breakpoint. An element isolated from 18q21 mediated translocations in all four t(14;18) bearing cell lines and in six of 11 follicular lymphomas, but did not normally rearrange in other B or non-B cells. The breakpoints clustered within a small 4.3 kb region on chromosome 18. The breakpoints on chromosome 14 were focused within or immediately 5' to JH. These breakpoints retained the Ig enhancer region close to a new transcriptional unit identified on chromosome segment 18q21. Since none of the cellular oncogenes are known to map to 18q21, cloning this element provides an opportunity to characterize a potentially new transforming gene.

Cell Line↗
PubMed1984

Cycloheximide blocks changes in rat liver carnitine palmitoyltransferase 1 activity in starvation.

Starvation (24h) increased the maximum activity of carnitine palmitoyltransferase 1 in rat liver and increased the concentration of malonyl-CoA required to cause 50% inhibition of the enzyme (I50). Re-feeding (24h) with a standard cube diet or a high-carbohydrate diet reversed both of these changes, whereas re-feeding with a high-fat diet did not. Administration of cycloheximide (200 micrograms/100 g body wt.) blocked the increases in carnitine palmitoyltransferase 1 activity and I50 on starvation. It is suggested that increase in carnitine palmitoyltransferase 1 activity in starvation may involve synthesis of new enzyme.

Acyltransferases↗
PubMed1984

Effect of nomifensine on the toxicity of 6-hydroxydopamine for mesotelencephalic dopamine neurons.

The ability of nomifensine to protect the dopaminergic cells of the substantia nigra and ventral tegmental areas against 6-hydroxydopamine-induced destruction was evaluated. Nomifensine at high doses (20 mg/kg, i.p.) protected the cells from the effects of low amounts of 6-hydroxydopamine (2 micrograms) injected intracerebrally. This protective effect was markedly decreased with an increased amount of 6-hydroxydopamine (8 micrograms), or by lower doses of nomifensine (6.7 mg/kg). These doses of nomifensine are higher than those required to protect dopaminergic nerve terminals.

Animals↗
PubMed1984

Amplitude and phase relations of electrocortical waves regulated by transhypothalamic dopaminergic neurones: a test for a linear theory.

We have previously proposed that electrocortical activity (EEG) arises as a manifestation of linear waves generated by resonance among telencephalic neurones, and that this activity is controlled in part by ascending neurones from the brain-stem, which regulate the damping of each resonance. The present experiments focus on a specific class of ascending neurones, the mesotelencephalic dopaminergic cells, because these cells are thought to mediate important psychological effects, and are conveniently subject to selective lesion. A critical test of the theory is undertaken, by performing selective unilateral lesion, assessing the changes in the power spectrum of the EEG attributable to lesion, and determining whether the changes in phase of the EEG correspond to that predicted from the changes in power. Results support the theory, although the model order applicable in these experiments in inadequate. The consequences of these findings for automata theory, linear network theory and their application to mammalian brains are briefly discussed.

Animals↗