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Biomedical subjects

C S Scott

Publications and source records attributed to C S Scott.

At least 91 records · Page 5Linked to original sources
PubMed1991

Current practice patterns and training status of selected graduates at the King Abdulaziz University College of Medicine, Saudi Arabia.

Graduate doctors are the primary output of medical education programmes. It is important for institutions to identify systematically the types of medical activities in which their former students are involved in order to determine the effectiveness of the curriculum, assessing academic standards and reviewing admissions policies. Information was obtained from a survey of men and women graduates from three of the early graduation classes of King Abdulaziz University College of Medicine in Saudi Arabia about postgraduate medical training, certification, practice patterns, and other curriculum issues. Information collected from 151 graduates (90%) indicated that 96% were practising medicine in a variety of medical specialties and subspecialties. Six were not practising at the time of the study. Significant differences were found in the specialties being practised when men and women were compared. Men tended to practise in medicine, surgery, dermatology, urology, ENT, ophthalmology and orthopaedics, while women concentrated in obstetrics and gynaecology and paediatrics. Certification beyond medical school was earned by 49% with no significant difference being found comparing men to women. Men earned the majority of their postgraduate certifications outside Saudi Arabia while most women earned theirs in Saudi Arabia. Graduates indicated that departments in the basic sciences were least helpful in preparing them as doctors, while selected clinical departments were most helpful. It was concluded from the study that the curriculum goals of the College of Medicine, namely a curriculum of international standards producing graduates to take leadership roles in both teaching and medical practice, were realized in part by the graduates surveyed.

Attitude of Health Personnel↗
PubMed1991

The MHC class I associated beta 2-microglobulin (beta 2m) light chain is expressed in a molar excess over HLA-ABC and CD1 on the membrane of leukaemic B cells but not leukaemic T cells: evidence for further beta 2m-associated molecules.

Beta 2-microglobulin (beta 2m) constitutes the common light chain of both the MHC-encoded HLA-ABC molecules and a group of structurally related glycoproteins recognized by antibodies of the first cluster of differentiation (CD1a, CD1b and CD1c). These CD1 antigens appear similar to murine T1 and Qa molecules in terms of structure and tissue distribution, although the question of inter-species homology is controversial. A further group of alloantigens expressed predominantly on T cells has been reported however, with immunogenetic characteristics more closely analogous to the murine T1/Qa system than the CD1 antigens, although their precise identity remains ill-defined. Having previously shown that malignant B cells may express membrane CD1c, we examined leukaemic B-cells corresponding to early lymphoblastic differentiation (null- and common acute lymphoblastic leukaemia) through to the terminal plasma cell stage for the expression of other non-HLA class I beta 2m-associated molecules. It was found that leukaemic B-cells at intermediate/late stages of differentiation, represented by non-Hodgkin's lymphoma (B-NHL) and 'hairy-cell' leukaemia (HCL), had significantly higher beta 2m:HLA-ABC ratios than did the cells from other types of B-cell malignancy. Although leukaemic B cells with a demonstrable non HLA-ABC-associated beta 2m component expressed detectable levels of CD1c, and insignificant levels of CD1a and CD1b, the antigen density was insufficient to account for the excess beta 2m. In vitro stimulation of leukaemic B cells by phorbol ester substantially increased the expression of HLA-ABC and CD1c, but also accentuated further the difference between the expression of these molecules and that of beta 2m. There was no detectable beta 2m other than that associated with HLA-ABC and CD1 on the surface of malignant T cells by contrast. Our findings strongly support the existence, at certain stages of leukaemic B-cell differentiation, of an additional beta 2m component(s) other than that associated with HLA-ABC and CD1.

Antigens, CD↗
PubMed1991

Suppression of natural killer cell activity by rabbit antibody to human beta 2-microglobulin (beta 2m) is an Fc-mediated phenomenon and is not beta 2m specific.

Natural killer (NK) cell cytotoxicity constitutes an important component of the host immune defence system. The NK effector cell has been relatively well defined in terms of immunophenotypic characteristics, but in contrast to the functional T-cell receptor molecule associated with major histocompatibility complex (MHC)-restricted cytotoxic activity, the NK cell receptor has not to date been defined. However, several studies have suggested that the beta 2-microglobulin (beta 2m) molecule is functionally associated with NK cell activity. Using various heterospecific and monoclonal antibodies, this study has shown that intact rabbit IgG antibody bound either directly or indirectly to peripheral mononuclear cell (PMNC) effector populations significantly reduced their lytic activity against K562 targets. Substitution of F(ab)2 fragments for rabbit IgG antibodies, or the use of monoclonal antibodies alone, failed to reduce peripheral blood mononuclear cell (PMNC) lytic activity. Addition of non-NK cell components labelled with rabbit anti-beta 2m to purified NK-enriched effector cell populations also suppressed K562 lysis. In contrast, pre-treatment of a NK-enriched PMNC fraction with rabbit anti-beta 2m enhanced target lysis. These results strongly suggest that antibody-induced suppression of PMNC NK activity is mediated via rabbit Fc attached to co-existing non-NK cells in the mononuclear fraction, and are inconsistent with the previously suggested functional association between NK activity and membrane beta 2m.

Animals↗
PubMed1991

Assessment and counseling of coronary risk factors by family practice residents.

A study was undertaken to determine (1) the likelihood that patients seen for episodic health care in a family medical center have been assessed and counseled for coronary heart disease (CHD) risk factors, and (2) the likelihood that patients having an identified risk factor have been assessed and counseled regarding other CHD risk factors. One thousand five hundred twenty-eight medical records were randomly selected from all visits occurring over two periods in 1986 and 1987 to 122 residents in an eight-site family medicine residency network. Patients with cardiovascular disease and those younger than 20 or older than 65 years of age were excluded. Assessments were made of (1) smoking history, blood pressure, weight, physical activity, and dietary content during the previous 12 months; (2) family history of cardiovascular disease during the previous 12 months and in the initial patient history; (3) and blood cholesterol during the prior 5 years. Risk-factor counseling practices were examined for the previous 12 months. Blood pressure was assessed in 96% of patients, smoking in 40%, cholesterol in 26%, and family history in 52%. Ninety-six percent of hypertensive patients were counseled for hypertension, but only 45% of smokers and 20% of patients with hypercholesterolemia were counseled for those risk factors. Of patients having a given risk factor, assessment for any other risk factor occurred in fewer than 60% of cases. Patients having a documented positive family history were only slightly more likely than other patients to be assessed for additional risk factors. There is continued need for enhancing coronary risk-factor assessment and counseling by resident physicians.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

In vitro beta 2-microglobulin (beta 2m) secretion by normal and leukaemic B-cells: effects of recombinant cytokines and evidence for a differential response to the combined stimulus of phorbol ester and calcium ionophore.

Due to the increasing therapeutic use of immunoregulatory agents and the potential effects on cellular function, we examined the modulation of in vitro beta 2-microglobulin (beta 2m) production rates by 'normal' tonsil and leukaemic B-cells in response to a number of these agents. Tonsil B-cells responded to phorbol ester (TPA) by an increased beta 2m production rate, which was further enhanced by the combined stimuli of TPA plus the calcium ionophore A23187. In marked contrast, however, lymphocytes from a majority (8/11) of B-cell malignancies showed a suppression of the TPA-induced beta 2m production rate in response to the combined TPA/A23187 stimulus. These different responses of 'normal' and malignant B-cells were not apparent when IgM production rates were examined. The recombinant cytokines IL-1, IL-2, IFN-alpha, IFN-gamma and TNF also enhanced beta 2m production rates of both normal and leukaemic B-cells, but to a considerably lesser extent than did TPA. Bryostatin-1 increased beta 2m production to a level intermediate between that obtained by TPA and the cytokines. It is suggested that beta 2m production rates may correspond to the degree of B-cell differentiation, and/or to the degree of cellular 'activation'. The results further indicate that the in vitro measurement of beta 2m production provides a different index of the cellular response than that obtained by the conventional measurement of IgM production.

Adjuvants, Immunologic↗
PubMed1990

Relationships between 2H4 (CD45RA) and UCHL1 (CD45RO) expression by normal blood CD4+CD8-, CD4-CD8+, CD4-CD8dim+, CD3+CD4-CD8- and CD3-CD4-CD8- lymphocytes.

We characterized and established relationships between the expression of membrane 2H4 (CD45RA) and UCHL1 (CD45RO) by enriched lymphocyte fractions prepared by selective immunomagnetic depletion of monoclonal antibody-defined populations. Cell fractions analysed in this study could be divided into two broad groups according to the presence (CD3+CD4+CD8-, CD3+CD4-CD8+, CD3+CD4-CD8dim+ and CD3+CD4-CD8-) or absence (CD3-CD4-CD8dim+ and CD3-CD4-CD8-) of the CD3 antigen. Preliminary studies confirmed a reciprocal relationship for CD45RA and CD45RO expression by major lymphoid components and further showed that the level or intensity of membrane 2H4 staining (2H4+, 2H4int and 2H4-) could be directly related to UCHL1 expression. As a reflection of their differential functions, the various CD3+ populations examined showed much greater heterogeneity in 2H4 and UCHL1 expression. CD3+CD4+CD8- cells generally showed significant proportions of 2H4+, 2H4int and 2H4- components, whereas the CD3+CD4-CD8+ population was characterized by a predominance of 2H4+ cells. The results of this current investigation further suggested a higher proportion of dual-positive (2H4+UCHL1+) cells and a much greater degree of inter-individual variation than previously suspected. In contrast to CD3+ lymphocytes, natural killer (NK) associated CD3-CD4-CD8dim+ and CD3-CD4-CD8- populations were mostly 2H4+ with only minor 2H4int components and very low expression of UCHL1. An additional observation of note was that the proportions of 2H4+ and 2H4- cells comprising the CD4+CD8- fraction in any given individual was highly correlated (P = 0.002) with the distributions of 2H4+ and 2H4- components within the CD4-CD8+ fraction. This suggests the possible existence of a common control mechanism for the acquisition of immunological memory by distinct lymphocyte populations and further indicates that individual variations in the distribution of 2H4/UCHL1 lymphocyte subpopulations may be a direct consequence of 'immunological experience' rather than age alone.

Antibodies, Monoclonal↗
PubMed1990

Flow cytometric analysis of membrane CD11b, CD11c and CD14 expression in acute myeloid leukaemia: relationships with monocytic subtypes and the concept of relative antigen expression.

Blast cells from 26 cases of acute myeloid leukaemia (AML) were examined, by single and "two-colour" flow cytometry, for relationships between membrane CD11b (monoclonal antibody OKM1), CD11c (KB90) and CD14 (Leu-M3). Increased expression of all three determinants was associated with myelomonocytic leukaemias, with their relative diagnostic value in discriminating monocytic (M4 and M5) from non-monocytic (M1, M2 and M3) subtypes being CD14 greater than CD11c greater than CD11b. However, the results also indicated, because of the heterogenous expression of CD11c in particular, and to a lesser extent CD11b, that the patterns or histograms of fluorescent staining were potentially more informative than an empirical subdivision of blasts into positive and negative subpopulations. In addition, analysis of phenotypic correlations by simultaneous two-colour fluorescence showed that the expression of CD11b and CD11c determinants by leukaemic myeloid blasts was highly correlated, in contrast to the expression of CD14 and CD11c which were relatively independent. Consequently, CD11c+ myeloid blasts almost always coexpressed CD11b whereas CD14+ cases of AML often comprised CD14+ CD11c+ and CD14+ CD11c- subpopulations. It is concluded from these observations that CD11c immunophenotyping is a useful supplementary investigation, particularly in CD14- cases of myelomonocytic leukaemia. However, it is also apparent that the presence of membrane CD11c per se is not lineage-specific and that the level of expression is perhaps a more discriminatory factor.

Antibodies, Monoclonal↗
PubMed1990

Sampling clinicians' activities using electronic pagers.

Pager-based activity sampling (PAS) is described as a cost-effective and unobtrusive method for sampling residents' activities in clinical settings. A sample program evaluation is presented using residents in an urban children's hospital resident-training program. The purposes of the program evaluation were: (a) to establish a behavioral baseline that would help clinical faculty understand how residents were using their time, and (b) to determine whether alterations in the way residents were assigned within the hospital resulted in desired changes to time spent. The primary rationale for changing resident-assignment policies were: (a) to decrease the time residents were spending in transit between various locations within the hospital, and (b) to increase the time spent by residents in educational activities and in direct contact with patients and their families. This PAS application demonstrates that the technique can produce statistically supportable conclusions, at minimal cost, without unduly disrupting either the residents or their patients. PAS is compared with other time-sampling methods, its limitations are discussed, and suggestions for future applications are provided.

Confidence Intervals↗
PubMed1990

Phenotypic switch from CD45RA+ to CD45RA- by normal blood T cells is associated with increased HLA-ABC expression for CD4+ and CD8+ populations but not for the NK-associated CD4-CD8dim+ or CD4-CD8- fractions.

Using the combined techniques of immunomagnetic depletion and multiple colour flow cytometry, the expression of HLA-ABC (W6/32) by normal T-cell subpopulations, defined by 2H4 (CD45RA) expression, was examined. It is thought that a CD45RA+CD45RO- phenotype defines the 'virgin' T-cell fraction, whereas a CD45RA-CD45RO+ phenotype defines the 'primed' or memory T-cell population. In addition, an intermediate phenotype (CD45RA+CD45RO+) appears to correspond to a transitional stage of development. In this study, these three phenotypic stages were represented by distinct levels of 2H4 staining defined as 2H4+, 2H4int and 2H4-, respectively. The results of this current investigation are of importance in two main areas. Firstly, when compared to the 2H4+ component, the HLA-ABC expression of 2H4- cells was significantly higher. This was true for both CD4+CD8- and CD4-CD8+ lymphocytes, but was not the case for CD4-CD8dim+, CD3+CD4-CD8- and CD3-CD4-CD8- fractions. Additionally, when HLA-ABC expression was examined as a function of 2H4 staining intensity, it was found that, for the CD4+ fraction, the greatest increase in HLA-ABC expression occurred between the 2H4int and 2H4- stages. In contrast, the increase in HLA-ABC expression by CD8+ lymphocytes was associated with transition from 2H4+ to 2H4int status, which suggests that increased HLA-ABC expression occurs at an earlier stage in the acquisition of CD45RO in CD8+ cells than for CD4+ cells. Secondly, for each individual blood examined, a close and highly significant correlation (P = 0.002) for membrane HLA-ABC expression was found between (i) CD4+2H4+ and CD8+2H4+ and (ii) CD4+2H4- and CD8+2H4- subpopulations. This suggests that modulation of HLA-ABC expression in CD4+ and CD8+ cells is subject to common control mechanisms and remains proportionate for these lymphocyte fractions in any given individual.

Antigens, CD↗
PubMed1990

Patterns of membrane TcR alpha beta and TcR gamma delta chain expression by normal blood CD4+CD8-, CD4-CD8+, CD4-CD8dim+ and CD4-CD8- lymphocytes.

Enriched CD4+CD8-/CD4-CD8-, CD4-CD8+/CD4-CD8- and CD4-CD8- cell suspensions were prepared from normal peripheral blood by selective immunomagnetic depletion of monoclonal antibody-defined lymphocyte populations. Subsequent examination of these modified cell fractions by two-colour flow cytometry provided a means of determining the expression of membrane T-cell receptor (TcR)alpha beta and TcR gamma delta chains by both major (CD4+ and CD8+) and minor (CD3+CD4-CD8dim+ and CD3+CD4-CD8-) lymphocyte subpopulations. Normal CD4+CD8- lymphocytes were almost invariably (greater than 99%) TcR alpha beta+, whereas lymphocytes expressing membrane CD8, which could be further subdivided according to differences in fluorescent staining intensity into CD3+CD4-CD8+, CD3+CD4-CD8dim+ and CD3-CD4-CD8dim+ components, were characterized by distinct differences in patterns of TcR chain expression. In contrast to CD3+CD4-CD8+ cells, which were predominantly (99%) TcR alpha beta+, CD3+CD4-CD8dim+ lymphocytes showed a significant proportion (33%) of TcR gamma delta+ cells (natural killer-associated CD3-CD4-CD8dim+ cells were uniformly TcR-). The highest proportion (62%) of TcR gamma delta+ cells was associated with the CD3+CD4-CD8- fraction, but these studies also revealed that a significant minority of this population was TcR alpha beta+. Despite some evidence for normal inter-individual variation, further analysis of membrane CD8 fluorescent intensities confirmed clear differential relationships for TcR alpha beta and TcR gamma delta chain expression.

Adult↗
PubMed1990

Sezary cell-like leukemia: a distinct type of mature T cell malignancy.

We describe the clinical, ultrastructural, and immunophenotypical characteristics of four cases of an unusual type of T cell leukemia. Clinical features included high WBC, ranging from 26-148 x 10(9)/liter, bone marrow infiltration, splenomegaly, and lymphadenopathy. Skin involvement was not documented at presentation, but it was seen as a terminal event in one patient with a pattern of dermal lymphocytic infiltration different from that usually seen in Sezary syndrome. By ultrastructural analysis, the circulating lymphoid cells were indistinguishable from small Sezary cells in two cases, resembled large Sezary cells in one case, and consisted of a mixture of small Sezary cells and prolymphocytes in the remaining case. The cells from all cases had a mature T cell phenotype, TdT-, CD1a-, CD2+/-, CD3+, CD5+. In addition, the cells were either CD8+, CD4- or CD8+, CD4+ or CD4-, CD8-; and, in only one case, the findings were similar to those of Sezary syndrome cells: CD4+, CD8-, CD7-, BE-2+. In the latter case, serological and immunological assays were positive for HTLV-I while these were negative in two other patients investigated. The features of these patients suggest that Sezary cell leukemia is a distinct clinico-pathological entity although the alternative diagnosis of adult T cell leukemia/lymphoma could not be excluded in the HTLV-I+ case. Sezary cell leukemia appears to be resistant to current chemotherapy regimens and is associated with an aggressive clinical course and short survival.

Adult↗
PubMed1990

Preventive cardiology education and practice in residency training: residents' attitudes, perceptions, and practices.

This paper presents results from two studies of primary care residency programs. Study I was a survey of preventive cardiology attitudes and practice-related intentions of internal medicine and family medicine residents from throughout the United States. Study II consisted of an examination of family medicine residents' perceptions regarding preventive practices and a series of 1,528 medical record reviews of their related assessment and counseling practices. The specific aims were to examine residents' perceptions about their residency programs and to determine the percentages of patients who were assessed for and, if necessary, counseled for coronary heart disease prevention. Results indicated that internal and family medicine residents believe that they should be prepared by their residency training to offer these services and that their residencies were preparing most of them to do so. While they report that they intend to assess and counsel patients in these areas, they do not seem to be doing so. The medical record reviews strongly indicated that they are not providing these services at the recommended levels, especially for assessment of and counseling for smoking and blood cholesterol levels.

Attitude of Health Personnel↗
PubMed1989

Diagnostic application of monoclonal antibody KB90 (CD11c) in acute myeloid leukaemia.

The expression of membrane CD11c by leukaemic blast cells was examined (indirect immunorosetting) in 75 cases of acute leukaemia (myeloid, n = 60; lymphoid, n = 15) and evaluated as a potential marker for the diagnostic discrimination between monocytic (AMML-M4 and AMoL-M5) and non-monocytic (M1, M2 and M3) AML subtypes. Preliminary studies of normal bone marrow cells indicated that CD11c expression was not restricted to cells of monocytic lineage but was also present, with apparent lower density, on significant proportions of mature and immature granulocytes. Examination of acute myeloid leukaemia (AML) subtypes revealed that the non-monocytic leukaemias (n = 33) were CD11c-, defined as less than 30% positive cells, whereas all but one of the AMML-M4 (n = 13) and AMoL-M5 (n = 14) cases were CD11c+. All 15 cases of lymphoblastic leukaemia (ALL) showed less than 5% CD11c+ blasts. Membrane CD11c expression was also compared to the more widely used markers of monocytic differentiation; cytoplasmic alpha-naphthyl acetate esterase (ANAE) and membrane CD14 expression. This analysis showed that all 13 AMML-M4 leukaemias studied, including seven cases that were CD14- and eight that were ANAE-, were CD11c+. In addition, the AMoL-M5 cases (all of which were ANAE+) could be phenotypically subdivided into CD11c+ CD14+ (n = 9), CD11c+ CD14- (n = 4) and CD11c- CD14- (n = 1) subgroups. The study also confirmed that the discriminitive ability and sensitivity of the immunorosetting procedure for the detection of membrane CD11c compared favourably to immunofluorescent staining intensities as measured by flow cytometry.

Antibodies, Monoclonal↗
PubMed1989

Menarche: the black American experience.

There is an increasing awareness that attitudes learned during socialization into a cultural/ethnic group may influence one's perception of and response to menarche. To date, studies have primarily involved white Americans. There is a lack of information regarding the experience of menarche among diverse ethnic groups. Our study of a sample of black American girls (mean age 13.5 years) revealed that the proportion of blacks who felt they were not prepared for menarche was almost twice that of whites. A comparison of the black adolescents' assessment of their level of preparedness suggests that the less prepared they perceive themselves to have been, the more negative feelings they express toward menarche--which is comparable to the findings among white Americans. The black and white adolescents alike attributed the most positive feelings about menarche to their mothers, compared with their own and their fathers' emotional response.

Adolescent↗
PubMed1989

Diagnostic differentiation of chronic B-cell malignancies using monoclonal antibody L161 (CD1c).

The expression of membrane CD1c, as defined by monoclonal antibody L161, was examined on malignant lymphoid cells from 191 cases of chronic lymphoproliferative disease and on eight 'normal' enriched tonsil B-cell extracts. Of 79 cases of chronic lymphocytic leukaemia (CLL) studied, 77 showed low (less than 20% positive cells) CD1c expression whereas 63/71 (89%) cases of B-PLL, HCL and B-NHL showed increased CD1c+ (but not CD1a or CD1b) components. In contrast, malignancies corresponding to terminal stages of B-cell differentiation (immunocytoma and myeloma) generally showed low CD1c expression as did lymphoid cells from 10 cases of post-thymic malignancy. Although there was some correlation between the expression of membrane CD1c and immunoglobulin (SIg) light chain densities (P less than 0.001), it is relevant in diagnostic terms that seven cases of B-NHL with low SIg staining intensities more typically associated with CLL were CD1c+. CD1c expression was not, however, correlated with the presence of CD23 or FMC7 determinants but did show a similar pattern of expression to that previously reported for beta-2 microglobulin. Determination of cellular CD1c by APAAP immunocytochemistry confirmed the presence of higher antigen densities in malignant B-cells at intermediate/late stages of differentiation and this interpretation was further supported by the finding that the majority of phenotypically mature tonsil B-cells were also CD1c+. The determination of CD1c expression by malignant B-cells may therefore be of particular value in the diagnostic differentiation of chronic lymphoproliferative disorders.

Antibodies, Monoclonal↗
PubMed1989

Immunophenotypic and enzymatic studies do not support the concept of mixed monocytic-granulocytic differentiation in acute promyelocytic leukaemia (M3): a study of 44 cases.

Leukaemic promyelocytes from 30 cases of hypergranular and 14 cases of hypogranular acute promyelocytic leukaemia (M3) were analysed for the presence of monocyte-associated characteristics to determine whether there was any evidence of mixed (hybrid) granulocytic-monocytic differentiation. Cytochemically, a high proportion of hypergranular cases showed significant alpha-naphthyl acetate esterase (ANAE) staining and simultaneous chloroacetate esterase, and ANAE expression by single cells was commonly seen. These atypical staining patterns were, however, not a feature of hypogranular cases. Immunophenotypic studies revealed that most hypergranular M3 cases were HLA-DR- and that monocyte-associated membrane CD14 expression was low in all cases tested. In addition, serum lysozyme concentrations (20 cases) were generally within the normal range and thus inconsistent with monocytic involvement in the leukaemic process. The significance of atypical ANAE staining of leukaemic promyelocytes was further examined by analysing ANAE isoenzyme components (defined by isoelectric focusing) in 11 cases. The patterns obtained (G1 and G2) were identical to those found in normal granulocytes and did not show any evidence of monocyte-associated esterase isoenzyme expression. On the basis of these findings, it is considered that the differentiation process in acute promyelocytic leukaemia is relatively well conserved and that the atypical esterase cytochemistry of hypergranular promyelocytes does not reflect their mixed lineage nature but is simply a consequence of increased granulation.

Cell Transformation, Neoplastic↗
PubMed1989

Bryostatin 1 induces differentiation of B-chronic lymphocytic leukemia cells.

Peripheral blood cells from nine patients with B-chronic lymphocytic leukemia (B-CLL) were treated in vitro with bryostatin 1 (a macrocyclic lactone derived from a marine invertebrate). Like the phorbol ester 12-0-tetradecanoyl-phorbol 13-acetate (TPA), bryostatin 1 activates protein kinase C (PKC), which plays a central role in the phosphatidylinositol signal transduction pathway. The effects of bryostatin 1 alone and in combination with TPA or with the calcium mobilizing ionophore A23187 were assessed by morphological appearance, cell adherence and aggregation, RNA and DNA synthesis, and immunoglobulin (Ig) production. While eight of nine B-CLL cultures remained proliferatively inert, bryostatin 1 could effectively trigger activation and differentiation of B-CLL cells in all cases as inferred by the induction of morphological changes, RNA synthesis, and monotypic Ig production. Addition of calcium ionophore A23187 to bryostatin 1-exposed cells resulted in significantly increased values for RNA synthesis and Ig production and in the acquisition of plasmacytoid morphology. Bryostatin 1 and the dual signal of bryostatin 1 plus A23187 mimicked the stimulatory action of TPA and the combination of TPA plus A23187, respectively. Overall, bryostatin 1 was less active than equivalent concentrations of TPA. This lesser efficacy may, however, reflect a quantitative rather than qualitative difference. Bryostatin 1 partially antagonized TPA-mediated effects on B-CLL cells suggesting different modes of action by the two activators. These studies indicate that bryostatin 1 has effective differentiation-inducing properties on B-CLL cells that can differentiation-inducing properties on B-CLL cells that can be accentuated by a calcium ionophore.

Aged↗