Biomedical subjects
Publications and source records attributed to B Rubin.
As medical treatment has become increasingly complex over the years, patient care has become more and more dehumanized. The author explains how this feeling of dehumanization can cause patients to file malpractice suits and explores ways in which hosptial administrators can attempt to remedy the situation.
Oral administration of SQ 14,225 (0.03--3 mg/kg) to conscious normotensive dogs caused inhibition of the pressor response to intravenously administered angiotensin I (AI), the duration of which was dose-dependent. All doses of 0.1 mg/kg or greater caused 85--95% inhibition 30 min after administration whereas 0.03 mg/kg produced only a 25% inhibition. Pressor responses to angiotensin II (AII) were not similarly inhibited. Blood pressure was moderately reduced in a dose-related manner and followed the same pattern as inhibition of the AI pressor responses. The maximum change occurred after 1.0 mg/kg with only a more rapid onset occurring after the 3.0 mg/kg dose. Heart rate was not appreciably changed. SQ 14,225 also increased plasma renin activity (PRA), the levels and duration of which were dose-related. These data indicate that SQ 14,225 is an orally effective, potent inhibitor of angiotensin I-converting enzyme (ACE) in dogs. It appears that in mongrel dogs, ACE inhibition results in a slight to moderate reduction in blood pressure and an increase in PRA.
Indirect systolic blood pressure (SBP) was monitored in 9 groups of 15 male conscious 2-kidney renal hypertensive rats (RHR) for over 6 months. Daily oral dosing with captopril (SQ 14,225, D-3-mercapto-2-methylpropanoyl-L-proline, 30 mg/kg), an orally active angiotensin I-converting enzyme inhibitor, lowered SBP 30--50 MM Hg during this period. Withdrawal of captopril for 5 days at 1, 3 and 6 months resulted in gradual return of SBP to control levels without overshoot. Resumption of dosage with captopril again decreased SBP. Daily oral dosing with hydrochlorothiazide (HCTZ, 6 mg/kg/day) alone for 6 months had little or no effect on SBP, but increased the antihypertensive effect of captopril. Daily oral dosing with hydralazine (6 mg/kg) caused an initial marked antihypertensive effect greater than that of captopril but almost complete tolerance developed within 4 weeks of dosing. Highest survival rates occurred in RHR treated with captopril plus HCTZ. In four other similarly treated groups of RHR and normotensive rats (NR), least cardiac hypertrophy and highest plasma renin activity occurred in captopril-treated animals compared with vehicle-treated controls. Plasma renin activity was about 2 to 4 fold higher in the rats dosed with captopril compared with vehicle-treated rats. Heart weight/body weight ratios, initially higher in the two RHR groups compared to NR, decreased only in the captopril treated group to or near those of the NR groups. These results indicate that chronic treatment with captopril decreased SBP and cardiac weights of RHR, and that HCTZ, or possibly other diuretics, can augment the antihypertensive effect of captopril while having little or no effect by themselves.
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The present experiments were carried out in order to answer the question whether the precursor T cells of cytotoxic T lymphocytes (PCTL) are Fc receptor positive (FcR+), Fc receptor negative (FcR-), or both. The data show that cytotoxic T lymphocytes (CTL) can be generated in vitro from both FcR+ and FcR- PCTL. Furthermore, we investigated if the function of FcR+ and FcR- CTL differed in the allograft response in vitro. Qualitatively, FcR- PCTL differentiate into FcR- CTL only, whereas FcR+ PCTL differentiate into both FcR+ and FcR- CTL. However, quantitatively, CTL generated from FcR- PCTL display a higher T cell mediated cytotoxicity than CTL generated from FcR+ PCTL. Mixing experiments indicate that FcR+ T cells regulate the differentiation of FcR- PCTL into CTL. These conclusions hold true for PCTL in both normal and memory responder cell populations.
The present study is an attempt to produce xenogeneic anti-idiotype antibodies (Id) against mouse anti-H2 antibodies. The purpose is to obtain such anti-Id antibodies with reactivity against both B and T cells in quantities which will allow thorough investigation of the biochemical nature of the T cell receptor for alloantigen. Data are presented from experiments performed with an antiserum 5936 which was obtained after immunization with C57B1/6 anti-CBA antibodies.
The present results show that mouse bone marrow (BM) cells responded in vitro against phytohaemagglutinin (PHA), concanavalin A (Con A) and lipopolysaccharide (LPS). In addition, BM cell suspensions contained relatively many cells with ADCC (antibody-dependent cell-mediated cytotoxicity) activity. BM cells were fractionated according to various cell surface characteristics. The results of these experiments were compared with previously published reports, showing that pre-T and pre-B cells could be separated on Ig anti-Ig columns (Ig = immunoglobulin). The combined results showed that pre-T cells may fractionate together with cells with the following characteristics: they displayed ADCC activity and had Fc receptors (FcR) and/or membrane Ig. Pre-B cells fractionated with cells with the following characteristics: they responded to LPS but had no ADCC activity. They were not adherent and/or phagocytic and were Ig-, FcR- and C3 receptor (C3R) negative.
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SQ 14,225 (D-3-mercapto-2-methylpropanoyl-L-proline) markedly lowered the blood pressure of the renin-dependent aortic-ligated and two-kidney Goldblatt hypertensive rat and failed to reduce blood pressure in the one-kidney Goldblatt hypertensive rat. In the two-kidney Goldblatt rat, SQ 14,225 (p.o.) was about 10 times as potent as teprotide, the nonapeptide SQ 20,881 (s.c.). Oral doses of SQ 14,225 moderately reduced the blood pressure of the Wistar-Kyoto spontaneously hypertensive rat but not that of the normotensive Wistar-Kyoto rat. Bilateral nephrectomy abolished the antihypertensive activity of SQ 14,225 in the spontaneously hypertensive rat. SQ 14,225 and SQ 20,881 elicited parallel dose-response curves in the two-kidney renal hypertensive rat. Post-treatment of spontaneously hypertensive rats with either agent failed to augment the antihypertensive effect produced by effective doses of the other agent. The results suggest that SQ 14,225 acts primarily by inhibiting the renin-angiotensin system to reduce elevated blood pressure, especially in presumably renin-dependent models of hypertension.
Cell-associated and serum beta2-microglobulin was estimated in seven patients with chronic lymphocytic leukaemia. The amount of cell-associated beta2-microglobulin was significantly reduced (P less than 0.01), due to a decrease in the fraction of beta2-microglobulin that passes unretarded through a concanavalin A affinity column (presumably non-HLA-associated beta2-microglobulin). Serum concentrations of beta2-microglobulin were increased, but no correlation was found between the decrease in cell-associated beta2-microglobulin and the increase in serum beta2-microglobulin. All of the beta2-microglobulin from leukaemic serum was eluted corresponding to a molecular weight of 11,800 and none of it was retarded on a concanavalin A affinity column. The decrease in cell-associated beta2-microglobulin might reflect a change in the qualitative or quantitative expression of beta2-microglobulin-associated membrane structures on the leukaemic cells, perhaps conferring resistance to the cells against hypothetical immunological host defence mechanisms.
A hypothetical model of the active site of angiotensin-converting enzyme, based on known chemical and kinetic properties of the enzyme, has enabled us to design a new class of potent and specific inhibitors. These compounds, carboxyalkanoyl and mercaptoalkanoyl derivatives of proline, inhibit the contractile response of guinea pig ileal strip to angiotensin I and augment its response to bradykinin. When administered orally to rats, these agents inhibit the pressor effect of angiotensin I, augment the vasodepressor effect of bradykinin, and lower blood pressure in a model of renovascular hypertension.
Upon in vivo alloactivation of Ig-anti-Ig column-purified splenic 'T' cells in lethally irradiated allogeneic recipients, a variable proportion of donor-derived cytotoxic T lymphocytes (CTLs) are able to bind IgG antibody-coated erythrocytes through surface Fc receptors (FcR) and form rosettes. The use of fractionation procedures based on the ability of these cells to form rosettes has enabled us to separate FcR-positive CTLs from FcR-negative CTLs and to examine the ability of these two cell populations to perform as effector cells in direct T-cell-mediated killing and in antibody-dependent cellular cytotoxicity. A series of experiments, either by direct isolation of the two cell populations or by deletion of the FcR-positive population by filtration through complexed immunoglobulin columns (Ig-anti-Ig), has shown both populations to be efficient in direct T-cell mediated cytotoxicity against the relevant target cell. The striking difference between the two populations is the exclusive ability of the FcR-positive population to function as effector cells in antibody-dependent cellular cytotoxicity (ADCC). Purification steps before in vivo alloactivation of our responding cells for the removal of 'B' cells and FcR-bearing cells with 'K'-cell activity, followed by procedures to remove phagocytic and adherent cells in the resulting immune spleen cell preparation and, finally, b y velocity sedimentation of the rosetting and nonrosetting blasts from the small lymphocyte population, has resulted in a population of FcR-positive cells 98% positive for the Thy 1.2 alloantigen. These fractionation steps and immunofluorescence criteria of purity strongly favor the contention that the ADCC activity within the FcR-positive T-cell population is indeed a property of the CTL itself.
The results of the present experiments have shown that activated thymocyte populations are endowed with a cytotoxic potential against antibody-coated target cells. The effector cells could be divided into at least two subpopulations. 1) host-derived macrophage-like cells and 2) thymocyte-derived donor cell T lymphocytes. These two subpopulations could be separated and identified by means of commonly used immunofractionation techniques. Such data show that effector cells which kill antibody-coated target cells may be of T cell nature.
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The present report deals with our attempts to characterize the potent stimulator cell(s) that induce Fc receptor (FcR)-negative T lymphocytes to differentiate into cytotoxic T lymphocytes in vitro. We found two categories of such cells: [1] resting B cells, FcR+ T cells, and macrophages and [2] T cells either activated in 800-R-irradiated mice against H-2 antigens or M-locus antigens or activated in vitro by concanavalin A. The distinction between potent and weak stimulator cells is discussed in relation to the surface antigenic markers and the immunological function of these cells.
Lymphocytes from some PPD (purified protein derivative from tubercle bacillus) skin test negative (Mantoux negative=Mx--) human beings reacted against PPD in the lymphoproliferative assay with a time course and dose response very similar to those of lymphocytes from Mantoux positive (Mx+) individuals. Other Mx-- persons were PPD non-responsive in the lymphoproliferative assay. The PPD response of (immunoglobulin=Ig) Ig anti-Ig column passed lymphocytes (T-cells) from Mx--/LP+ (LP+=lymphoproliferative) persons was significantly reduced whereas the in vitro PPD response of T-lymphocytes from Mx+/LP+ was the same or increased. Purified B-lymphocytes from all kinds of tested individuals did not respond in vitro against PPD. Serological investigations indicated that one of the reasons for the negative skin reaction of individuals whose lymphocytes gave a positive lymphoproliferative response against PPD in vitro, is that such individuals had recirculating PPD of high molecular weight (greater than 900,000) and/or PPD anti-PPD antibody complexes in the serum. These substances could block the PPD-specific T-lymphocytes.
Immune guinea pig lymph node cells were fractionated on Ig anti-Ig or HSA anti-HSA affinity columns or on plastic surface in medium containing carbonyl iron. These techniques selectively removed B lymphocytes, K lymphocytes or adherent cells. The residual cells (Fc receptor-negative T lymphocytes) responded to soluble antigen in vitro in the same way or even better compared with nonfractionated cells. In addition, there was no indication that antigen-antibody complexes were superior to antigen in triggering lymph node cells or purified lymph code T lymphocytes into DNA synthesis. The results obtained suggested that memory T lymphocytes can be stimulated by antigen autonomously.
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