HIV type 1 envelope sequence diversity in inner city community.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
J L Hurwitz
Publications and source records attributed to J L Hurwitz.
Peripheral T cell receptor repertoire among CD4+ and CD8+ subsets during acute infectious mononucleosis.
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Acute Disease↗
Importance of abortive shock capability with electrogram storage in cardioverter-defibrillator devices.
OBJECTIVES: This study evaluates the ability of a third-generation cardioverter-defibrillator to abort energy delivery and the importance of electrogram storage in analyzing the aborted events. BACKGROUND: In the Cadence Tiered Therapy Defibrillator, when a tachycardia satisfies detection criteria for cardioversion or defibrillation therapy, high voltage capacitors begin charging. The Cadence defibrillator continues monitoring the rhythm during charging and if the rate decreases to below the rate triggering therapy, charging is terminated. This event is registered as an aborted shock. The defibrillator also has the ability to store intracardiac electrogram recordings of the electrical events that precipitate device therapy or aborted shocks. METHODS: During a mean follow-up interval of 10 +/- 7 months, 55 aborted events were registered by the Cadence defibrillator in 18 of the 49 patients who received it. Thirty-two stored ventricular electrograms of events leading to aborted shocks were available for analysis in 15 patients. RESULTS: Intracardiac electrogram recordings demonstrated the probable electrical events leading to these aborted shocks included nonsustained ventricular tachycardia (n = 10), nonsustained rapid polymorphic ventricular tachycardia/ventricular fibrillation (n = 2), atrial fibrillation (n = 5), supraventricular tachycardia (n = 2) and electrical noise (n = 13). Eleven patients had a therapeutic intervention initiated as a consequence of the diagnostic information provided by analysis of intracardiac electrogram recordings. Four of the 15 patients had no changes made. During a follow-up period of 9 +/- 5 months after therapy was altered, no patient had subsequent aborted shocks. Five patients have had seven appropriate shocks for sustained ventricular tachycardias. CONCLUSIONS: The ability of Cadence defibrillator to continue tachycardia sensing during capacitor charging and to abort shock therapy for self-terminating events prevented unnecessary shocks in 18 (37%) of the 49 patients. Intracardiac electrogram recordings were critical for instituting appropriate therapy that may have prevented unnecessary device charging and inappropriate discharges.
Adult↗
Fetal thymocyte potential for T cell receptor V gamma 3-J gamma 1 junctional modification.
Junctional modifications of T cell receptor (TcR) and immunoglobulin (Ig) gene joining regions provide great diversity to respective protein repertoires. The addition of non-germ-line-encoded nucleotides (N-regions) in the V-J gamma junction is one such modification which is developmentally regulated, rarely evident in the fetal animal, but common in the adult. A question has recently arisen as to whether developmentally patterned N-region additions in V-J gamma joins are a reflection of T cell progenitors which are committed to particular types of rearrangement prior to the event, or of changing environmental influences on uncommitted cell populations. To address this question with regard to the V gamma 3-J gamma 1 join, T cells were examined in the fetal thymic organ culture (FTOC), a system with which the environment of early progenitor cells could be deliberately altered. At various times following FTOC initiation, cells were isolated for examination by the polymerase chain reaction, cloning and sequencing. V gamma 3-J gamma 1 sequences within genomic DNA as well as cDNA were evaluated. Data from these studies revealed frequent N-region additions within V-J gamma joins among day 14 fetal thymocyte populations, a situation dissimilar from that in vivo. Also dissimilar from the in vivo situation was the degree of exonuclease activity evident in FTOC. The canonical V gamma 3-J gamma 1 join (a frequent junction lacking N-region addition) was recognized in all experiments, but was least common among DNA versus cDNA sequences. Results illustrate that early progenitor cell populations are not programmed to exclude junctional modifications from V gamma 3-J gamma 1 joins.
Animals↗
T-cell receptor heterogeneity among Epstein-Barr virus-stimulated T-cell populations.
The mechanism by which Epstein-Barr Virus (EBV) escapes T-cell activity during latency in immunocompetent individuals has long been debated. In order to identify potential weaknesses in the EBV-specific immune response, a study of T-cell receptors (TCR) within virus stimulated T-cell populations was performed. Membrane staining techniques and the polymerase chain reaction were used to address two questions: (1) Does EBV behave as a superantigen, thus stimulating, and possibly eliminating, T-cell subsets based on TCR V beta expression?, and (2) Are T-cells dependent on a predominant TCR V beta segment for effective cytotoxic function towards EBV? In search for superantigen effects, V beta repertoires among PBL from seropositive and seronegative individuals were compared both before and after short term in vitro exposure to EBV. In order to characterize functional TCR, the V beta usage among CD8+ EBV-specific cytotoxic T-cell clones was determined. Taken together, results illustrated the strengths rather than weaknesses of the EBV-specific T-cell immune response. T-cells did not respond to EBV in a manner typifying potent superantigen activity, nor did T-cells rely on the expression of a single V beta gene segment for efficient, EBV-specific cytotoxic function.
Base Sequence↗
Restricted usage of T-cell receptor V alpha sequence and variable-joining pairs after normal T-cell development and bone marrow transplantation.
TCR V alpha 3 and V alpha 5 transcripts in PBLs from healthy individuals of multiple age groups and from BMT recipients were analyzed. PCR, cloning, and sequencing studies revealed significant V-J junctional diversity among TCR transcripts from all tested blood samples, as provided both by N/P-region addition and exonuclease activity. However, results illustrated restrictions in TCR alpha diversity at several additional levels. First, V alpha 5 and V alpha 3 gene families, which were expected to be composed of multiple members, were dominated in each case by a single sequence at the transcript level. Second, restrictions existed in V-J pairing in that J alpha genes, which were encoded toward the 5' region of the locus, were rearranged frequently with V alpha 3 and rarely with V alpha 5. Conversely, J alpha genes encoded toward the 3' region of the locus preferentially rearranged with V alpha 5. Healthy individuals showed few differences with regard to V-J pairing patterns, while one of three BMT recipients demonstrated a skewed usage of 3' J alpha genes. In total, results demonstrated qualitative restrictions that may limit the working TCR repertoire in human peripheral tissues, both among BMT recipients and their healthy donors.
Adolescent↗
Cervical aortic arch associated with tetralogy of Fallot.
Forty-seven cases of cervical aortic arch have been reported in the literature. Eleven of these patients had congenital cardiac defects, including tetralogy of Fallot in three. An additional case of cervical aortic arch and tetralogy of Fallot is presented along with a brief review of the literature pertaining to this rare condition.
Adult↗
Environmental influence on T cell receptor alpha gene rearrangement and expression in vitro.
Experiments were designed to test whether T cell progenitors are committed to particular T cell receptor (TcR) gene rearrangement and expression patterns (prior to rearrangement) or whether such patients are molded by the thymic microenvironment in which T cells develop. To this end, day 14 fetal thymocytes were removed from their normal environment and grown in organ culture (FTOC) for 5 to 12 days. RNA was extracted from organ-cultured cells, processed to cDNA, and TcR alpha sequences were amplified by the polymerase chain reaction for cloning and sequencing. By the examination of N-region additions and V-gene usage, and by the comparison of resultant patterns with those of early vs. adult stages of T cell differentiation in vivo, it was demonstrated that thymocytes in FTOC did not maintain early patterns of gene rearrangement. The thymocyte patterns were most dissimilar from those of normal, early ontogeny when interleukin-4 was added to FTOC. Taken together, results demonstrated the flexibility of T cell progenitors and that environment plays a critical role in the molding of TcR alpha rearrangement and expression patterns.
Animals↗
Diversity of T-cell receptor alpha gene transcripts in the newborn and adult periphery.
Recent studies have demonstrated that the diversity of T-cell receptor alpha (Tcra) gene expression may be confined by a developmental program for gene rearrangement. To examine the effect of age on Tcra gene usage in peripheral tissues, a comparison of Tcr transcripts from newborn and adult mouse splenocytes was made. RNA was first isolated from the spleens of newborn (within five days from birth) and adult B10.BR mice. The polymerase chain reaction was then used to assess the presence of Tcra-V1, Tcra-V2, and Tcra-V3 gene sequences within the two RNA pools. The Tcra-V2 transcript was frequent in both newborn and adult populations and was therefore selected for sequencing analyses, by which V-gene family member and J gene usage could be delineated. Forty-one sequences were obtained, demonstrating Tcra-V2 gene family structure in the B10.BR mouse. Six family members were identified, of which four were new. Although there were differences in gene usage between newborn and adult animals, some junctional diversity added to the repertoire of both populations. A striking feature of V-J joining, as illustrated by this study, was the restriction of combinations based on the J gene location within the Tcra locus. The Tcra-V2 gene of dominant expression in the newborn (B10.BR.6) rearranged exclusively with the 30 most 5' Tcra-J genes. The Tcra-V2 gene of dominant expression at the adult stage (B10.BR.1) rearranged exclusively with the 21 most 3' Tcra-J genes in the locus. Thus, V-J combinatorial diversity was restricted in both newborn and adult mice, yielding a trend from 5'-3' Tcra-J gene usage with age. Inherent restrictions in V-J combinations should now be considered with regard to antigen responsiveness, particularly in the young animal. Qualitative restrictions in Tcr repertoire, compounding low T-cell numbers in peripheral tissues, may well contribute to functional voids and immunodeficiencies in early life.
Age Factors↗
Reconstitution of the T cell receptor alpha beta repertoire in recipients of allogeneic BMT.
This report describes the qualitative analysis of T cell receptor (TCR) repertoire regeneration in recipients of BMT. RNA samples from patient and control peripheral blood lymphocytes were prepared and tested for the presence of multiple V alpha and V beta transcripts by the polymerase chain reaction. TCR V gene expression was highly diverse within the first 6 months post-transplantation in recipients receiving either T cell-depleted or T cell-replete marrow, and in HLA mismatched as well as matched donor-recipient pairs. The sequencing of TCR message from BMT recipients also demonstrated J gene diversity and apparently normal junctional diversity at the V-J alpha join. Thus, T cell pools in BMT recipients are largely heterogeneous, not mono- or oligoclonal.
Adolescent↗
Sudden cardiac death in patients with chronic coronary heart disease.
Sudden cardiac death (SCD) is responsible for 300,000-400,000 deaths per year with a recurrence rate of up to 40% in survivors within the first 2 years. SCD often occurs in patients with chronic coronary artery disease, which is manifested by myocardial infarction and left ventricular dysfunction but is infrequently associated with acute infarction. SCD may be the initial symptom of coronary artery disease. Primary or rapid ventricular tachycardia are the most common arrhythmic causes of SCD. Endocardial mapping studies during electrophysiological study have shown areas of slowed conduction with abnormal endocardial electrograms in SCD patients with moderately damaged ventricles. SCD increases with age and occurs more frequently in men with coronary artery disease as a significant risk factor. Complex ventricular ectopy, once thought of as an independent risk factor, is not as good a predictor as poor left ventricular function for recurrence of SCD. While signal-averaged electrocardiograms can identify patients with slowed conduction, their positive predictive value for SCD is poor. Initial evaluation should be aimed at the identification of ischemia, since those patients with SCD and acute myocardial infarction do well when treated for their ischemia. The arrhythmias that are inducible during electrophysiological study are rapid and poorly tolerated. Patients with inducible ventricular tachycardia who are rendered noninducible pharmacologically have a good prognosis, whereas those who are still inducible or have no inducible arrhythmias have a high recurrence rate of SCD and should be considered for subendocardial resection when appropriate or for placement of an implantable defibrillator.
Arrhythmias, Cardiac↗
Developmental T cell receptor gene rearrangements: relatedness of the alpha/beta and gamma/delta T cell precursor.
To examine the relationships between T cell populations at various stages of development, T cell receptor (TcR) gene rearrangements were compared between the four murine populations of (a) early thymocytes, (b) early splenocytes, (c) adult thymocytes and (d) adult splenocytes. TcR alpha gene rearrangements were shown to progress from 5' to 3' regions of the J alpha locus and from 3' to 5' regions of the V alpha locus during the development of T cells in both the thymus and spleen. Thus, the gene rearrangement potentials of proximal genes varied with age, yielding a biased repertoire in the young vs. adult animal. As evidence that gamma/delta and alpha/beta gene rearrangements appeared concomitantly in individual precursors, it was found that: (a) multiple adult thymocytes bore alpha gene rearrangements on one chromosome and delta gene rearrangements on the homologous chromosome, and (b) V gamma 3-J gamma 1 rearrangements, prominent joins in the early gamma/delta T cell population, were also prominent in the early alpha/beta T cell subset. These data illustrate the non-random nature of the developmental TcR gene rearrangement and suggest that alpha/beta and gamma/delta T cell populations derive from related, if not identical, T cell precursor populations.
Animals↗
Environmental and allele-specific influences on T cell receptor gene rearrangement: skewed alpha, delta, and gamma gene rearrangement patterns in chimeric mice.
This study was performed as a means to examine the effects of environment and stem cell origin on the molding of T cell receptor gene rearrangements during T cell development. Lethally irradiated adult mice were first reconstituted with (C57BL/6 x DBA/2)F1 stem cells, which derived either from a fetal liver or adult bone marrow source. The gene rearrangements in the irradiated thymi were then compared to those in normal fetal or adult thymi by hybridoma analysis. Results showed a general absence of gene rearrangements typical of the normal fetal thymus in both sets of chimeras. alpha and gamma gene rearrangements in chimeric mice matched normal adult patterns. However, chimeric thymocytes were unique in an unusually low frequency of rearrangements at the delta locus. The use of the bone marrow vs. fetal liver as stem cell sources in chimeric mice did not affect the patterns, indicating that environmental factors played a major role in the molding of gene rearrangement at multiple T cell receptor loci. Interestingly, the chromosomal sequence added an additional influence as homologous chromosomes showed allele-specific rearrangement patterns. We now question whether the unique patterns of rearrangement in irradiated adult thymi may substantially affect developing T cell populations in chimeric animals, particularly with regard to the gamma/delta T cell subset. Further analyses are warranted, both in experimental and clinical settings, regarding ultimate potentials for T cell diversity and function in transplantation recipients.
Alleles↗
A source of bias in the analysis of single channel data: assessing the apparent interaction between channel proteins.
A recent study of single sodium channel currents in neuroblastoma cells suggested interaction between ion channels in close proximity to one another (T. Kiss and K. Nagy, Eur. Biophys. J. 12, 13, 1985). The opening of one channel appeared to affect the likelihood that neighboring channels might open. Some of the conclusions were based on the analysis of observed channel openings that were segregated depending on whether one channel or more than one channel was open at the same time. We hypothesized that the longer one channel remained open, the more likely another channel operating independently, would open, thereby creating the impression of an apparent coupling of channel behavior. We performed simulations and measurements of single sodium channel currents to determine whether the technique of event segregation could account for apparent channel interactions. The simulations showed that the segregation of overlapping (more than one channel open at the same time) and nonoverlapping events led to a bias in the estimated open time and the derived closing rate. To avoid the bias, we found that random pairing of opening and closing events provided an unbiased estimate of the mean closing rate. Using this random assignment approach, we showed that the mean closing rate of single sodium channels in neonatal rat myocytes decreased with depolarization over a limited range of membrane potential. This suggested that the underlying closure mechanism(s) was voltage dependent. From the analysis of open times, we found no evidence for channel interaction in the time scale of tens of milliseconds. Depolarizing steps without events occurred in runs suggesting the existence of long-lived shut state(s). Double pulse experiments with the prepulse and test pulse above threshold showed significant inactivation of channels that did not open. The rate of inactivation of shut channels was substantially slower than the closure rate of open channels. The rate of inactivation of cardiac sodium channels appeared to be strongly dependent on the initial channel state.
Animals↗
Syncope secondary to paroxysmal high grade AV block in a heavily trained man.
J.B. is a well-trained male with syncope due to paroxysmal AV nodal heart block who ultimately required a permanent pacemaker despite an initial attempt at cessation of training only. Baseline sinus node function was normal, but AV nodal conduction remained abnormal even after autonomic blockade supporting intrinsic AV nodal dysfunction. This case illustrates that vigorous physical training may unmask previously unrecognized intrinsic dysfunction of AV nodal conduction or, as previously reported for physical training induced sinus node dysfunction, cause AV nodal dysfunction. Simple cessation of training to treat this problem is often recommended but may not be adequate for some patients who remain at risk for recurrent syncope during the deconditioning period.
Autonomic Nervous System↗
First T cell receptor alpha gene rearrangements during T cell ontogeny skew to the 5' region of the J alpha locus.
Fetal, neonatal, and early postnatal thymi were assessed for TCR J alpha gene rearrangements. Gene probes spanning the distance from 5' to 3' regions of the J alpha locus were used to determine the approximate location of gene rearrangements within hybridomas representing each of the early thymocyte populations. The predominant location of rearrangements was within the 5' region of the J alpha locus. Among the several cells in which rearrangements were found on only one chromosome, the one rearrangements was always in the 5' region. When two rearrangements were found, the rearrangements on homologous chromosomes were usually in the same region. The overall pattern among thymocytes was in great contrast to that previously observed among hybridomas derived from stimulated adult spleen cells within which rearrangements fell mostly to the 3' side of the alpha-locus. Results reveal the nonrandom nature of the TCR-alpha gene rearrangement event and may reflect an incidence of multiple V-J alpha joining events on each chromosome during T cell development in vivo. Due to the fact that most mature cells bear two J alpha joins, the allelic exclusion of alpha-chains cannot be explained by a mechanism whereby a functional rearrangement on one chromosome inhibits subsequent rearrangement on the second. Instead allelic exclusion may rely on a low frequency of productive vs nonproductive rearrangement events and an incompatibility between multiple alpha- and beta-protein pairs.
Animals↗
Nonrandom rearrangement of T cell receptor J alpha genes in bone marrow T cell differentiation cultures.
TCR J alpha genes span a distance of approximately 65 kb on mouse chromosome 14. Due to the existence of 50 to 100 discrete J genes, a potential for great diversity exists within the V-J-C alpha gene products and within the ultimate repertoire of alpha beta TCR. We have prepared hybridomas from an in vitro system that supports T cell differentiation among bone marrow cells. We have examined the J alpha genes among these cells and categorized rearrangements according to their location within the J alpha locus. It was found that alpha rearrangements were always present among the hybridomas bearing beta gene rearrangements. When two bone marrow-derived alpha-bearing chromosomes could be demonstrated in these hybridomas, both were always rearranged and rearrangements on homologous chromosomes were shown to reside in similar regions of the J alpha locus. Most surprisingly, when hybridomas were categorized by the culture from which they derived, cells from the same culture (designated as a set) demonstrated a skewing of alpha rearrangements to restricted segments of J alpha genes. In one hybridoma, rearrangements on homologous chromosomes involved J alpha genes that were either identical or situated within a 1-kb segment of DNA. The skewing within sets could not be due to clonal identity between hybridomas as the beta and gamma rearrangements in all hybridomas were different. Results suggested that skewing of J alpha gene rearrangements occurred during the course of T cell development in vitro. Should the same situation occur in vivo, the number of distinct TCR J alpha sequences available for expression in early development may be far less than that predicted by gene number alone.
Animals↗
AV blockade via selective AV nodal artery injection in a patient.
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Adult↗