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Biomedical subjects

A D Weinberg

Publications and source records attributed to A D Weinberg.

At least 19 recordsLinked to original sources
PubMed1992

Transforming growth factor-beta enhances the in vivo effector function and memory phenotype of antigen-specific T helper cells in experimental autoimmune encephalomyelitis.

Transforming growth factor-beta (TGF-beta) had a profound effect on the in vitro phenotypic development of Ag-activated Th cells and enhanced the in vivo effector function of these cells upon adoptive transfer. Previous studies have shown that there are two types of Th cell populations found in unimmunized animals, naive helper cells, which are short-lived and express low levels of CD44 and high levels of CD45R and Mel-14, and memory helper cells, which have a long life span and express high levels of CD44 and low levels of CD45R and Mel-14. Culturing of Ag-specific murine Th cell lines and clones in the presence of TGF-beta greatly enhanced both the memory phenotype of the cultured cells and the effector function upon adoptive transfer in experimental autoimmune encephalomyelitis. Histologic evaluation of spinal cords from recipients receiving passively transferred murine T cell lines cultured with TGF-beta revealed large demyelinated plaques (multiple sclerosis-like) that were not present in animals receiving cells cultured with Ag alone. TGF-beta also enhanced the capability of myelin basic protein-specific Lewis rat T cell lines to transfer experimental autoimmune encephalomyelitis and potentiated a purified protein derivative-specific rat helper cell line to transfer delayed type hypersensitivity. Thus, the effects of TGF-beta did not appear to be limited by species specificity, Ag specificity, or in vivo T cell function. This is the first study showing that TGF-beta can potentiate the development and maintenance of the Th cell memory phenotype in vitro and enhance their in vivo effector function in an animal disease model.

Animals↗
PubMed1992

Cholesterol screening using the school as a worksite.

This article illustrates the appropriateness of the school as a worksite for health promotion programs and demonstrates how cholesterol screening is an effective tool to introduce such a program into a school system. Of 1,639 employees, 1,217 elected to have their cholesterol measured (74% response rate). Forty-five percent had elevated cholesterol according to the NIH Consensus Panel. Of these, 12% were in the "high" category (greater than or equal to 240 mg/dl) while 33% had levels that placed them in the "borderline high" risk category (200-239 mg/dl). Cholesterol screening can be incorporated easily into most school systems due to the presence of nursing staff and health educators. Systematic planning is essential for success and must include a counseling and educational intervention coupled with an active referral and follow-up program. This type of screening should be part of a multicomponent health promotion program.

Adolescent↗
PubMed1992

Controlling breast cancer in older women: the physician's role.

The number of women older than 65 years is the highest in history and continues to increase. Given that breast cancer is one of the most common cancers among women and that risk increases with age, it is important that older women participate in regular screening. Physician referral is the reason most women receive a screening mammogram. However, as women's ages and risk increase, the frequency of screening declines, potentially putting older women at greater risk. It is advocated that physicians adopt guidelines for breast cancer screening and practice them with their elderly, as well as younger, patients.

Age Factors↗
PubMed1992

Prevention of familial cardiovascular disease by screening for family history and lipids in youths.

We analyzed medical family history information from 51,053 families of high school students in Utah and Texas and cholesterol measurements from 853 youths and 1618 adults in Utah families with cardiovascular disease (CVD) to assess the utility of different approaches to risk-factor evaluation for youths. The major question addressed was in which youths should blood cholesterol be tested? Applying National Cholesterol Education Program recommendations suggested that 36% in Utah and 38% in Texas be tested. Heterozygous familial hypercholesterolemia (hFH) is the best documented and most serious cholesterol disorder readily diagnosed in youths. In Utah families ascertained for CVD in adults, blood cholesterol levels among youths were significantly bimodal with hFH present in 84% of youths in the upper cholesterol mode. Blood cholesterol levels in adults from the same families were less bimodal with hFH present in 38% of adults in the upper mode. More overlap existed between high and normal modes in adults than in youths. Data from this study suggest that family histories and cholesterol concentrations obtained from high school students may meet the needs of cholesterol screening, education, and follow-up in a controlled and cost-effective setting.

Adolescent↗
PubMed1991

Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development.

We have concentrated here on the lymphokines which might serve to regulate the different pathways of precursor development. We suggest that, as a result of antigenic stimulation, specific precursor cells both proliferate and become committed to develop into either an effector cell, a memory cell or an anergized cell. Anergy has not been dealt with in this review, but it is likely to be one of the options available. The development of an effector population takes 4-7 d (quite analogous to the time it takes for CTLp to become CTL and for resting B to become Ab-forming cells). The effector populations are large, generally IL-2R-positive cells. These cells have upregulated many adhesion molecule systems [e.g., Pgp-1, LFA-1 and ICAM-1 (Swain unpublished)], but downregulated the Mel-14 homing receptor. Effectors are ready to respond to APC such as specific B cells with a rapid synthesis and secretion of lymphokines. The effector population is then quickly downregulated, both by the turn off of lymphokine synthesis/secretion and possibly by its own suicide. This kind of pattern makes teleological sense since the cells making such high titers of lymphokines could have many potent pleitropic effects. It also seems to be the strategy employed in the generation of other terminally differentiated effectors (such as CTL and plasma cells). The requirement for restimulation and the requirement for direct and perhaps prolonged contact between the helper effector and the APC-B cell can be expected to help ensure that these lymphokines are localized (reviewed in Swain & Dutton 1987, Swain & Croft 1990) and effectively delivered to specific responding cells. We postulate that at the same time, or perhaps subsequent to this, another set of signals drives precursors to generate prememory cells. Our studies suggest these emerging memory cells may be phenotypically unique and we postulate that they are specialized to become a "long-lived" population of memory cells that will persist indefinitely as a protective population of increased frequency for the antigen encountered and which is also able to respond more rapidly and effectively. The greater effectiveness of the memory response would thus be due to dramatically increased frequency, to characteristic and stable changes in adhesion molecule expression and to the fact that, in addition to IL-2, resting memory cells also secrete at least low titers of IL-3, IL-4, IFN-gamma and other lymphokines upon initial restimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

IL-4 directs the development of Th2-like helper effectors.

Our studies show that the presence of IL-4 during the response of naive Th cells causes precursors to develop into a population comprised largely of "Th2-like" effectors that secrete IL-4 and IL-5, but little IL-2 or IFN-gamma. We find that the levels of IL-4 and IL-2 determine both the level of effectors developed in response to mitogen or Ag and the patterns of lymphokines they secrete when restimulated. IL-2 is required for optimum generation of effectors, and increasing levels of IL-2, augments the expansion of effectors secreting both IL-4/IL-5 and IFN-gamma. In contrast, IL-4 is required for the development of IL-4/IL-5 secreting effectors but suppresses the development of IL-2 and at higher doses IFN-gamma-secreting effectors detected after 4 days. Also dramatic are the effects of the presence or absence of IL-4 evaluated after an additional 1 to 2 wk. When cultures with or without initial IL-4 are cultured in IL-2 alone from days 4 to 11, they retain their distinct patterns of lymphokine production. Those cells that developed in cultures without IL-4 progressively secrete more IL-2 and can be maintained and expanded in IL-2. They continue to produce IFN-gamma, though the levels decrease somewhat with time, but they do not acquire the ability to produce IL-4 or IL-5. These cells thus increasingly resemble Th1 cell lines. In contrast, those cells in cultures initially exposed to IL-4, generate effectors which secrete high levels of IL-4/IL-5 (plus variable levels of IFN-gamma) at days 4 to 5, but the populations of cells developed, are not maintained well on IL-2 alone. Those cells that do survive continue to secrete IL-4 and IL-5 but not IL-2. In addition, IFN-gamma production, if present, falls off with time. Thus the cells in these cultures take on an increasingly Th2-like phenotype. It appears that the effects of low levels of IL-4 in suppressing IL-2 production by day 4 effectors appear to be transient whereas the higher levels appear to drive the development along a distinct pathway which is irreversible. These studies support the concept that different subsets of helper cells, which correspond roughly to Th1 and Th2 subsets, can develop rapidly in short term culture with respectively low vs high levels of IL-4. They support the concept that such distinct phenotypes arise from alternate pathways of differentiation that can be expected to reflect pathways available for helper T cell differentiation in the animal.

Animals↗
PubMed1990

IL-2 receptor (Tac antigen) protein expression is down-regulated by the 5'-untranslated region of the mRNA.

We have investigated the regulatory role of the 5'-untranslated region (5'-UTR) of the IL-2R mRNA. We noticed a region of striking homology (92%) between the human and bovine IL-2R cDNA in a stretch of 26 nucleotides located in the 5'-UTR. Within this 26 nucleotide region is an AUG that is out of frame with the IL-2R coding sequence. The murine IL-2R cDNA has an 11 bp direct repeat in the 5'-UTR that includes an upstream AUG, and this sequence is identical to the translational start site for the murine IL-2R protein. These observations raised the possibility that the two upstream AUG start codons might down regulate translation of the IL-2R by acting as false translational start sites. To investigate the possibility of IL-2R translational control, we examined sucrose gradient polysome profiles from Con A stimulated murine CD4+ splenocytes. The IL-2R mRNA was found in the portion of the gradient where free RNA, mono, and disomes migrate, whereas actively translated mRNA (lymphokines and beta-actin) were found in the portion of the gradient that contained the polysome fractions. This finding was consistent with translational down-regulation of the IL-2R mediated by ribosomal binding to the 5'-UTR start sites. We next examined cells transfected with the IL-2R cDNA that had the 5'-UTR deleted and compared protein expression to cells transfected with the full length construct. Flow microfluorometry analysis of cell surface IL-2R expression, showed that a clone transfected with the 5'-UTR deletion expressed five- to six-fold more IL-2R than a clone transfected with the full-length construct, even though both clones produced equivalent IL-2R mRNA levels. In clones transfected with the full length construct, the IL-2R mRNA associated with a reduced number of ribosomes compared to the mRNA in the deleted construct clones. These results indicate that sequences in the 5'-UTR of IL-2R mRNA lead to a decrease in the amount of ribosomes bound per IL-2R RNA molecule, and suggest that the level of IL-2R expression can thus be translationally down-regulated. This is the first growth factor receptor shown to be posttranscriptionally controlled at the translational level, and these findings have important implications for IL-2R synthesis and cell surface expression of this immunologically active cell surface receptor.

Animals↗
PubMed1990

CD4+ T cell subsets. Lymphokine secretion of memory cells and of effector cells that develop from precursors in vitro.

We have studied the properties of several developmentally defined subpopulations of CD4+ T cells from normal animals which can be stimulated to secrete lymphokines. We find that the Th cells responsible for direct secretion of lymphokines after stimulation are from a resting, very long lived subpopulation of CD4+ T cells which persists for over 25 wk after adult thymectomy. These T cells are depleted by in vivo administration of antithymocyte serum and they are enriched among T cells which express high levels of Pgp-1. This phenotype suggests that the T cells responsible are most likely memory T cells which have resulted from antigen exposure in vivo. T cells in this subset secrete predominantly IL-2 with small quantities of IL-3, granulocyte/macrophage CSF, and IFN-gamma. In contrast, the CD4+ T cells which require in vitro culture and restimulation before they develop into an effector population with the ability to secrete lymphokines after restimulation, differ dramatically by most of these criteria. The precursors we study are resting Th cells which are considerably shorter lived after adult thymectomy (5 to 10 wk) and resistant to the same doses of antithymocyte serum which deplete the putative memory population. We hypothesize that this precursor population represents naive helper cells which have not yet encountered Ag. The effectors derived from such precursors can be stimulated to secrete high levels of both Th cell types 1 and 2 lymphokines (IFN-gamma, IL-4, IL-5, granulocyte/macrophage CSF, and IL-3). Generation of effectors requires proliferation and differentiation events which occur during a mandatory culture with lymphokines and antigen presenting cells for 3 to 4 days. We discuss the striking phenotypic and functional differences among these subpopulations of helper cells--the precursor population and the two types--memory and cultured effector Th which secrete lymphokines. We also discuss the relationship of these populations to CD4+ T cell subsets defined by other studies of patterns of lymphokine secretion and by cell surface phenotype.

Animals↗
PubMed1990

Distinct regulation of lymphokine production is found in fresh versus in vitro primed murine helper T cells.

The kinetics of lymphokine RNA induction and secretion of biologically active lymphokine from CD4-enriched splenic T cell populations was investigated. Cells stimulated immediately after isolation from murine spleen ("fresh" T cells) and cells restimulated after 4 days of in vitro culture ("primed" T cells) were compared. Northern blot analysis and bioassays were used to analyze and quantitate production of eight lymphokines and the IL-2R. Fresh T cells produced high levels of IL-2 and low to moderate levels of IL-3, granulocyte/macrophage-CSF, and IFN-gamma. In vitro primed T cells produced IL-2, IL-3, IL-4, IL-5, IL-6, granulocyte/macrophage-CSF, IFN-gamma, and high levels of IL-2R RNA. Comparison of RNA levels and bioassays of supernatants from these populations indicated that primed T cells produced at least 10-fold more of six of the lymphokines than fresh T cells. Only IL-2 was produced in near equal amounts by fresh and primed T cells. There were also marked differences in the kinetics of lymphokine production by fresh and primed CD4+ T cells. After restimulation with Con A and PMA, primed cells produced a short burst of lymphokine RNA that peaked between 7.5 and 13 h and declined after 18 h. Fresh T cells lagged in the initial production of lymphokine RNA, with levels peaking 18 to 44 h after mitogenic stimulation. Depletion of CD4+ cells indicated that cells of helper phenotype were responsible for the majority of lymphokine production from the primed cells. Thus different subpopulations of Th cells defined by their respective ability to respond either directly (fresh T cells) or only after culture and restimulation (primed T cells) show different patterns of lymphokine gene regulation. Other studies suggest that the activity of "fresh" Th cells is due to a population with a "memory" phenotype, while the cells which require culture have a "precursor" phenotype. These distinct patterns of lymphokine gene regulation in the two populations of Th cells may account in part for differences seen in the kinetics and magnitude of the naive and memory immune responses which are regulated by Th cells.

Animals↗
PubMed1989

Ethical issues in research and publication.

Ethical considerations inherent in the process of research and publication represent one issue of particular concern to professionals. Members of a profession usually are guided by a code of ethics that specifies standards for practice. However, rarely do professional preparation programs sufficiently prepare students to deal with the concerns associated with research and professional publication. The authors address three specific areas of concern for health educators: the student-professor relationship, joint authorship, and ethics in publishing. Potential problems are discussed, and implications for the profession are cited.

Authorship↗
PubMed1989

Inhibition of T-lymphocyte mitogenic responses and effects on cell functions by bovine herpesvirus 1.

The mitogenic response of bovine peripheral blood mononuclear cells stimulated by concanavalin A (ConA) was suppressed by infectious bovine herpesvirus 1 (BHV-1). Proliferation in response to interleukin-2 (IL-2) by IL-2-dependent lymphocyte cultures was also inhibited by BHV-1. Although inhibition of mitogenesis approached 100%, less than 1 cell in 1,000 was productively infected by BHV-1 in ConA-stimulated cultures. Neither conditioned medium from mitogen-stimulated peripheral blood mononuclear cell cultures nor human recombinant IL-2 reversed suppression by the virus. Infection by BHV-1 did not influence the expression of IL-2 or IL-2 receptor mRNA in ConA-stimulated cultures, nor did it affect the cytolytic capabilities of lymphocytes. The data suggest that the inhibition of T-lymphocyte proliferation is the result of a nonproductive BHV-1 infection.

Animals↗
PubMed1989

Death in the nursing home: senescence, infection and other causes.

1. Clinical reasons for death in a skilled nursing home continue to show infectious causes as the leading etiology. 2. The concept of senescence is probably overlooked as a legitimate explanation for death in elderly patients. Senescence can be defined as a protracted and progressive decline of multiple body functions not attributable to one specific etiology and culminating in the patient's death. 3. The majority of deaths occurred within the first year after admission to the skilled nursing home setting. 4. The majority of deaths among the patients in this study occurred in the nursing home setting, not the hospital.

Aged↗
PubMed1989

Call to arms.

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Health Policy↗
PubMed1988

Characterization of T helper 1 and 2 cell subsets in normal mice. Helper T cells responsible for IL-4 and IL-5 production are present as precursors that require priming before they develop into lymphokine-secreting cells.

We have shown that the requirements for the production of IL-4 and IL-5 by normal L3T4+T cells from murine spleen are very different from those for the production of IL-2. Secretion of detectable quantities of IL-4 and IL-5 and induction of the mRNA for each lymphokine occurs in vitro only after cells are primed and re-stimulated. This priming can be achieved by mitogens (Con A), by antibodies to the TCR (anti-T3) or by stimulation with alloantigen. In contrast, requirements for induction of lymphokine production after priming resemble those for initial production of IL-2. Thus the majority of T cells of helper phenotype that have the potential to become IL-4- and IL-5-secreting T cells, exist in the form of precursors requiring stimulation and several days of culture as well as re-stimulation with mitogen or Ag before they become detectable as lymphokine-secreting cells. In contrast, among fresh CD4+T cells, secretion of IL-2, IL-3, granulocyte/macrophage CSF, and IFN-gamma is easily detected within 24 h of stimulation with mitogen or Ag. These observations establish that distinct phenotypes of Th cells are found at different times after stimulation and support the concept that synthesis and secretion of different lymphokines or groups of lymphokines are regulated independently. Furthermore the patterns of lymphokines secreted by fresh vs primed Th cells, which largely correspond to the patterns that have been used to define the Th1 and Th2 subsets among Th cell lines, provides evidence that different subsets of normal T cells exist that may correspond to these designations. Secretion of different lymphokines by two subsets of Th cells at different times in an immune response, and perhaps in different places, suggests a model in which the ratio of the two T cell subsets (Th1 vs Th2) and state of differentiation of each (precursor vs effector), influence or determine the direction of the response, with variations in these parameters leading to differing responses.

Animals↗
PubMed1988

Evidence for two discrete phases of IL-2 production in bovine lymphocytes.

Regulation of IL-2 production in Con A-stimulated bovine lymph node cells was studied by following the time course of IL-2 synthesis and secretion over a 24-h period. A biphasic time course curve of IL-2 secretion was observed after stimulation with Con A alone or with Con A plus PMA. Both phases of IL-2 production were confirmed by three separate biochemical techniques: IL-2 protein bioassay, mRNA Northern blots, and anti-IL-2 antibody detection. Bovine IL-2 transcripts were detected as early as 2 h after Con A stimulation. The early phase of IL-2 protein secretion was initially detected 3 h after Con A stimulation, and the late phase occurred between 10 and 16 h. Both phases of IL-2 production were enhanced when PMA was added to the Con A stimulation. Each phase of IL-2 protein secretion was preceded by the accumulation of IL-2 mRNA.

Animals↗
PubMed1988

A pilot study on cholesterol screening in the school environment.

A newly-developed analyzer measures total cholesterol from a single drop of blood and gives results within minutes. This procedure has made mass cholesterol screening inexpensive and less invasive than methods requiring a venipuncture blood sample, and it offers the opportunity for on-the-spot counseling and referral. In a pilot study, 610 high school students in the Victoria (Tex.) School District were screened for elevated cholesterol. Eighteen percent were found to have cholesterol levels above 180 mg/dl. Mean cholesterol values were higher for females than males, and higher for blacks and Hispanics than whites. Follow-up questionnaires indicated students and their parents understood the basic relationship between cholesterol and cardiovascular disease and how to modify their diet to reduce cholesterol intake. Telephone contact with parents of students with elevated cholesterol showed only about 27% of students with elevated cholesterol had visited a physician subsequent to the cholesterol testing.

Adolescent↗