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Biomedical subjects

R A Phillips

Publications and source records attributed to R A Phillips.

At least 109 records · Page 6Linked to original sources
PubMed1991

Bone marrow from children in relapse with pre-B acute lymphoblastic leukemia proliferates and disseminates rapidly in scid mice.

Bone marrow samples from patients with pre-B acute lymphoblastic leukemia (pre-B ALL), either at diagnosis or at relapse, were transplanted into scid mice to determine whether these freshly obtained leukemic cells could proliferate in vivo and whether there were any differences in their in vivo growth characteristics. Cells from three patients who relapsed within 13 months of diagnosis proliferated rapidly in the murine bone marrow, spleen, and thymus, invaded peripheral organs, and resulted in morbidity and mortality of the animals within 4 to 16 weeks. Cells from two patients who relapsed 3.5 years after diagnosis grew much slower than the early relapse samples, taking up to 30 weeks to infiltrate the bone marrow of recipient mice. In contrast, leukemic cells were absent or were detected at low numbers in scid mice transplanted with cells obtained at diagnosis from three patients who have not yet relapsed. These results show an increased ability of leukemic cells from patients with aggressive lymphoblastic leukemia of poor prognosis to proliferate in scid mice.

Adolescent↗
PubMed1991

Normalization of left ventricular mass and associated changes in neurohormones and atrial natriuretic peptide after 1 year of sustained nifedipine therapy for severe hypertension.

Sixteen patients with severe hypertension were treated for 1 year with extended release nifedipine, during which time serial changes in left ventricular mass index and associated alterations in left ventricular systolic function, left ventricular filling, plasma renin activity, atrial natriuretic peptide and catecholamines were evaluated. Mean seated blood pressure (+/- SE) was significantly reduced from 200 +/- 8/122 +/- 3 to 144 +/- 5/89 +/- 2 mm Hg (p less than 0.0001) at 1 year. After 6 months, left ventricular mass index was significantly reduced by 19% from 121 +/- 8 to 96 +/- 7 g/m2 and this reduction was sustained at 1 year. Septal and posterior wall thickness were reduced from 13.4 +/- 0.1 to 11.2 +/- 0.04 mm and from 12.8 +/- 0.1 to 10.0 +/- 0.03 mm (p less than 0.001), respectively. The prevalence of left ventricular hypertrophy decreased from 63% to 25%. Left ventricular fractional shortening increased from 34 +/- 2% to 41 +/- 3% (p less than 0.05) and the relation between fractional shortening and end-systolic stress did not change. Over the year of sustained blood pressure reduction, the peak velocity of early filling increased from 57 +/- 3 to 63 +/- 4 cm/s (p = 0.07), peak velocity of late filling did not change and the ratio of late to early peak left ventricular filling velocity significantly decreased (p less than 0.05). Plasma atrial natriuretic peptide levels, markedly elevated at entry, decreased from 70 +/- 15 to 41 +/- 8 pg/ml at 1 year (p less than 0.05). Plasma renin activity and catecholamine levels were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗
PubMed1991

The genetics of retinoblastoma. Relevance to the patient.

The understanding of the molecular biology of human cancer has advanced rapidly in the last decade, in part due to discoveries in the rare, pediatric ocular tumor, retinoblastoma. RB studies have led to recognition of a class of human genes, the tumor suppressor genes, that are critical in the initiation and progression of the malignant process. Mutations in the RB1 gene initiate RB and other specific tumors. They may also contribute to progressive stages of many other malignancies. The protein product of RB1 (p110RB1) is a basic regulator of the cell cycle. In the absence of normal protein, the cell proceeds to the next cell division without the potential to become quiescent. Understanding the genetics of RB has benefited the patients, as the precise identification of the RB1 mutations in families has led to accurate prediction of individuals at risk for RB tumors. It seems unlikely, in the foreseeable future, that direct genetic manipulation of mutant RB1 genes will play a role in therapy, but complete understanding of the function of p110RB1 may eventually allow exploitation of its powerful antiproliferative effect. Other molecular genetic events in addition to RB1 mutations are documented in RB tumors, and may play a critical role in the full malignant phenotype. The oncogene, N-myc, is amplified in some RB tumors and is expressed in normal fetal retina. The cytogenetic abnormality, i(6p), is almost unique to RB tumors. The molecular and tissue-specific roles of these abnormalities are not yet known. Many RB tumors also acquire excessive expression of the cell surface membrane glycoprotein, p170, linked to multidrug resistance, whether or not the RB tumor has been exposed to chemotherapy. We anticipate that ways to avoid or counteract the drug resistance of excessive p170 expression will be developed for other pediatric tumors and eventually will be applied to chemotherapy for RB patients.

Child↗
PubMed1991

Isolated T-wave abnormalities and evaluation of left ventricular wall motion after nifedipine for severe hypertension.

Rapid reduction of blood pressure by vasodilators in severe hypertensives has been associated with T-wave inversion. The significance of these changes in the absence of chest pain or other manifestations of ischemia is not known. To determine if these T-wave inversions are due to myocardial ischemia, we obtained electrocardiograms and left ventricular wall motion studies (2-D echocardiography) before and 1 h after rapid blood pressure reduction with nifedipine in 23 severe hypertensives. One hour after 10 mg nifedipine blood pressure was markedly reduced from 189 +/- 6/117 +/- 3 (mean +/- SE) to 151 +/- 5/91 +/- 3 mm Hg (P less than .001). New T-wave inversions developed in 6 of 23 (26%) subjects, but blinded evaluation of 2-D echocardiograms revealed no new wall motion abnormalities. Wall motion score, which at pretreatment was abnormal in 11 of 23 patients, improved significantly after nifedipine from 1.4 +/- 0.1 to 1.2 +/- 0.1 (P less than .05). Therefore, rapid and marked reduction of blood pressure with nifedipine is accompanied by a high incidence of asymptomatic T-wave inversions which are not accompanied by left ventricular wall motion abnormalities, suggesting that significant myocardial ischemia did not occur.

Echocardiography↗
PubMed1991

Effect of nifedipine GITS on left ventricular mass and diastolic function in severe hypertension.

Treatment of severe hypertension is beneficial, but reversibility of target-organ damage has not been characterized. Serial studies were performed in 15 patients with severe essential hypertension (age of 56 +/- 3 years, mean +/- SEM) treated for 1 year with 60 to 150 mg/day of continuous-release nifedipine; 3 patients required 50 mg of chlorthalidone/day to lower diastolic blood pressure (BP) to less than 95 mm Hg. Left ventricular (LV) structure and function was evaluated with two-dimensional-directed M-mode echocardiography, digitized from videotape and analyzed blindly. BP was markedly reduced from 194 +/- 8/115 +/- 4 to 146 +/- 4/88 +/- 14 mm Hg (p less than 0.0001) and maintained at this level for 1 year. Posterior wall and septal LV thickness, elevated at entry (12.9 +/- 0.1 and 13.4 +/- 0.1 mm), dropped steadily over 1 year into the normal range (10.0 +/- 0.03 and 11.2 +/- 0.1 mm, p less than 0.001). LV mass index, above 95% for normals at entry, decreased by 19% at 6 months (129 +/- 10 to 104 +/- 7 g/m2, p less than 0.01), and remained at this level at 1 year. LV fractional shortening rose steadily over 1 year from 34 to 42% (p less than 0.02). Atrial natriuretic peptide, which reflects LV filling pressures, was markedly elevated at entry, but was significantly reduced by 6 months (76 +/- 22 vs. 45 +/- 14 pg/ml, p less than 0.05). Sustained reduction of arterial BP with continuous-release nifedipine for 1 year normalizes LV mass, improves LV systolic function, and reduces circulating levels of atrial natriuretic peptide.

Blood Pressure↗
PubMed1991

Hematopoietic stem cells: concepts, assays, and controversies.

Mature cells of the hematopoietic system, including B and T lymphocytes, have a limited life span and must be continuously replenished by differentiation from immature precursors. The stability of the hematopoietic system depends on the maintenance of a pool of pluripotent hematopoietic stem cells. During the past 30 years, the development of quantitative assays for stem cells and their progeny has led to an explosion of information concerning the stages of differentiation, regulatory factors and receptors, and characterization of surface markers. Nevertheless, there remain many controversies about the properties of cells in the stem cell compartment. The degree of heterogeneity within the stem cell compartment is unknown. The detailed mechanisms for regulation of stem cells are uncertain. Finally, the factors which control the recruitment of quiescent stem cells are unknown and controversial.

Animals↗
PubMed1990

The scid mutation in mice causes a general defect in DNA repair.

Mice homozygous for the scid mutation on chromosome 16 have a severe combined immune deficiency as a result of their inability to correctly rearrange their immunoglobulin and T-cell receptor genes. In scid mice, when precursors for B and T lymphocytes reach the stage of development requiring expression of these surface receptors, a defective recombinase system aberrantly cuts and rejoins the receptor gene segments greatly reducing the efficiency of producing functional receptors. As a result, most scid mice have no detectable B or T lymphocytes. We have demonstrated that the scid defect is not specific to lymphocyte development. Myeloid cells and fibroblasts from scid mice show a marked increase in sensitivity to ionizing radiation, indicating that the scid mutation leads to an inability to repair DNA damage induced by ionizing radiation as well as interfering with rearrangement of the immunoglobulin and T-cell receptor genes.

Animals↗
PubMed1990

A physical map around the retinoblastoma gene.

The gene predisposing to retinoblastoma, RB1, has been mapped to 13q14 and a cDNA clone has been isolated. Alterations of this chromosomal region are found not only in retinoblastoma, but in other tumor types including bone and soft tissue sarcomas, gastric tumors, small cell lung cancer, hematologic malignancies, rhabdomyosarcoma, and breast cancer. Genetic alterations implicating RB1 in some of these cancers have been observed. A long-range, overlapping restriction map around RB1 has been derived to provide a basis for study of rearrangements in tumors. Putative CpG islands closely linked to RB1 were identified, the effect of methylation was investigated, and RB1 transcriptional direction was determined. Using data in the literature, the map was oriented with respect to the centromere and it was determined that the distance between esterase D, a nearby gene, and RB1 was greater than 200 kb.

Carboxylesterase↗
PubMed1990

Use of the RB1 cDNA as a diagnostic probe in retinoblastoma families.

Use of an intragenic BamHI restriction fragment length polymorphism within the 5' end of the retinoblastoma gene (RB1) provided improved genetic counselling for five familial and ten non-familial retinoblastoma patients and their relatives. All other polymorphic probes within RB1 were uninformative in three families, and accuracy of diagnosis was improved by use of this polymorphism in two families. In 10/14 informative constitutional DNA-RB tumor DNA pairs, a reduction to homozygosity allowed identification of the RB1 allele at risk to carry a germline RB1 mutation.

Child↗
PubMed1990

Hyperphosphorylation of the retinoblastoma gene product is determined by domains outside the simian virus 40 large-T-antigen-binding regions.

With the murine retinoblastoma (RB) cDNA, a series of RB mutants were expressed in COS-1 cells and the pRB products were assessed for their ability (i) to bind to large T antigen (large T), (ii) to become modified by phosphorylation, and (iii) to localize in the nucleus. All point mutations and deletions introduced into regions previously defined as contributing to binding to large T abolished pRB-large T complex formation and prevented hyperphosphorylation of the RB protein. In contrast, a series of deletions 5' to these sites did not interfere with binding to large T. While some of the 5' deletion mutants were clearly phosphorylated in a cell cycle-dependent manner, one, delta Pvu, failed to be phosphorylated depsite binding to large T. pRB with mutations created at three putative p34cdc2 phosphorylation sites in the N-terminal region behaved similarly to wild-type pRB, whereas the construct delta P5-6-7-8, mutated at four serine residues C terminal to the large T-binding site, failed to become hyperphosphorylated despite retaining the ability to bind large T. All of the mutants described were also found to localize in the nucleus. These results demonstrate that the domains in pRB responsible for binding to large T are distinct from those recognized by the relevant pRB-specific kinase(s) and/or those which contain cell cycle-dependent phosphorylation sites. Furthermore, these data are consistent with a model in which cell cycle-dependent phosphorylation of pRB requires complex formation with other cellular proteins.

Animals↗
PubMed1990

Sustained calcium channel blockade in the treatment of severe hypertension. A two year experience.

Thirty-nine patients with severe hypertension (diastolic blood pressure greater than 120 mm Hg) predominantly drawn from an inner-city population were placed on nifedipine gastrointestinal therapeutic system (GITS) for long-term treatment to achieve a sustained diastolic blood pressure less than 95 mm Hg. Fourteen patients failed to complete 6 months of therapy. For the 25 who remained in treatment for 6 months or more, systolic/diastolic blood pressure reductions were 62 +/- 5/40 +/- 2 mm Hg at 6 months; for those followed more than 12 months (n = 18), 58 +/- 7/37 +/- 3 mm Hg at 12 months; and for those followed more than 18 months (n = 11), 54 +/- 6/37 +/- 3 mm Hg at 18 months. Overall, 75% of these severely hypertensive patients were controlled with nifedipine GITS alone; 80% required 90 mg/day or more. During the two years of observation, no patient had a severe medical event, and 44% of those who entered remain in treatment. Left ventricular hypertrophy, as determined by echocardiography, diminished significantly during the course of treatment. These results indicate nifedipine GITS is well-tolerated and effective as monotherapy in the treatment of severe hypertension.

Adult↗
PubMed1990

Differences in ambulatory blood pressure between men and women with mild hypertension.

Non-invasive ambulatory blood pressure monitoring was performed in a consecutive series of 87 subjects with recently detected mild uncomplicated hypertension. Obese subjects, diabetics and those with secondary hypertension were excluded. Ambulatory pressures were recorded on a day of usual activity. Average ambulatory systolic and diastolic pressures were significantly lower than referral pressures determined in clinics or screening sites and initial pressures taken by the monitors. Whereas men (57) and women (30) had similar referral and initial pressures, average ambulatory systolic pressure was significantly higher in men; diastolic pressure was not different. Men also had a significantly higher fraction of ambulatory systolic pressures greater than 140 mmHg compared to women. Fifty-six percent of the men and 80% of the women had average ambulatory systolic pressures less than 140 mmHg and diastolic pressures less than 90 mmHg; the difference between the sexes was significant (chi 2 = 6.99, P less than 0.01). Thus, in mild hypertension, women have lower average systolic pressure than men during ordinary daily activity. These results may account for lower long-term cardiovascular morbidity in hypertensive women compared with men.

Adult↗
PubMed1990

Double-blind crossover trial of diltiazem versus propranolol in the management of thyrotoxic symptoms.

We compared the efficacy of diltiazem and propranolol in a randomized, prospective, double-blind, crossover study in six patients with untreated thyrotoxicosis (mean age 31 yrs). The patients received either diltiazem 60 mg orally four times a day or propranolol 40 mg orally four times a day, each for 1 week, separated by a 3-day drug-free period. Blood pressure, heart rate, thyroid hormone levels (free T4, T3), electrocardiogram, two-dimensional and M-mode echocardiograms, and Doppler studies were performed. In addition, 8 clinical signs and 18 symptoms of thyrotoxicosis were graded. All subjects felt better with drug therapy, with three preferring diltiazem to propranolol. No significant difference in clinical response or in hemodynamic effects was noted between the agents. These data suggest that diltiazem may serve as an alternative therapy for beta blockers in controlling thyrotoxic symptoms in patients in whom beta blockade may be contraindicated.

Administration, Oral↗