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Biomedical subjects

T Larson

Publications and source records attributed to T Larson.

At least 37 records · Page 2Linked to original sources
PubMed1995

The Hox11 gene is essential for cell survival during spleen development.

The HOX11 homeobox gene was identified via the translocation t(10;14) in T cell leukaemia. To determine the function of this gene in mice, null mutations were made using homologous recombination in ES cells to incorporate lacZ into the hox11 transcription unit. Production of beta-galactosidase from the recombinant hox11 allele in +/- mutants allowed identification of sites of hox11 expression which included the developing spleen. Newborn hox11 -/- mice exhibit asplenia. Spleen formation commences normally at E11.5 in hox11 -/- mutant embryos but the spleen anlage undergoes rapid and complete resorption between E12.5 and E13.5. Dying spleen cells exhibit molecular features of apoptosis, suggesting that programmed cell death is initiated at this stage of organ development in the absence of hox11 protein. Thus hox11 is not required to initiate spleen development but is essential for the survival of splenic precursors during organogenesis. This function for hox11 suggests that enhanced cell survival may result from the t(10;14) which activates HOX11 in T cell leukaemias, further strengthening the association between oncogene-induced cell survival and tumorigenesis.

Animals↗
PubMed1995

Managing the child infected with HIV.

Care of the HIV-infected/exposed infant and child is both routine and challenging. Routine well child care and immunizations are an important part of maintaining and monitoring health status. Challenges arise in the management of acute illnesses and the numerous crises that are experienced by the family caring for that child. Therapy guidelines now provide a logical way in which to initiate antiretroviral treatment and PCP prophylaxis. In HIV-infected children with early disease, common pathogens initially predominate, and only in advanced immune suppression does care become complicated enough to require expert consultation. With increasing numbers of HIV-infected women, perinatally acquired infections in infants will become more common. Early testing and identification will increasingly be important as a way to impact on the significant morbidity and mortality seen in infants less than 6 months old. A caring, compassionate, and comprehensive approach to the care of HIV-infected infants and children results in increased survival and lengthening of disease-free time. Providing this vitally needed care is both satisfying and stimulating.

AIDS-Related Opportunistic Infections↗
PubMed1994

Antibodies generated from human immunoglobulin miniloci in transgenic mice.

One approach to the production of human monoclonal antibodies focusses on the creation of transgenic mice bearing human immunoglobulin gene miniloci. Whilst such loci undergo lymphoid-specific gene rearrangement, only a small proportion of mouse B cells express the human immunoglobulin chains; the miniloci thus contribute poorly to serum immunoglobulin. Attributing this poor performance to competition between the transgenic and endogenous immunoglobulin loci, we crossed mice bearing a human immunoglobulin heavy-chain (HulgH) minilocus with animals that had been rendered B cell-deficient by disruption of their endogenous heavy-chain locus. The results were dramatic: the human minilocus rescued B cell differentiation such that effectively all B cells now expressed human mu chains. The concentration of antibody in the mouse serum recognised by anti-human mu increased to a concentration about one sixth that in human serum. The HulgH antibodies are heterogenous with diversity being generated by both combinatorial and junctional processes. Following antigen challenge, specific antibody is elicited but at low titre.

Amino Acid Sequence↗
PubMed1994

Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region.

Following encounter with antigen, the immunoglobulin genes in B lymphocytes undergo somatic hypermutation. Most nucleotide substitutions are introduced into a region flanked by the V gene promoter and intron enhancer. Experiments described here using transgenic mice revealed that the V kappa promoter does not contain specific signals since hypermutation was retained on substituting it by a beta-globin promoter. However, both the kappa intron and kappa 3' enhancer regions were found to be essential for full hypermutation. This dependence of hypermutation on both enhancers contrasts with transgene expression in hybridomas in which only the 3' enhancer (and not the intron enhancer) is necessary to achieve high mRNA levels. The results show that full hypermutation depends on multiple elements, removal of some of which may drastically impair but not totally abolish the process.

Amino Acid Sequence↗
PubMed1994

The CD45 tyrosine phosphatase regulates specific pools of antigen receptor-associated p59fyn and CD4-associated p56lck tyrosine in human T-cells.

A newly isolated T-cell line (CB1) derived from a T-acute lymphoblastic leukaemia (T-ALL) patient contained cells (40% of total) which did not express the CD45 phosphotyrosine phosphatase. The cells were sorted into CD45- and CD45+ populations and shown to be clonal in origin. T-cell receptor (TCR) cross-linking or coligation of the TCR with its CD4/CD8 co-receptors induced tyrosine phosphorylation and calcium signals in CD45+ but not in CD45- cells. Unexpectedly, whole cell p56lck and p59fyn tyrosine kinase activities were not reduced in CD45- compared to CD45+ cells. A novel technique was therefore developed to isolated specific pools of aggregated receptors expressed at the cell surface, together with their associated tyrosine kinases. Using this technique it was shown that cell surface CD4-p56lck kinase activity was 78% lower in CD45- than in CD45+ cells. Phosphorylation of TCR zeta- and gamma-chains occurred in TCR immunocomplexes from CD45+ but not CD45- cells, despite comparable levels of p59fyn and TCR proteins. Furthermore, TCR-associated tyrosine kinase activity towards an exogenous substrate was 84% lower in CD45- than in CD45+ cells. Addition of recombinant p59fyn to TCR immunocomplexes isolated from CD45-cells restored the phosphorylation of the TCR zeta- and gamma-chains. Our results demonstrate that CD45 selectively regulates the pools of p59fyn and p56lck kinases which are associated with the TCR and CD4 at the cell surface. Activation by CD45 of these receptor-associated kinase pools correlates with the ability of the TCR and its coreceptors to couple to intracellular signalling pathways.

CD4 Antigens↗
PubMed1993

Human, rodent, and canine pancreatic beta-cells express a sodium channel alpha 1-subunit related to a fetal brain isoform.

Voltage-dependent, tetrodotoxin-sensitive Na+ currents have been identified by the patch-clamp technique in rodent, canine, and human pancreatic beta-cells, but their exact role in insulin secretion remains uncertain. Misler et al. (Diabetes 41:1221-28, 1992) recently reviewed data showing that human and rat beta-cell action potentials differ, in that trains of Na(+)-dependent action potentials are seen in human (and canine) cells, but the vast majority of rat beta-cell Na+ channels are inactivated. We have now identified Na+ channel alpha 1-subunit mRNAs expressed in normal adult human, canine, and rat islets, and two insulinoma cell lines, by mRNA amplification (reverse transcription followed by polymerase chain reaction). cDNA sequencing showed that all amplified human islet products and the majority of rodent islet cDNAs are most closely related to the rat brain III alpha 1-subunit isoform, previously found to be expressed primarily in fetal rat brain. Canine islets expressed both brain II and brain III isoforms. Reverse transcription followed by polymerase chain reaction experiments with hamster and mouse insulinoma cell lines also showed expression of the message related to the rat brain III isoform. In situ hybridization of human pancreas sections using a partial human Na+ channel III cDNA probe showed the message to be expressed in the majority of islet cells, and not in the acinar tissue, confirming its presence in pancreatic beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

T-cell acute lymphoblastic lymphoma induced in transgenic mice by the RBTN1 and RBTN2 LIM-domain genes.

Two members of the RBTN gene family, RBTN1/Ttg-1 and RBTN2/Ttg-2, were found by their association with T-cell tumour-specific chromosomal translocations and are thought to be involved in the aetiology of such T-cell tumours. Here a transgenic mouse model is described in which T-cell tumours are induced by the presence of RBTN1 and RBTN2 transgenes that direct expression in thymus-derived cells. The latency period for lymphoid tumour appearance is variable, and tumours occur in a small proportion of transgenic animals that develop T-cell acute lymphoblastic malignancies. No significant increase in the rate of tumour development was observed in RBTN1 transgenic mice infected with Moloney murine leukaemia virus, nor did tumours arise in mice bearing a construct in which RBTN1 was expressed from the insulin transcriptional promoter. These data, which provide formal proof of the oncogenic activity of these genes, suggest that aberrant expression of transcription factor genes, such as RBTN1 and RBTN2, functions in tumour aetiology by disturbing some aspect of T-cell differentiation.

Animals↗
PubMed1988

Effects of intrarenal adenosine on renal function and medullary blood flow in the rat.

Adenosine is a potent vasodilator of the systemic circulation. Infusion of adenosine into the aorta causes water and sodium retention and a fall in glomerular filtration rate and renal blood flow. The effect of adenosine on medullary blood flow is unknown. Because systemic vasodilatory effects may confound its renal actions, adenosine was infused into the renal artery of anesthetized Munich-Wistar rats at doses of 2, 6, and 15 micrograms/min. A marked dose-dependent increase in urinary flow and sodium excretion was observed. Inulin and p-aminohippuric acid clearance did not change significantly. Blood flow in vasa recta in the exposed renal papilla, as determined by fluorescence videomicroscopy, increased significantly only with the highest dose of adenosine. In control animals infused with the vehicle only, there was no change in any of the above variables. These results indicate that direct intrarenal infusion of adenosine in the rat increases urinary flow and sodium excretion and at higher doses also increases vasa recta blood flow. The effects on urinary flow and sodium excretion were therefore mediated by a mechanism other than an increase in vasa recta blood flow.

Adenosine↗
PubMed1987

Posterior pituitary gland: appearance on MR images in normal and pathologic states.

T1-weighted magnetic resonance (MR) images of the pituitary gland and sella turcica routinely demonstrate a region of high signal intensity in the neurohypophysis. High-resolution MR imaging studies of the sella turcica in 200 subjects with a normal or abnormal sella were analyzed. The hyperintensity was found in the images of about 90% of healthy subjects and patients with microadenoma, in only 43% of patients with macroadenoma, and in 12% of patients with empty sellae. The signal was absent in several patients with functional or anatomic abnormalities of the hypothalamic-hypophyseal axis. It is concluded that the high signal intensity in the posterior lobe of the pituitary gland is present in most healthy individuals and that its absence in many patients with large intrasellar masses and empty sellae is due to compression of posterior lobe tissue. Its absence in diabetes insipidus further suggests a relationship between hyperintensity and the functional status of the hypothalamic-hypophyseal axis.

Adenoma↗
PubMed1987

Effect of V2-receptor-mediated changes on inner medullary blood flow induced by AVP.

We have previously shown that arginine vasopressin (AVP) in physiological amounts reduces inner medullary blood flow and that the mechanism of this decrease is at least in part mediated by the vasopressor (V1-receptor) action of AVP. To determine whether the antidiuretic action of AVP (V2-receptor) also contributes to the reduction in inner medullary blood flow, we determined capillary blood flow (QVR) in individual descending vasa recta (DVR) and ascending vasa recta (AVR) using fluorescence videomicroscopy in the exposed renal papilla of the anesthetized rat. Three groups of chronically water-diuretic rats were studied in three consecutive periods: control (period 1), experimental (period 2), and recovery (period 3). Group I rats (designated the AVP group) received AVP, 45 ng X h-1 X kg body wt-1; group II (AVP + V2-inhibitor), AVP plus its specific antidiuretic antagonist d(CH2)5[D-Ile2,Thr4]AVP; and group III (V2-inhibitor), the antagonist alone, respectively, in the experimental period 2. Only group I rats concentrated their urine, urine osmolality (Uosmol) = 499 +/- 48 mosmol/kgH2O, whereas urine remained hypotonic throughout in groups II and III. In group I, QVR in DVR and AVR decreased in period 2; but in groups II and III, QVR tended to increase. These results suggest that the AVP-induced decrease in papillary vasa recta blood flow is in part mediated by its antidiuretic V2-receptor as well as by its vasopressor (V1-receptor). They also suggest that the rate of urinary flow in the medullary collecting ducts is a determinant of inner medullary blood flow.

Aminohippuric Acids↗
PubMed1986

Pharmacodynamics and side effects of flecainide acetate.

We compared side effects with flecainide trough levels and ECG intervals among 43 patients who received flecainide for up to 34 months. Flecainide plasma levels were higher when associated with cardiovascular side effects (mean 1063 ng/ml; range 296 to 2050 ng/ml) than when no side effects occurred (mean 609 ng/ml; range 89 to 1508 ng/ml; P less than 0.001). The PR interval (P less than 0.001), QRS interval (P less than 0.001), and the rate-corrected QT interval (P less than 0.001) were greater at the time of cardiovascular side effects, but the rate-corrected JT interval was not. The therapeutic-toxic window for flecainide plasma level was 381 ng/ml (at least 50% probability of efficacy) to 710 ng/ml (less than 10% probability of cardiovascular side effects). The risk of cardiovascular side effects increases at higher plasma levels of flecainide and is associated with greater increases in the PR and QRS intervals from baseline than are routinely observed during flecainide dosing.

Aged↗