Chromosomal translocations involving the T-cell receptor delta chain locus and two loci on the short arm of chromosome 11.
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Chromosome Mapping↗
Biomedical subjects
R Baer
Publications and source records attributed to R Baer.
Physiological effects of a mouth-borne heat exchanger during heavy exercise in a cold environment.
A mouth-borne heat and moisture exchanger (HME) was tested. Nine healthy subjects performed an incremental-load cycle ergometry test to exhaustion, breathing once through the HME and once through a similar device without heat-exchange function (control). HME substantially increased inspired gas temperatures and decreased expired gas temperatures measured at the mouth; at 260 W (pulmonary ventilation (VE) approximately 1001 min-1) these changes amounted to + 15 degrees C and -5 degrees C, respectively. The breathing resistance was increased by HME but remained well within tolerable levels even during severe exercise. This was reflected in the subjective assessments of breathing resistance and breathing discomfort which, at any given workload, were rated similarly in the HME and control conditions. Also, time to exhaustion as well as oxygen uptake and VE at a given workload were unaffected by HME. That even at high pulmonary ventilations HME provided a good heat-exchange function while keeping breathing resistance relatively low suggests HME to be a useful aid for individuals suffering from cold-induced bronchospasm.
Adult↗
Effects of continuous positive- and negative-pressure breathing on the pattern of breathing in man during exercise.
Breathing pattern and static lung volumes were studied in 10 subjects at rest and during incremental-load cycle ergometry under three different conditions, viz. with normal pressure in the airways (control) and during continuous positive- and negative-pressure breathing (CPPB, CNPB) of +15 and -15 cmH2O. End-expiratory, end-inspiratory and mid-expiratory volumes were increased by CPPB and decreased by CNPB; these effects were especially pronounced at rest and during mild exercise. Both at rest and during exercise mean inspiratory flow (VT/TI) was exaggerated by CPPB and attenuated by CNPB. At rest these changes were due mainly to concomitant changes in tidal volume (VT) which was increased by CPPB and decreased by CNPB, while inspiratory time duration (TI) was relatively unaffected by pressure breathing. The transition from rest to loadless pedalling induced an increase in VT but no change in TI in the control condition, whereas in the CPPB and CNPB conditions TI decreased and VT remained unaltered. This CPPB- and CNPB-induced change in the volume-time threshold relationship at the onset of pedalling is attributed to increased stretch receptor activity in the extrathoracic portion of the trachea as a result of the increments in transmural pressure. During the course of exercise there was an inverse relationship between the slope of the VT-TI curve and the mid-expiratory volume in that the slope was greater in the control than in the CPPB condition and greatest during CNPB, suggesting that in exercise hyperpnoea the VT-TI relationship is also determined by pulmonary and/or thoracic wall stretch receptors capable of sensing the absolute lung volume.
Adult↗
Mechanism of rib cage inspiratory muscle recruitment in diaphragmatic paralysis.
Paralysis of the diaphragm promotes an increase in the activation of the rib cage inspiratory muscles, and previous studies have suggested that this compensation is primarily due to vagal mechanisms (6). To test this hypothesis, we have assessed the effect of diaphragmatic paralysis on the electrical response of 19 parasternal intercostal muscles in eight anesthetized, vagotomized, spontaneously breathing dogs in the supine posture. Complete diaphragmatic paralysis was induced by section of the C5, C6, and C7 phrenic nerve roots in the neck. With the animals breathing room air, diaphragmatic paralysis resulted in a mean 94% increase in the peak height of integrated parasternal activity (p less than 0.001) associated with a 14 mm Hg decrease in arterial PO2 (p less than 0.05) and an 8 mm Hg increase in arterial PCO2 (p less than 0.001). The augmented parasternal activity was unrelated to the duration of inspiration and persisted when the animals were given a hyperoxic gas mixture. Thus the rib cage inspiratory muscles still compensate for diaphragmatic paralysis in the absence of vagal signals and of hypoxemia. This compensation probably results from the considerably augmented CO2 load placed on the extradiaphragmatic muscles.
Animals↗
The chromosome translocation (11;14)(p13;q11) associated with T-cell acute lymphocytic leukemia: an 11p13 breakpoint cluster region.
The translocation (11;14)(p13;q11) was observed in karyotypes of leukemic cells from a 3-year-old boy with T-cell acute lymphocytic leukemia (T-ALL). Since this translocation is a recurrent marker of T-ALL, we undertook to investigate its mode of formation and role in leukemogenesis. The cytogenetic breakpoint on chromosome 14 occurs in 14q11, the same band wherein lies the T-cell receptor alpha/delta chain gene; and Southern hybridization analysis of peripheral blood and bone marrow DNA uncovered a tumor-specific rearrangement in the D delta-J delta region of this locus. DNA encompassing the rearrangement was isolated by molecular cloning, and further analysis revealed it to be the t(11;14)(p13;q11) junction. Nucleotide sequence determination of the junction indicates that the 14q11 breakpoint occurs immediately adjacent to the D delta 2 gene segment. Hence, the translocation arose as an aberrant rearrangement between the downstream recombination signal of D delta 2 and a pseudo recombination signal adjacent to the chromosome 11 breakpoint. Finally, comparison of the breakpoint in band 11p13 with those of other translocations (11;14)(p13;q11) identified a breakpoint cluster region of approximately 1.2 kilobase-pairs (kb), alterations of which may promote the development of T-ALL.
Base Sequence↗
Immunoglobulin VH genes are transcribed by T cells in association with a new 5' exon.
We previously detected mRNAs in a number of human T cell lines with a probe from within the Ig VH gene locus. We now show these mRNAs consist of Ig VH genes expressed in T cells. In one human T cell line, two RNA species have been studied and found to come from transcripts of unrearranged VH segments in which the leader exon, normally associated with VH transcripts in B cells, is replaced by a novel 5' exon (ET) not encoding a hydrophobic leader peptide. In genomic DNA, this new ET exon is adjacent to a pseudo-VH gene that has not been observed in mature mRNA. This implies that RNA splicing controls association of the new exon with the expressed VH segments. Hence, VH transcription does indeed occur in T cells, but is qualitatively different from that in B cells.
Amino Acid Sequence↗
The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15.
A chromosomal translocation t(11;14) (p15;q11) is described in a human acute T-cell leukaemia of immature phenotype (CD3-, CD4-, CD8-). The translocation occurs at a T-cell receptor joining J delta segment, 12 kb upstream of the constant C delta gene and 98 kb upstream of the C alpha gene at chromosome band 14q11. Nucleotide sequencing shows that both J delta and C delta are very conserved between mouse and man. The region of chromosome 11 involved in the translocation is transcriptionally active and produces a 4-kb mRNA. The DNA sequence at the chromosome 11 junction shows a perfect match to a recombinase signal sequence implying that this translocation occurred by recombinase error. The occurrence of the translocation breakpoint at the C delta locus, normally rearranged in immature T cells, and the structure of the translocation junctions suggests that the translocation occurred during an attempt at normal rearrangement of the J delta segment in an early thymocyte.
Amino Acid Sequence↗
Complex rearrangements within the human J delta-C delta/J alpha-C alpha locus and aberrant recombination between J alpha segments.
We have examined DNA rearrangements within a 120 kb cloned region of the human T cell receptor J delta-C delta/J alpha-C alpha locus. Three types of pattern emerge from an analysis of T cell lines and clones. Firstly, cells with two rearrangements within J delta-C delta; secondly, cells with one rearrangement within J delta-C delta and one or more J alpha rearrangements, and finally, cells with rearrangements within J alpha and consequential deletion of the delta locus. Further analysis by cloning of rearrangements within the J alpha locus show that, in addition to V alpha-J alpha joins, J alpha-J alpha aberrant recombinations occur and rearrangement data indicate that such events are frequent. A model is presented to account for such recombinations.
Amino Acid Sequence↗
Transsphenoidal chiasmopexy for long standing visual failure in the secondary empty sella syndrome.
The development of an empty sella syndrome is a well recognized complication in the treatment of pituitary tumours and usually presents with visual failure. Transsphenoidal chiasmopexy has been successful in reversing the visual loss when performed in the acute stage. A case, where a delay of 18 months in the surgery does not appear to have affected the outcome, is presented and the literature reviewed.
Adenoma↗
The mechanism of chromosome 14 inversion in a human T cell lymphoma.
The chromosome 14 inversion produces cytogenetic breakpoints at either end of the long arm of this chromosome. Previous studies have shown that a hybrid gene (designated IgT) consisting of an immunoglobulin VH gene segment and T cell receptor J alpha C alpha segments encompasses the telomeric breakpoint in SUP-T1, a cell line derived from a human T cell lymphoma. Here, we report that the centromeric breakpoint in SUP-T1 constitutes the reciprocal of a VH-J alpha join but involves gene segments different from those at the telomeric breakpoint. Therefore, chromosome inversion and IgT formation were mediated by two sequential VH-J alpha joining events. Moreover, sequences adjacent to the centromeric breakpoint detect a T-cell-specific RNA, encoded within the immunoglobulin VH locus, whose transcriptional activity may have facilitated the illegitimate VH-J alpha rearrangements.
Chromosome Inversion↗
Human T-cell tumours containing chromosome 14 inversion or translocation with breakpoints proximal to immunoglobulin joining regions at 14q32.
T-cell tumours are frequently found to carry an inversion of chromosome 14 (inv(14)) (q11;q32) or more rarely a chromosome 14 translocation t(14;14) with the same cytogenetic breakpoints (q11;q32). We have examined the molecular junctions of an inv(14) and a translocation t(14;14) using T-cell receptor (TCR) alpha joining (J) region probes. Both of these chromosomal abnormalities have breakpoints within the TCR J alpha locus at 14q11 and both have breakpoints which are proximal (i.e. on the centromeric side) to the immunoglobulin heavy chain JH region at 14q32. The cloned segments corresponding to the junctions at 14q32 are not associated with obvious immunoglobulin-like sequences. This contrasts to the previously described inv(14) in the cell line SUP-T1 and places a potential cluster of chromosome 14 breakpoints downstream of the Ig JH locus. The possible role of the varying breakpoints in the development of these tumours is discussed.
Amino Acid Sequence↗
The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: sequences downstream of the immunoglobulin heavy chain locus are implicated in tumorigenesis.
T-cell tumors are characterized by inversions or translocations of chromosome 14. The breakpoints of these karyotypic abnormalities occur in chromosome bands 14q11 and 14q32--the same bands in which the T-cell receptor (TCR) alpha-chain and immunoglobulin heavy chain genes have been mapped, respectively. Patients with ataxia-telangiectasia are particularly prone to development of T-cell chronic lymphocytic leukemia with such chromosomal abnormalities. We now describe DNA rearrangements of the TCR alpha-chain gene in an ataxia-telangiectasia-associated leukemia containing both a normal and an inverted chromosome 14. The normal chromosome 14 has undergone a productive join of TCR alpha-chain variable (V alpha) and joining (J alpha) gene segments. The other allele of the TCR alpha-chain gene features a DNA rearrangement, about 50 kilobases from the TCR alpha-chain constant (C alpha) gene, that represents the breakpoint of the chromosome 14 inversion; this breakpoint is comprised of a TCR J alpha segment (from 14q11) fused to sequences derived from 14q32 but on the centromeric side of C mu. These results imply that 14q32 sequences located at an undetermined distance downstream of the immunoglobulin C mu locus can contribute to the development of T-cell tumors.
Ataxia Telangiectasia↗
Alpha, beta and gamma T-cell receptor genes: rearrangements correlate with haematological phenotype in T cell leukaemias.
We have studied the arrangement of the alpha, beta and gamma T cell receptor (TCR) genes in 27 patients with T cell lymphoproliferative disorders. Nine patients had acute lymphoblastic leukaemia (T-ALL), nine patients had prolymphocytic leukaemia (PLL), six patients presented with a T-CLL/T-lymphocytosis syndrome, two patients had Sezary syndrome (SS) and one patient had HTLV-I positive T-cell leukaemia/lymphoma (ATLL). alpha TCR gene rearrangement could be demonstrated by the use of three available probes in only one case. By contrast, both beta and gamma TCR gene rearrangement could be demonstrated by Southern blot analysis of DNA samples digested with appropriate restriction enzymes in the majority of cases. In general, when rearrangements were present they involved both alleles. The proportion of rearranged chromosomes was lower in T-ALL than in other forms of T-cell leukaemia and it was lower in cases with the CD4-/CD8+ phenotype than in those with a CD4+/CD8- phenotype. In three out of 34 cases of B-cell leukaemia the TCR beta-gene but not the TCR gamma-gene was rearranged, just as in two out of 26 cases of T-cell leukaemia the immunoglobulin (Ig) heavy chain but not the light chain genes were rearranged. These data suggest that development of the machinery required for gene rearrangement may precede commitment to B or T cell lineage. The use of this technique is especially useful for the classification of cases of ALL in which the cells are negative with respect to most current phenotypic markers and in cases of T cell lymphocytosis in which the finding of a gene rearrangement identifies a monoclonal cell population.
Adolescent↗
Effects of triglycyl-lysine-vasopressin on cardiovascular responses to orthostatic stress.
The influence of triglycyl-lysine-vasopressin (TGLVP) on cardiovascular responses to orthostatic stress was studied. Arterial pressures, heart rate (HR) and stroke volume (SV) were measured in eight healthy males subjected to 20 min 70 degrees head-up tilt. On different days they received either 0.01 mg/kg b.w. of TGLVP or a corresponding volume of 0.9% saline i.v. after 15 min supine rest. After the drug injection, in supine subjects, HR had decreased from 58 to 50 beats min-1, total peripheral resistance (TPR) was elevated by 29%, systolic (SAP) and diastolic pressure (DAP) had increased by 7 and 8 mmHg, respectively. During tilt, values for HR and SAP were similar with and without TGLVP whereas DAP and MAP were elevated 8 and 7 mmHg, respectively, by the drug. 4-8 min into the tilt, TGLVP caused an 8% sustained curtailment of SV. Both with and without the drug TPR increased by about 30% in response to head-up tilt. Thus, the marked peripheral arteriolar constriction after vasopressin in the supine position was not affected by head-up tilt. Tilting also abolished the drug-induced elevation in SAP, most likely explained by the reduction in SV. Although TPR was markedly increased by TGLVP during head-up tilt, reflected in the behaviour of DAP, the response of SV speaks against any beneficial effect of this drug on orthostatic tolerance in healthy subjects.
Adult↗
Cardiovascular effects of head-up tilt as affected by a vasopressin analogue.
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Adult↗
Pulmonary mechanics and atelectasis during immersion in oxygen-breathing subjects.
It has been suggested that vital capacity (VC) reduction seen during head-out immersion and oxygen breathing is due to atelectasis formation. In this study VC was reduced in 8 healthy subjects by 8.7% as an effect of immersion per se and by a further 14.3% as an effect of oxygen breathing during 30 min of immersion. Every 2nd min during the exposure, functional residual capacity (FRC), dynamic compliance (C-dyn), and static esophageal pressure at end-expiration (Pes-frc) were measured by body plethysmographic technique. Results were compared with an air-breathing, immersed control situation to evaluate any possible atelectasis formation. The only significant changes during immersion were observed after 30 min of air breathing, where FRC decreased linearly by 8.5% and C-dyn by 13.2%. The main conclusion is that atelectases acting solely as volume restrictors cannot explain the whole VC reduction without other additive or synergistic mechanisms. We suggest that the linear decrements in FRC and C-dyn as an effect of immersion time might be explained by either inspiratory muscle fatigue or increasing thoracic fluid compartment during the first 30 min of head-out immersion.
Adult↗
Diversity and rearrangement of the human T cell rearranging gamma genes: nine germ-line variable genes belonging to two subgroups.
We describe nine T cell gamma variable (V) gene segments isolated from human DNA. These genes, which fall into two subgroups, are mapped in two DNA regions covering 54 kb and probably represent the majority of human V gamma genes. One subgroup (V gamma I) contains eight genes, consisting of four active genes and four pseudogenes. The single V gamma II gene is potentially active. Sequence analysis of the V gamma I genes shows variation clustered in hypervariable regions, but somatic variability is restricted to N-region diversity. Studies on rearrangement in T cell lines and in thymic DNA show that major rearrangements can be observed that are attributable to the five active V gamma genes. In addition, human cells with the phenotype of helper T cells can undergo productive V gamma-J gamma joining.
Bacteriophage lambda↗
The chromosome breakpoint at 14q32 in an ataxia telangiectasia t(14;14) T cell clone is different from the 14q32 breakpoint in Burkitts and an inv(14) T cell lymphoma.
The T cell receptor alpha chain gene locus and the immunoglobulin heavy chain gene locus (IgH) have previously been mapped to the q11 and q32 positions respectively of the human chromosome 14. Both of these sites are also common breakpoints in lymphocytes from ataxia telangiectasia (A-T) patients. Using in situ hybridisation we show that the 14q32 breakpoint in an A-T non-leukaemic T cell clone with t(14;14) translocation, lies outside the IgH locus and proximal to it with respect to the centromere. The 14q11-14qter segment of the homologous chromosome 14 carrying the constant gene region of the alpha chain locus is translocated to this 14q32 position.
Ataxia Telangiectasia↗