Biomedical subjects
Publications and source records attributed to G B Weiss.
The accumulation, binding, and mobilization of Ca++ in vascular smooth muscle directly affects intracellular free Ca++ levels and contractility. Techniques have been developed to delineate Ca++ uptake and efflux parameters in isolated vessels. Similar Ca++-related components are present in different types of vessels, but their relative importance for induction and maintenance of tension differ.
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Correlations between tension responses elicited with acetylcholine (ACh) and high K+ and corresponding alterations in Ca++ mobilization were obtained in rabbit and canine tracheal smooth muscle. Removal of Ca++ or preincubation with D-600 (50 microM) inhibited responses to K+ (50 or 80 mM) and low ACh (89 nM) and had only a small effect on responses to high ACh (8.9 microM). Conversely, solutions containing Sr++ instead of Ca++ inhibited responses to both concentrations of ACh to a greater degree than were those to K+. Washout of slow component 45Ca into a O-Ca solution was more rapid in rabbit trachea than reported previously for rabbit aorta. Washout of tracheal smooth muscle into an 80.8 mM La -substituted solution at 0.5 degrees C removed superficial (La -accessible) 45Ca and blocked both 45Ca uptake and most 45Ca efflux. D-600, which had no significant effect on control 45Ca uptake in rabbit aortic smooth muscle, decreased 45Ca uptake by 33% in rabbit tracheal smooth muscle. The uptake of 45Ca from the Ca++ binding sites with low affinity for Ca++ was increased by 80 mM K+, 50 mM K+ or 8.9 microM ACh, and the accumulation of Ca++ from the Ca++ binding sites with high affinity for 45Ca was inhibited by Sr++. The stronger effect of either Ca++ removal or D-600 on responses to K+ and the correspondingly greater effect of Sr++ on responses to ACh indicate that different Ca++ stores are present in tracheal smooth muscle. These Ca++ components appear to be qualitatively similar to those present in aortic smooth muscle but they differ quantitatively and are not as readily dissociated as are aortic Ca++ components.
Two patients with warm autoantibodies to their red cells had a mean cell volume artifactually elevated by red cell agglutination. Red cell size distribution histograms directly showed doublets and triplets of normal-size red cells. This phenomenon is similar to the spurious macrocytosis previously reported due to cold agglutinins, but was not reversible by warming.
Phase II trials can be conducted in an integrated fashion that minimizes assignment of patients to potentially ineffective treatments. The technique allows definitions of response to include survival; earlier identification of more effective drugs; and completion of more Phase II studies in a given time period. It also encourages investigators to analyse results promptly. Because the analysis of each trial is independent, the statistical power of the analysis of results is retained. Identified shortcomings of the method include the need for a central mechanism to assign patients to treatment, the need for several drugs to be tested, physicians' uncertainty about which drug a particular patient will receive, and the increased time it may take to complete an individual trial.
Little attention has been given in medical ethics literature to issues relating to the truthfulness of patients. Beginning with an actual medical case, this paper first explores truth-telling by doctors and patients as related to two prominent models of the physician-patient relationship. Utilizing this discussion and the literature on the truthfulness and accuracy of the information patients convey to doctors, these models are then critically assessed. It is argued that the patient agency (patient autonomy or contractual) model is inherently and seriously flawed in numerous circumstances, even those involving informed and competent adult patients.
The expression of a mouse mammary tumor virus is inducible by hormones, and the virus contains a hormone-responsive element. Viral particles and RNA-directed DNA polymerase (RDDP, EC 2.7.7.7; reverse transcriptase) are both detectable in human breast tumors but the frequency and significance of these findings are unknown. Breast tumor biopsy specimens (from either the primary site or a metastasis), frozen in liquid nitrogen at the time of surgery, were routinely obtained to determine estrogen receptor (ERP) concentration. A sample of the tissue was pulverized, homogenized and centrifuged at low speed to remove nuclei and mitochondria. The supernate was then centrifuged at 225,000 g to obtain the cytosol fraction for estrogen and progestin receptor (PgR) assays. Partially purified membranes for the RDDP assays were prepared from the high-speed pellet by discontinuous sucrose density gradient centrifugation. The RDDP assay involved measuring primer-dependent poly(dT) synthesis in the presence of poly(A) as template and oligo-(dT)12-18 as primer. To date, we have studied biopsy specimens from 46 patients with breast cancer. 27 (59%) had ERP and 23 (50%) were RDDP-positive. There was no significant correlation between ERP concentration and RDDP activity. PgR data were available on 36 of the patients; 17 (47%) were positive. No correlation between RDDP and PgR was apparent. Similarly, there was no correlation between RDDP and clinical stage of the disease.
It appears that, in smooth muscle, there are two distinct types of Ca2+ channel, a voltage-dependent Ca2+ channel and a receptor-linked Ca2+ channel. The former is activated by decreases in membrane potential and the latter is regulated by drug-receptor interactions. These Ca2+ channels exist as separate channels in the aorta of the adult rabbit and of some rat strains; organic Ca2+ antagonists and sodium nitroprusside selectively inhibit each of these two respective channels. By examining the effects of these two specific antagonists, characterization of the Ca2+ channels in other types of smooth muscle was attempted. In a wide variety of vascular smooth muscle (except aorta of above-mentioned animals), however, these two Ca2+ channels showed some sensitivity to both types of inhibitor. It is proposed that in most types of vascular smooth muscle as well as in gastric fundus and corpus, the two types of Ca2+ channel are functionally not completely separated. These subtypes of Ca2+ channels are at least partly sensitive to both organic Ca2+ antagonists and sodium nitroprusside. Intestinal, genital, and tracheal smooth muscles also seem to have two types of Ca2+ channel. These subtypes of Ca2+ channels are, however, sensitive only to organic Ca2+ antagonists and are not affected by sodium nitroprusside.
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The 5,6-; 8,9-; 11,12- and 14,15-epoxyeicosatrienoic acids and their respective hydration products, the vic-diols, recently reported as metabolites of arachidonic acid in rat liver microsomes, were examined for effect on release of 45Ca from canine aortic smooth muscle microsomes. At 10(-6) M, the diols had no effect, but the 5,6-; 11,12- and 14,15-epoxyacids increased the loss of 45Ca. Further studies with the 14,15-epoxyacid demonstrated a dose-dependent decrease of Ca++ uptake (ATP present) in canine aortic microsomes in 0.03 mM Ca++, whereas Ca++ binding (ATP absent) was not affected. Ca++ uptake, binding and release in rat liver microsomes was similarly affected by the 14,15-epoxyacid, the major epoxyeicosatrienoic acid derivative produced by rat liver microsomal incubations. It is suggested that alterations in Ca++ metabolism might be a possible mechanism of action for these derivatives of arachidonic acid.
The comparison of survival distributions between patients who respond to therapy and those who do not can present methodologic and interpretational difficulties. Since assignment of patients to the responder or nonresponder groups is not random, statistical procedures that test the equality of survival distributions only demonstrate association between response and survival, not cause and effect. This association may have no relevance to the efficacy of treatment. The assignment of patients to response categories also represents a methodologic problem. Variability in the definition of a nonresponder and the handling of early deaths can both lead to varying conclusions concerning survival. In spite of these problems, statistical comparisons of survival distributions of responders and nonresponders are reported in approximately 20% of phase II and phase III clinical trials. Descriptive statistics may be more useful than inferential statistics in this situation.
Observations in a patient with recurrent hyperthyroidism, each time associated with neutropenia which resolved after therapy, prompted a chart review of other patients referred for radioactive iodine therapy. Of 99 untreated patients, 18 had neutrophil counts of less than 2,000/cu mm. After therapy with either thionamides or 131I, 41 of 53 (77%) evaluable patients had an increase in neutrophil count. Eleven of these evaluable patients had neutropenia before therapy; after therapy, all 11 had an increase in their neutrophil counts into the normal range, with a mean increase of 170%. In one patient, studies on the mechanism of neutropenia indicate that bone marrow production and reserve remain normal and that circulating neutrophils are normally marginated. A decreased neutrophil circulation time may be the cause of neutropenia associated with hyperthyroidism.
A RNA-directed DNA polymerase was partially purified from a human homologous, mixed mesodermal sarcoma by DEAE-cellulose chromatography after sucrose density centrifugation. The enzyme transcribed poly(rA) most effectively but also transcribed poly(rI), poly(dA) and poly(rG) and to a lesser extent, poly(rmC). It was unable to transcribe poly(rU). The product with poly(rA) as template contained large material (greater than 28S) in addition to some proper size product demonstrating a slippage reaction. This pattern of transcription, while similar to avian myeloblastosis virus DNA polymerase, reveals qualitative differences making direct extrapolation from studies with animal oncornaviruses to human cancer difficult. In this paper, the detection and purification of RNA-directed DNA polymerase from a patient with an uncommon uterine sarcoma is reported along with the template specificities of the enzyme.
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Effects of phosphatidylserine (PS), phosphatidylinositol (PI), and phosphatidylcholine (PC) on high and low affinity 45Ca uptake (ATP present) and binding (ATP absent) in microsomes prepared from canine aortic media-intima were examined. When high affinity Ca++ uptake predominated (in 0.03 mM Ca++), PS and PI (but not PC) increased 45Ca binding but not 45Ca uptake. Only PI increased binding and uptake when low affinity Ca++ uptake predominated (in 3.0 mM Ca++). Oxalate-potentiated Ca++ uptake was inhibited by only PS and PI. PS and PI induced a reuptake of 45Ca that was blocked or reversed by EGTA (0.1 mM) or neomycin (0.14 mM). The Ca++ ionophore A23187 (10(-6) M) decreased high affinity 45Ca uptake to a level similar to that of high affinity 45Ca binding and, when added during 45Ca washout, increased 45Ca loss. Net negatively charged exogenous PS or PI may enter the microsomal membranes and provide additional high affinity Ca++ binding sites. The actions of PS and PI differ qualitatively from those of the Ca++ ionophore A23187.
A 52-year-old man with Ph1-positive chronic myelogenous leukemia (CML) developed a blastic transformation in which the predominant cell type micromegakaryocytes. He did not respond to treatment. A review of the 15 previously reported cases of patients with circulating megakaryocyte abnormalities in association with either CML or a Ph1 chromosome positive myeloproliferative disorder suggests a female predominance rather than the usual male predominance of CML. Survival of the six patients reported as megakaryoblastic transformation of CML as well as this patient was poor.
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