Search PubMed⌕ Search

Biomedical subjects

R A Phillips

Publications and source records attributed to R A Phillips.

At least 127 records · Page 7Linked to original sources
PubMed1989

A model of human acute lymphoblastic leukemia in immune-deficient SCID mice.

A human acute lymphoblastic leukemia (ALL) cell line that was transplanted into immune-deficient SCID mice proliferated in the hematopoietic tissues, invaded various organs, and led to the death of the mice. The distribution of leukemic cells in SCID mice was similar to the course of the disease in children. A-1 cells marked with a retrovirus vector showed clonal evolution after the transplant. SCID mice that were injected with bone marrow from three patients with non-T ALL had leukemic cells in their bone marrow and spleen. This in vivo model of human leukemia is an approach to understanding leukemic growth and progression and is a novel system for testing new treatment strategies.

Animals↗
PubMed1989

Noninvasive ambulatory blood pressure monitoring in patients with recently detected systemic hypertension.

Noninvasive ambulatory blood pressure monitoring and Doppler echocardiography were used in a recent study evaluating persons aged 18 to 50 years who were initially found to have mild hypertension by casual blood pressure determination. Ambulatory blood pressure recordings were performed on a day of usual activity in 54 subjects; a subgroup of 24 patients had evaluation of left ventricular dimensions and diastolic filling patterns by Doppler echocardiography. Average ambulatory systolic pressures of 42% of subjects were greater than or equal to 130 mm Hg. Only 35% had average diastolic pressures greater than or equal to 85 mm Hg, and 57% had either systolic or diastolic pressures greater than or equal to 130/85 mm Hg. Correlation between casual and ambulatory pressures was not significant. No subject had left ventricular hypertrophy determined by echocardiography. Abnormal left ventricular diastolic filling was noted in 38% of those patients with average ambulatory pressures greater than or equal to 130/85 mm Hg, but in no patients with average pressures less than 130/85 mm Hg (p less than 0.05). These results suggest that ambulatory blood pressure monitoring may be a specific method for detecting those patients with mild hypertension who may have early and potentially reversible cardiac abnormalities.

Adult↗
PubMed1989

Preferential germline mutation of the paternal allele in retinoblastoma.

The event triggering malignant proliferation in 70% of retinoblastoma tumours is loss of heterozygosity for chromosome 13q14, whereby the normal retinoblastoma gene (RB1) allele is lost and an already mutated RB1 allele remains in the tumour. The first allele suffers a mutational event--deletion, duplication or point mutation (manuscript in preparation)--either in the germ line (all bilateral patients) or in a somatic retinal cell (most unilateral patients). Most bilateral patients have no family history of retinoblastoma and are presumed to have new germline mutations which arose in the egg, sperm or early embryo. We have determined the parental origin of the retained allele in nine retinoblastoma tumours from eight unrelated non-familial cases by using RB1-linked genetic markers. Six tumours retained the paternal allele and three retained the maternal allele. Of the three unilateral tumours, only one retained the paternal RB1 allele. Thus, there is no evidence that the paternal RB1 allele is preferentially retained in retinoblastoma, as has been suggested to be the case in osteosarcoma. By contrast, tumours from four of the five bilateral patients retained the paternal RB1 allele. This suggests either that new germline RB1 mutations arise more frequently during spermatogenesis than during oogenesis, or that imprinting in the early embryo affects chromosomal susceptibility to mutation.

Alleles↗
PubMed1989

Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome.

The results of this controlled study of the treatment of 57 patients with Gilles de la Tourette's syndrome suggested that both haloperidol and pimozide were more effective than placebo, but that haloperidol was slightly more effective than pimozide. Adverse effects occurred more frequently with haloperidol vs placebo than with pimozide vs placebo, but the frequency was not significantly different for haloperidol compared with pimozide. Clinically significant cardiac effects did not occur at a maximum dosage of 0.3 mg/kg or 20 mg/d for pimozide and 10 mg/d for haloperidol. However, the QTc interval was prolonged during pimozide treatment compared with that during haloperidol treatment, although the values for both medications were not in an abnormal range.

Adolescent↗
PubMed1989

Isolation of scid pre-B cells that rearrange kappa light chain genes: formation of normal signal and abnormal coding joins.

Consistent with an ordered immunoglobulin (Ig) gene assembly process during precursor (pre-) B cell differentiation, we find that most Abelson murine leukemia virus (A-MuLV)-transformed pre-B cells derived from scid (severe combined immune deficient) mice actively form aberrant rearrangements of their Ig heavy chain locus but do not rearrange endogenous kappa light chain variable region gene segments. However, we have identified several scid A-MuLV transformants that transcribe the germline Ig kappa light chain constant region and actively rearrange the kappa variable region gene locus. In one case progression to the stage of kappa light chain gene rearrangement did not require expression of Ig mu heavy chains; furthermore, this progression could not be efficiently induced following expression of mu heavy chains from an introduced vector. As observed in pre-B cell lines from normal mice, attempted V kappa-to-J kappa rearrangements in scid transformants occur by inversion at least as frequently as by deletion. The inverted rearrangements result in retention of both products of the recombination event in the chromosome, thus allowing their examination. scid kappa coding sequence joins are aberrant and analogous in structure to previously described scid heavy chain coding joins. In contrast, the recognition signals that flank involved coding segments frequently are joined precisely back-to-back in normal fashion. The scid VDJ recombinase defect therefore does not significantly impair recognition of, site-specific cutting at, or juxtaposition and appropriate ligation of signal sequences. Our finding that the scid defect prevents formation of correct coding but not signal joins distinguishes these events mechanistically.

Abelson murine leukemia virus↗
PubMed1989

The effect of the scid mutation on mechanism and control of immunoglobulin heavy and light chain gene rearrangement.

Most Abelson murine leukemia virus (A-MuLV)-transformed cell lines derived from scid (severe combined immune deficient) mice actively rearrange their endogenous immunoglobulin (Ig) heavy (H), but not light (L) chain variable region genes. Such cell lines express germline VH segments and other RNA transcripts that are characteristically produced by early precursor (pre)-B lymphocytes, but do not express high levels of transcripts from the germline kappa (k) constant region (C kappa) locus. However, we have derived scid A-MuLV transformants that express germline C kappa transcripts and attempt kappa gene assembly. In one case kappa gene expression and rearrangement occurred in the absence of mu H chain expression, and in another was not induced efficiently by introduction of a mu-expression vector. Although the vast majority of scid H and L chain coding sequence joins are grossly aberrant, scid A-MuLV transformants can form normal coding joints at a very low frequency. In contrast, these cells form generally normal signal sequence joins at an approximately normal efficiency. Thus, these findings mechanistically distinguish coding and signal join formation. Subcloning analyses suggest that scid A-MuLV transformants that do not attempt chromosomal coding sequence joining may have a relative survival advantage, and therefore that these events may often result in unrepaired chromosomal breakage and cell death.

Animals↗
PubMed1989

The scid mouse as a model to identify and quantify myeloid and lymphoid stem cells.

Scid mice are excellent recipients for studying the characteristics of stem cells. Sublethal irradiation not only enhances engraftment of stem cells but enables one to graft limiting numbers of cells without compromising the survival of the recipient. This enables one to estimate the frequency of stem cells by limiting dilution analysis. Compared to fresh bone marrow, LTBMC are slightly enriched for stem cells capable of reconstituting lymphoid function in scid recipients. The stem cells have self-renewal ability since bone marrow from cured primary scid recipients can cure secondary recipients. Our results indicate that lymphoid reconstitution following engraftment with LTBMC occurs from a lymphoid-restricted stem cell; similar restricted stem cells also exist in normal bone marrow.

Animals↗
PubMed1989

Determinants of abnormal left ventricular filling in early hypertension.

Thirty-seven untreated subjects with borderline or mild hypertension were studied to establish the prevalence and clinical characteristics associated with abnormal left ventricular filling in this disorder. Subjects were referred to this study because of casual office blood pressure measurements of greater than or equal to 140/90 mm Hg; all were less than 50 years old, had no other cardiovascular or systemic disease and had not received antihypertensive medication for at least 1 year. To precisely determine blood pressure, measurements were made over 30 min with the patient in the supine position and during awake hours with ambulatory monitoring. Left ventricular mass was determined echocardiographically, and Doppler echocardiography was used to assess left ventricular filling. No subject had increased left ventricular mass, but 8 (22%) of the 37 had abnormal left ventricular filling. All eight subjects with abnormal left ventricular filling had an ambulatory systolic blood pressure greater than 130 mm Hg and a supine systolic blood pressure greater than 122 mm Hg. Abnormal filling was not related to left ventricular mass or heart rate. In multivariate analysis, the degree of abnormal filling could best be predicted from a combination of age and supine systolic blood pressure (r = 0.69; p less than 0.001). This study suggests that in untreated early essential hypertension, abnormal left ventricular filling is present in greater than 20% of subjects, precedes detectable left ventricular hypertrophy and is related to age and prevailing level of blood pressure.

Adult↗
PubMed1989

Cardiac and hemodynamic adjustments to rapid and sustained blood pressure reduction.

The most effective strategies for achieving immediate and long-term control of blood pressure and reversal of left ventricular (LV) hypertrophy and dysfunction in severe hypertensives is not known. In this preliminary communication, we report our experience with long-term blood pressure control in severe hypertensives who were treated with up to 150 mg of nifedipine gastrointestinal therapeutic system (GITS)--a once daily nifedipine formulation. In 23 subjects with diastolic blood pressures greater than 120 mm Hg, treatment was begun with nifedipine capsules for immediate reduction of diastolic blood pressure to less than 110 mm Hg. Doppler echocardiography was used to measure LV mass, percent LV fractional shortening (%FS), and cardiac output (CO). To achieve a goal diastolic blood pressure of less than 95 mm Hg, the 22 subjects who responded to nifedipine capsules were titrated up to 150 mg of nifedipine GITS. To date, 12 subjects completed two months of goal blood pressure with nifedipine GITS. CO, heart rate (HR), and %FS were elevated following nifedipine capsules. During long-term therapy with nifedipine GITS, CO and HR returned to baseline, while %FS remained elevated. These preliminary data suggest that in patients with severe hypertension, effective long-term control of BP with a once-a-day dosage of nifedipine in the GITS formulation may be achieved without adverse hemodynamic effects.

Blood Pressure↗
PubMed1989

Mutations in the RB1 gene and their effects on transcription.

Inactivation of both alleles of the RB1 gene during normal retinal development initiates the formation of a retinoblastoma (RB) tumor. To identify the mutations which inactivate RB1, 21 RB tumors isolated from 19 patients were analyzed with the polymerase chain reaction or an RNase protection assay or both. Mutations were identified in 13 of 21 RB tumors; in 8 tumors, the precise errors in nucleotide sequence were characterized. Each of four germ line mutations involved a small deletion or duplication, while three somatic mutations were point mutations leading to splice alterations and loss of an exon from the mature RB1 mRNA. We were unable to detect expression of the mutant allele in lymphoblasts of three bilaterally affected patients, although the mutation was present in the genomic DNA and transcripts containing the mutations were obvious in the RB tumors in the absence of a normal RB1 allele. The variations in the level of expression of mutant transcripts suggest deregulation of RB1 transcription in the absence of a functional RB1 gene product.

Alleles↗
PubMed1989

Use of scid mice to identify and quantitate lymphoid-restricted stem cells in long-term bone marrow cultures.

Mice homozygous for an autosomal recessive scid (severe combined immune deficiency) mutation on chromosome 16 exhibit a defect that specifically impairs lymphoid differentiation but not myelopoiesis. Consequently such mice are deficient in both humoral and cell-mediated immune functions. Despite their defect, scid mice survive under pathogen-free conditions and are fertile. The mutation does not impair the hematopoietic microenvironment necessary for lymphoid differentiation, since these mice can be cured with grafts of normal bone marrow (BM) or cells from long-term BM cultures (LTBMC); however, reconstitution requires sublethal (400 cGy) irradiation of recipients. Engraftment with cells from LTBMC gave near-normal levels of colony-forming B cells (CFU-B) in spleen and BM of the recipients by 6 weeks postgrafting. Since LTBMC are devoid of all mature B and pre-B cells but contain stem cells that restore lymphoid function in scid mice, we used a limiting-dilution assay to characterize and enumerate the number of stem cells in LTBMC capable of restoring lymphoid function. Curing was determined by the CFU-B-cell assay, since CFU-B are not detectable in normal scid mice. The results indicate that fewer cells from LTBMC than from fresh BM are required to obtain lymphoid reconstitution. As few as 10(3) LTBMC cells can repopulate significant B- and T-cell function in scid recipients. From these results we conclude that scid mice can be used as recipients to quantify lymphoid-restricted stem cells and that there is a functional separation of lymphoid- and myeloid-restricted stem cells in LTBMC with an enrichment for lymphoid-restricted stem cells in these cultures.

Animals↗
PubMed1989

Value of blood-pool subtraction in cardiac indium-111-labeled platelet imaging.

Blood-pool subtraction has been proposed to enhance 111In-labeled platelet imaging of intracardiac thrombi. We tested the accuracy of labeled platelet imaging, with and without blood-pool subtraction, in ten subjects with cardiac thrombi of varying age, eight with endocarditis being treated with antimicrobial therapy and ten normal controls. Imaging was performed early after labeled platelet injection (24 hr or less) and late (48 hr or more). Blood-pool subtraction was carried out. All images were graded subjectively by four experienced, "blinded" readers. Detection accuracy was measured by the sensitivity at three fixed levels of specificity estimated from receiver operator characteristic curve analysis and tested by three-way analysis of variance. Detection accuracy was generally improved on delayed images. Blood-pool subtraction did not improve accuracy. Although blood-pool subtraction increased detection sensitivity, this was offset by decreased specificity. For this population studied, blood-pool subtraction did not improve subjective detection of abnormal platelet deposition by 111In platelet imaging.

Adult↗
PubMed1989

Murine lymphocytes with natural killer activity express CTL-derived serine protease genes.

Serine protease genes (C11, B10 and HF) derived from activated cytolytic T lymphocytes have been shown to be important in CTL-mediated cytotoxicity. In this study, we examined the expression of these genes in fresh natural killer (NK) cells from severe combined immunodeficiency (SCID) and athymic nude mice, as well as in T-cell lines with NK activity. All of these serine protease genes were expressed in NK cells freshly isolated from SCID and athymic nude mice. In addition, all lines showed similar strong levels of expression of C11 and B10 genes, but not the HF gene. However, levels of expression in the T-cell lines did not correlate with levels of NK-like cytotoxicity. These results suggest that C11, B10 and HF serine protease genes are necessary but not sufficient for NK-like cytotoxicity.

Animals↗
PubMed1988

Identification of germline and somatic mutations affecting the retinoblastoma gene.

Retinoblastoma (RB) is a malignant tumor of developing retina that arises when abnormalities resulting in loss of function affect both alleles of the gene at the retinoblastoma locus (RB1) on chromosome 13q. The majority of RB tumors do not show gross alterations in a 4.7-kb fragment (4.7R), which is a candidate RB1 gene. To search for more subtle mutations, the ribonuclease protection method was used to analyze 4.7R messenger RNA from RB tumors. Five of 11 RB tumors, which exhibit normal 4.7R DNA and normal-sized RNA transcripts, showed abnormal ribonuclease cleavage patterns. Three of the five mutations affected the same region of the messenger RNA, consistent with an effect on splicing involving an as yet unidentified 5' exon. The high frequency of mutations in 4.7R supports the identification of 4.7R as the RB1 gene. However, the unusual nature of some of the abnormalities of 4.7 R alleles indicates that the accepted sequence of genetic events involved in the genesis of RB may require reevaluation.

Base Sequence↗
PubMed1988

Early B-cell precursors in scid mice: normal numbers of cells transformable with Abelson murine leukemia virus (A-MuLV).

scid mice lack detectable B and T lymphocytes; there are no typical pre-B cells as defined by c mu and surface markers in their bone marrow and their thymus contains only 1% of the normal number of cells. In these characters scid mice seem to lack lymphoid stem cells. However, some mice have detectable serum immunoglobulin and others develop thymomas; both observations indicate that the block in lymphoid development is not absolute. To determine whether scid mice have any B-cell precursors, we looked for pre-B cells by their ability to be transformed by Abelson murine leukemia virus (A-MuLV). Surprisingly, scid mice contain as many B-cell precursors transformable with A-MuLV as normal control mice. Cell-surface markers specific for pre-B and B cells were detected on the A-MuLV-transformed bone marrow cells of both scid and normal mice, indicating that the A-MuLV-transformed cells belong to the B lineage. Interestingly, the same surface markers were undetectable on nontransformed scid bone marrow cells. We conclude from these results that scid mice have normal numbers of early B-cell precursors but that their differentiation into functional B cells is severely impaired.

Abelson murine leukemia virus↗