An integrated approach to management of Marfan syndrome caused by an FBN1 exon 18 mutation in an Australian Aboriginal family.
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Adolescent↗
Biomedical subjects
A Galbraith
Publications and source records attributed to A Galbraith.
Primary oxalosis with cardiac involvement: echocardiographic features of an unusual form of cardiomyopathy.
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Adult↗
IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation.
Thymic-dependent differentiation of bone marrow (BM)-derived progenitors and thymic-independent antigen-driven peripheral expansion of mature T cells represent the 2 primary pathways for T-cell regeneration. These pathways are interregulated such that peripheral T-cell expansion is increased in thymectomized versus thymus-bearing hosts after bone marrow transplantation (BMT). This study shows that this interregulation is due to competition between progeny of these 2 pathways because depletion of thymic progeny leads to increased peripheral expansion in thymus-bearing hosts. To test the hypothesis that competition for growth factors modulates the magnitude of antigen-driven peripheral expansion during immune reconstitution in vivo, a variety of T-cell active cytokines were administered after BMT. Of the cytokines (interleukins) tested (IL-3, IL-12, IL-6, IL-2, and IL-7), IL-2 modestly increased peripheral expansion in the face of increasing numbers of thymic emigrants, whereas IL-7 potently accomplished this. This report also demonstrates that the beneficial effect of IL-7 on immune reconstitution is related to both increases in thymopoiesis as well as a direct increase in the magnitude of antigen-driven peripheral expansion. Therefore, the administration of exogenous IL-7, and to a lesser extent IL-2, abrogates the down-regulation in antigen-driven peripheral expansion that occurs in thymus-bearing hosts after BMT. These results suggest that one mechanism by which T-cell-depleted hosts may support antigen-driven T-cell expansion in vivo is via an increased availability of T-cell-active cytokines to support clonal expansion.
Animals↗
Activation and adoptive transfer of Epstein-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease.
The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (PTLD) in EBV seronegative solid organ transplant recipients who acquire their EBV infection after engraftment poses a considerable challenge because of underlying immunosuppression that inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. We have developed a protocol for activating autologous EBV-specific CTL lines from these patients and show their potential use for immunotherapy against PTLD in solid organ transplant patients. Peripheral blood mononuclear cells from a panel of solid organ transplant recipients with and without active PTLD were used to assess EBV-specific memory CTL responses. The activation protocol involved cocultivation of peripheral blood mononuclear cells with an autologous lymphoblastoid cell line under conditions that favored expansion of virus-specific CTL and hindered the proliferation of allospecific T cells. These CTL consistently showed (i) strong EBV-specificity, including reactivity through defined epitopes in spite of concurrent immunosuppressive therapy, and (ii) no alloreactivity toward donor alloantigens. More importantly, adoptive transfer of these autologous CTLs into a single patient with active PTLD was coincident with a very significant regression of the PTLD. These results demonstrate that a potent EBV-specific memory response can be expanded from solid organ recipients who have acquired their primary EBV infection under high levels of immunosuppressive therapy and that these T cells may have therapeutic potential against PTLD.
Adoptive Transfer↗
Lack of effect of coenzyme Q on left ventricular function in patients with congestive heart failure.
OBJECTIVES: This study evaluated the effects of oral therapy with coenzyme Q on echocardiographic and hemodynamic indexes of left ventricular function and on quality of life in patients with chronic left ventricular dysfunction. BACKGROUND: Coenzyme Q is a coenzyme for oxidative phosphorylation and an antioxidant and free radical scavenger. It has been claimed to improve symptoms, quality of life, left ventricular ejection fraction and prognosis in patients with cardiac failure. METHODS: Thirty patients with ischemic or idiopathic dilated cardiomyopathy and chronic left ventricular dysfunction (ejection fraction 26 +/- 6%) were randomized to a double-blind crossover trial of oral coenzyme Q versus placebo, each for 3 months. Right heart pressures, cardiac output and echocardiographic left ventricular volumes were measured at baseline and after each treatment phase, and quality of life was assessed using the Minnesota "Living With Heart Failure" questionnaire. It was calculated that to demonstrate an increase in left ventricular ejection fraction from 25% to 30% with a standard deviation of 5% using 95% confidence intervals with a power of 80% we would require 17 patients. RESULTS: Twenty-seven completed both treatment phases. There was no significant difference in left ventricular ejection fraction, cardiac volumes or hemodynamic and quality of life indices after treatment with coenzyme Q or placebo, although plasma coenzyme Q levels increased from 903 +/- 345 nmol/l(-1) to 2,029 +/- 856 nmol/l(-1). CONCLUSIONS: In patients with left ventricular dysfunction, treatment for three months with oral coenzyme Q failed to improve resting left ventricular systolic function or quality of life despite an increase in plasma levels of coenzyme Q to more than twice basal values.
Administration, Oral↗
Are you overlooking oral rehydration therapy in childhood diarrhea? It's not just for use in developing countries.
In 1978, Lancet declared that development of effective oral rehydration solutions might prove to be the most important medical advance of the century. Since then, according to estimates of the World Health Organization, use of the solutions has saved a million children a year worldwide. Why, then, has this method of treating diarrhea-induced dehydration been so overlooked in the United States, where several hundred children still die annually of effects of diarrhea? One reason, the authors believe, is that physicians in developed countries have only limited exposure to serious dehydration and so are poorly informed on the principles of intervention. The authors provide practical advice on assessing dehydration in children, providing initial and maintenance rehydration, and reinstituting feeding.
Antidiarrheals↗
Yes, you can evaluate new caregiver roles.
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Delivery of Health Care↗
Marketing. Kwik off the mark.
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Delivery of Health Care↗
We must change too.
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Economics, Nursing↗
Developing a market orientation in the Health Service: a survey of acute NHS Trusts in Scotland.
Argues that the introduction of the quasi market mechanism into the Health Service has required that managers within NHS trusts acquire new managerial skills relating to market operations and, more importantly, reorientate their organizations towards the marketplace. Examines the pattern of development which has occurred within acute trusts across Scotland in the past three years, and argues that managers in the majority of trusts have developed a remarkably robust and relevant conceptualization of the nature and application of marketing within the NHS, reflecting the difficulties managers have faced in selling the concept of marketing to a generally sceptical body of clinicians. Notes, in part owing to such professional scepticism, that the development of marketing as an implementable approach to operations has lagged significantly behind the managerial conceptualization, although this cannot be attributed solely to resistance from clinicians and other health care professionals. Rather, suggests that such limited progress in implementing a market orientation reflects a range of "structural" barriers, both within individual trusts and the specific market environment faced by trusts.
Attitude of Health Personnel↗
11 beta-hydroxysteroid dehydrogenase modulation of glucocorticoid activities in lymphoid organs.
The immunoregulatory effects of glucocorticoids (GCS) are linked to their capacity to alter the production of various species of cytokines associated with immune and inflammatory processes. The present study determined that the influences of GCS within particular lymphoid organs vary, depending on the specific activity of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) within the tissue. This enzyme converts active GCS to inactive metabolites and was found to display greater activity in peripheral than in mucosal lymphoid organs. A direct correlation was found between 11 beta-HSD activity and the preferential production of type 1 cytokines by T-cells residing within certain lymphoid organs. It was established that lymphoid organ 11 beta-HSD was localized in the immobile stromal cell components. Inhibition of 11 beta-HSD activity in vivo reduced type 1 and enhanced type 2 cytokine production by activated T-cells, and it also depressed the ability of animals to generate contact hypersensitivity responses. We conclude that GCS levels can be controlled within lymphoid organs through oxidative inactivation by 11 beta-HSD. GCS action is, therefore, dependent on tissue levels of 11 beta-HSD activity, the number of GCS receptors in a responsive cell, and the concentration of circulating GCS.
11-beta-Hydroxysteroid Dehydrogenases↗
Heart failure. New treatment options.
Heart failure is still not well treated and the published information concerning treatment options has been slow in filtering through to general practitioners. Once a diagnosis of heart failure is made, treatment should begin with an angiotensin converting inhibitor. The dose should be increased relatively quickly. Diuretics and digoxin can be added if there is oedema. If this does not result in adequate improvement, other vasodilators or beta-blockers can be added. Other forms of therapy including antiarrhythmics, anticoagulants and surgery are discussed.
Angiotensin-Converting Enzyme Inhibitors↗
Strategic marketing in the NHS: Kwik-health NHS Trust.
Unlike managers in most service organizations, hospital managers do not have significant control over the shape or cost of the service product or the manner of its delivery. Hence, the crucial issue for hospital management to address is how to develop the marketing of a service the control of which is divorced from those with the strategic market perspective. While the internal management of hospital care in NHS is in its infancy, initial developments such as clinical directorates point the way forward in creating a market orientation within provider units. Ultimately, it must be considered what degree of influence over clinical decisions affecting hospital services is realistic, ethical and desirable for strategic marketing and business services. Arguably there is a case for the adoption of some middle ground, with both sides moving from their present positions but perhaps with the clinicians moving furthest.
Consumer Behavior↗
Towards a vaccine for rheumatic fever: identification of a conserved target epitope on M protein of group A streptococci.
Rheumatic fever and rheumatic heart disease remain very common in developing countries, and a vaccine to protect against these disorders would have a great impact on public health. A vaccine must target the M protein of group A streptococci (Streptococcus pyogenes), but until lately immunity was thought to be strain-specific and dependent on antibodies to the variable serotype-specific regions of the protein. Experiments in animals have suggested the conserved region of the M protein as a possible alternative target for protective antibodies. We constructed a 20-aminoacid peptide (peptide 145) within the conserved region of the carboxyl terminus of the protein. In mice the peptide induced serum antibodies that could opsonise reference type 5 streptococci. By enzyme-linked immunosorbent assay, positive responses to peptide 145 were obtained with serum from 77 (90%) of 86 Aboriginal subjects and 135 (81%) of 167 Thai subjects living in areas with high exposure to streptococci. Only 10 (14%) of 71 Caucasian subjects with low exposure to streptococci showed positive responses. There was no difference in the proportion positive between subjects with rheumatic heart disease and control groups (other or no heart disease). Antibodies to peptide 145 were able to opsonise isolates of streptococci from Aboriginal and Thai subjects with acute rheumatic fever as well as reference strains. This highly conserved part of the M protein may be a suitable target for vaccines to prevent streptococcal infections and their sequelae.
Amino Acid Sequence↗
Sponsored symposia on environmental tobacco smoke.
OBJECTIVE--To test the hypothesis that symposia on environmental tobacco smoke (ETS) are more likely to present unbalanced data and be authored by tobacco industry-affiliated individuals than journal articles on ETS. To compare the publication records and affiliations of authors of symposia with the authors of scientific consensus documents on ETS. DESIGN--Content analysis of articles; computerized literature searches of English-language publications (except for one symposium) supplemented with additional sources. PARTICIPANTS (ARTICLES)--All 297 symposium articles on ETS and a random sample of 100 journal articles on ETS published between January 1, 1965, and March 31, 1993; the 1986 Surgeon General's report on ETS; and the 1986 National Research Council's report on ETS. MAIN OUTCOME MEASURES--For each article, regardless of whether it had a methods section, agreement with the tobacco industry position that ETS is not harmful; topic; funding source(s); affiliation(s) of author; and publication records of authors. RESULTS--Of the symposium articles 41% were reviews, compared with 10% of journal articles. A total of 83% of original symposium articles and 100% of journal articles contained methods sections (P = .0001). Symposium articles were more likely to agree with the tobacco industry position (46% vs 20%), less likely to assess the health effects of ETS (22% vs 49%), less likely to disclose their source of funding (22% vs 60%), and more likely to be written by tobacco industry-affiliated authors (35% vs 6%) than journal articles (P = .0001). Symposium authors published a lower proportion of peer-reviewed articles (71% vs 81%) (P = .0001) and were more likely to be affiliated with the tobacco industry (50% vs 0%) than consensus document authors (P = .0004). CONCLUSIONS--Symposium articles on ETS differ from journal articles and consensus documents in ways that suggest that symposia are not balanced.
Authorship↗
Identification of T cell autoepitopes that cross-react with the C-terminal segment of the M protein of group A streptococci.
Rheumatic fever (RF) follows a throat infection with different M-serotypes of beta-hemolytic group A streptococci (GAS) and can affect different tissues, predominantly the heart. It is thought to be an autoimmune illness. Although histological examination of affected heart shows an infiltrate consisting mainly of T cells, antigens or epitopes that could be putative targets of autoimmune T cells have not been identified. We have examined the T cell response to the conserved C-terminal region of the M protein--a streptococcal surface coiled-coil protein which is the target of opsonic antibodies and antibodies which cross-react with human heart tissue. Australian Aborigine, Caucasian and Thai patients, controls and mice were studied to define regions of the protein immunogenic for T cells, and T cell lines and clones were tested for cross-reactivity to myosin as well as an extract of RF-diseased mitral heart valve. Murine (B10, B10.D2, B10.BR) M peptide-specific T cells were often cross-reactive for other M peptides but did not cross-react with human heart antigens. Patients with RF or other heart diseases, or control subjects exposed more commonly to GAS were more likely to have T cell responses to the M protein, with many regions of the C-terminus being recognized. T cell lines and a clone specific for different M peptides were generated from five donors. Cross-reactivity could be shown between different M peptides, but unlike murine M peptide-specific T cells three of the human T cell lines reacted strongly to peptides representing homologous regions of cardiac and skeletal muscle myosins, and two of these lines also responded to porcine myosin and an extract of human rheumatic mitral valve. However, these last two lines were derived from a normal donor without history of RF or other heart disease. Our data demonstrate that regions of the M protein, including regions that are being considered as subunit vaccines, have the potential to stimulate pre-existing heart cross-reactive T cells, but that the ability of such T cells to cross-react (as measured in vitro) is not in itself sufficient to lead to disease.
Adolescent↗
The publication of sponsored symposiums in medical journals.
BACKGROUND: An increasing proportion of spending by the pharmaceutical industry has gone to funding symposiums that are published by peer-reviewed medical journals. This study tests the hypothesis that such sponsorship, particularly by a single pharmaceutical company, is associated with a promotional orientation of the symposium and a distortion of the peer-review process. METHODS: We counted the symposiums published in 58 journals of clinical medicine and surveyed the journal editors regarding their policies for symposium issues. We analyzed the symposium issues that appeared in the 11 journals that published the most symposiums in order to determine the sponsor or sponsors, the topics, whether the titles were misleading, whether brand names were used, and whether the featured drugs were classified by the Food and Drug Administration as innovative or approved. RESULTS: The number of symposiums published per year increased steadily from 1966 through 1989. Forty-two percent of those analyzed (262 of 625) had a single pharmaceutical company as the sponsor. These symposiums were more likely than those with other sponsors to have misleading titles (P less than 0.001) and to use brand names (P less than 0.001), and less likely to be peer-reviewed in the same manner as other articles in the parent journal (P less than 0.001). Of the 161 symposiums that focused on a single drug, 51 percent concerned unapproved therapies; 14 percent concerned drugs classified as bringing important therapeutic gains. CONCLUSIONS: Symposiums sponsored by drug companies often have promotional attributes and are not peer-reviewed. Financial relations among symposium participants, sponsors, and journals should be completely disclosed, symposiums should be clearly identified, and journal editors should maintain editorial control over contributions from symposiums.
Congresses as Topic↗
Conserved T and B cell epitopes on the M protein of group A streptococci. Induction of bactericidal antibodies.
To identify conserved T and B cell epitopes on the M protein of group A beta-hemolytic streptococci, overlapping synthetic peptides that span the conserved carboxyl-terminal segment of the M-5 protein were constructed and used to immunize a panel of H-2 congenic mice. Proliferative T cell epitopes were identified and, in many cases, mice immunized with these peptides produced high titer antibodies to the same peptides indicating that these proliferative epitopes could also stimulate Th cells. Peptide-specific T cells and antisera were tested for their reactivity with porcine myosin, tropomyosin, human heart myosin synthetic peptides, and extracts of human pericardial and atrial heart tissue. Although there was minimal response of M peptide-specific T cells to any of these Ag, certain M peptide-specific antisera reacted to immunoblotted porcine myosin and to an immunoblotted extract of human atrial heart tissue. However, two conserved peptides, LRRDLDASREAKKQVEKALE and KLTEKEKAELQAKLEAEAKA, stimulated peptide-specific antibodies in B10.BR and B10.D2 mice respectively, which reacted minimally if at all with human atrial heart tissue extract. Furthermore, antisera to the former peptide, in a bactericidal assay involving human monocytes, could mediate killing of streptococci (82% of bacteria). Although this level of killing is less than that produced by antisera to the highly polymorphic type-specific aminoterminus (up to 100% killing), it provides evidence that conserved epitopes can be the targets of bactericidal antibodies. These conserved epitopes may be useful in a vaccine because they also stimulate T cells, thus allowing development of immunologic memory and natural boosting of an immune response after natural exposure.
Amino Acid Sequence↗