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J Currier

Publications and source records attributed to J Currier.

33 records · Page 2Linked to original sources
PubMed1995

Guidelines for management of HIV infection with computer-based patient's record.

Computers are steadily being incorporated in clinical practice. We conducted a nonrandomised, controlled, prospective trial of electronic messages designed to enhance adherence to clinical practice guidelines. We studied 126 physicians and nurse practitioners who used electronic medical records when caring for 349 patients with HIV infection in a primary care practice. We analysed the response times of clinicians to the situations that triggered alerts and reminders, the number of ambulatory visits, and hospitalisation. The median response times to 303 alerts in the intervention group and 388 alerts in the control group were 11 and 52 days (p < 0.0001), respectively. The median response time to 432 reminders in the intervention group was 114 days and that for 360 reminders in the control group was over 500 days (p < 0.0001). There was no effect on visits to the primary care practice. There was, however, a significant increase in the rate of visits outside the primary care practice (p = 0.02), which is explained by the increased frequency of visits to ophthalmologists. There were no differences in admission rates (p = 0.47), in admissions for pneumocystosis (p = 0.09), in visits to the emergency ward (p = 0.24), or in survival (p = 0.19). We conclude that the electronic medical record was effective in helping clinicians adhere to practice guidelines.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Antigens released at schizont burst stimulate Plasmodium falciparum-specific CD4+ T cells from non-exposed donors: potential for cross-reactive memory T cells to cause disease.

In an individual experiencing the first attack of malaria, symptoms of disease can occur at very low parasitemia. T cells and cytokines have been implicated in the etiology of disease symptoms, and others and ourselves have shown that T cells from non-exposed individuals can be stimulated by malaria parasites. Here, we show that nine from 11 blood samples, naturally infected with malaria parasites, could stimulate proliferation of a malaria-specific T cell clone derived from a non-exposed donor. T cells were able to respond to infected blood at a parasitaemia as low as 0.000003% (comparable to the level at which individuals can first experience symptoms of malaria) and secrete cytokines implicated in pathology. Antigens capable of stimulating T cells are expressed throughout the blood stage, but are specifically released at the time of schizont rupture. While most TCR V beta genes are expressed during the T cell response of naive donors to malaria parasites, processing of parasite antigens is blocked by chloroquine and monensin, and activation of 36 of 41 malaria-specific clones tested was restricted by defined MHC class II allelic antigens, strongly suggesting that parasites do not act as mitogens nor as superantigens. The clones react to various commonly encountered pathogenic and non-pathogenic microbes. These data support the concept that activation of cross-reactive memory T cells by malaria parasites contributes to disease symptoms in individuals experiencing their first attack of malaria.

Adolescent↗
PubMed1994

Analysis of human T cell clones specific for conserved peptide sequences within malaria proteins. Paucity of clones responsive to intact parasites.

T cells are thought to be of central importance in malaria immunity. Peptides copying malaria protein sequences often stimulate human CD4+ T cells and it was thought that they represented T cell epitopes present in the parasite and may thus have particular relevance to malaria vaccine development. To verify whether synthetic peptides representing highly conserved regions of parasite Ags may contribute to a malaria vaccine, we searched the data bank for conserved regions of Plasmodium falciparum malaria proteins that were not homologous to known self (human) proteins. We synthesized 24 such peptides representing 11 of the cloned and sequenced malaria asexual stage Ags, which were predicted by algorithms to represent T cell epitopes, and 6 peptides not predicted to be T cell epitopes and used these to generate T cell clones from individuals with an extensive previous history of malaria exposure. The T cell clones responded vigorously to many peptides but only a single clone, specific for a peptide within merozoite surface protein-1, 20-39, VTHESYQELVKKLEALEDAV, and not previously defined to be a T cell epitope responded to malaria parasites by proliferation and secretion of IFN-gamma. This epitope was not revealed by studying parasite-induced T cell lines and is thus subdominant. The clone was able to significantly inhibit parasite growth in vitro. The final step in the inhibition of parasite growth appears to be nonspecific because other activated clones (not specific for malaria sequences) can inhibit parasite growth. Our data suggest that few conserved peptides within malaria parasites can be processed from the intact parasite. However, such peptides that can be processed from malaria parasites may be expected to stimulate parasite-specific T cells that could inhibit parasite growth and as such may be lead candidates for a vaccine aimed at inducing cellular immunity to malaria.

Adult↗
PubMed1994

Inhibition of Plasmodium falciparum growth in vitro by CD4+ and CD8+ T cells from non-exposed donors.

T cells from most adult non-exposed donors, which express a memory phenotype (CD45RO+), can respond by proliferation to P. falciparum asexual stages in vitro. Such cells may have arisen from exposure to environmental organisms. To address the efficacy of such cells in eliminating parasites and investigate the mechanisms involved, we have used an in vitro assay where parasite growth can be precisely monitored in the presence of different cell preparations. Unfractionated peripheral blood mononuclear cells (PBMC) from both malaria-exposed and non-exposed donors inhibited parasite growth by up to 62% in a two day assay. Purified T cells in the presence of adherent cells had a similar effect, but purified T cells alone or adherent cells alone had minimal effect. Antigens released at the time of schizont rupture were maximally effective in stimulating interferon-gamma (IFN gamma) production. Neutralizing antibodies to IFN gamma showed a partial reduction of growth inhibition in some individuals tested suggesting that different mechanisms may be operative. Neutralizing antibody to TNF alpha had a partial effect in combination with anti-IFN gamma. Antibodies to IL-1 and IL-4 had no effect. T cell fractionation experiments showed that while purified CD4+ T cells from some donors produced IFN gamma and inhibited parasite growth, purified CD8+ T cells could inhibit parasite growth to a greater extent without production of detectable IFN gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

'Original antigenic sin', T cell memory, and malaria sporozoite immunity: an hypothesis for immune evasion.

Prior to any exposure to malaria, most adults have T cells specific for malaria parasites and various malaria proteins. The protein for which this has been shown more than any other is the circumsporozoite protein (CSP) of Plasmodium falciparum. These T cells can be present in high frequency and appear to have arisen through exposure to other (non-malaria) organisms. Although T cells are thought to provide protection against sporozoites, these T cells specific for cross-reactive organisms are clearly unable to protect against malaria, and may be preferentially expanded following exposure to malaria sporozoites. Thus, cross-reactive organisms have the potential to skew the repertoire of sporozoite-induced T cells and affect the induction of protective immunity. This is analogous to the concept of 'original antigenic sin' whereby prior exposure to one strain of influenza virus was shown to be able to divert the antibody response to a second challenging strain to focus on the shared (cross-reactive) epitopes.

Animals↗
PubMed1993

An electronic medical record that helps care for patients with HIV infection.

We have built a clinical workstation to help doctors and nurses care for patients with HIV infection. This knowledge-based medical record system provides medication alerts, reminders about primary care, and on-line information to support the care of patients with HIV infection. We are conducting a controlled clinical trial of this computer system in a single practice setting, which consists of 18 staff physicians, 13 nurses, and 113 residents, who cooperatively practice in four teams. Two teams of physicians are assigned to an intervention group and two teams to a control group. This paper reports preliminary results from the first year of study, January 15, 1992, through January 14, 1993. During this period 274 patients with HIV infection were followed by the general medical practice--130 in a control group and 144 in an intervention group. Physicians in the intervention group more rapidly and more completely followed primary care guidelines than did physicians in the control group. Patients in the intervention group had 2476 ambulatory or emergency visits (17.2 visits per patient) compared with 1882 visits (14.5 visits per patient) for the control patients (p < 0.01). There were 101 hospitalizations for 51 patients in the intervention group (an admission rate of 0.7) compared with 104 admissions for 54 patients in the control group (an admission rate of 0.8) (p = NS). There were 8 deaths in the intervention group (5.6%) compared with 13 (10%) in the control group (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Artificial Intelligence↗
PubMed1992

High frequency of malaria-specific T cells in non-exposed humans.

A major goal of current candidate malaria vaccines is to stimulate the expansion of clones of malaria-specific lymphocytes. We have examined the in vitro T cell responses of a group of malaria exposed and non-exposed adult Caucasian donors to recombinant circumsporozoite (CS) proteins, one of which is undergoing clinical trials, to blood-stage parasites, and to synthetic peptides copying the CS protein and defined blood-stage proteins. In nearly all individuals tested, CD4 T cell proliferation or lymphokine production occurred in response to whole parasite or CS protein stimulation, and T cells from many individuals responded to synthetic peptides. T cell responses were major histocompatibility complex-restricted, and stimulation of T cells with malaria parasites or CS protein did not appear to expand a population of T cell receptor gamma/delta cells. Malaria-specific responses were independent of prior malaria exposure, and in some cases exceeded the magnitude of response to tetanus toxoid. Specific T cells are present in high frequency in the peripheral blood of many donors who have never been exposed to malaria. Although malaria-specific CD4 T cells play an important role in immunity, these data question whether vaccines need to stimulate such cells, and focus attention on other aspects of malaria immunity which may be more critical to a successful vaccine.

Amino Acid Sequence↗
PubMed1992

The importance of T cell homing and the spleen in reaching a balance between malaria immunity and immunopathology: the moulding of immunity by early exposure to cross-reactive organisms.

It takes a number of years to develop clinical immunity to malaria and malaria pathology is also most evident a number of years after birth. T cells are known to play an important role in defence from malaria parasites but may also contribute to the disease symptoms associated with malaria. T cells which react against malaria parasites have arisen through stimulation with organisms which cross-react with malaria or through exposure to the malaria parasites themselves and express a memory phenotype (CD45Ro+, CD45Ra-, CD4+). T clones which have arisen through exposure to cross-reactive organisms may be expected to home to the tissues where initial exposure occurred as determined by tissue-specific adhesion molecules on the lymphocyte surface. Such tissues may not be appropriate to parasite killing and localization of T cells in such sites may contribute to the immunopathology of malaria. The sharp increase in immunity and decline in pathology observed in later childhood in malaria endemic areas may result from an increase in the number of T cells induced by the parasite itself (as opposed to cross-reactive organisms). Such T cells may not have a preferential trafficking to other organs and may be more likely to circulate through the spleen. Splenic changes may also allow more malaria-specific T cells to concentrate in the spleen and may facilitate interactions between T cells, monocytes, neutrophils and parasites resulting in parasite death. Whereas cytokines secreted by parasite-reactive T cells in all locations may contribute to cerebral malaria and other forms of pathology, cytokines in the spleen at least, should directly contribute to parasite death.

Age Factors↗
PubMed1992

'Natural' T cells responsive to malaria: evidence implicating immunological cross-reactivity in the maintenance of TCR alpha beta+ malaria-specific responses from non-exposed donors.

It is now generally accepted that peripheral blood of humans not exposed previously to malaria contains T cells which proliferate vigorously in response to malaria parasites and antigens. Although it has been claimed that these cells express a memory phenotype, their origin is uncertain. We have examined the phenotype and immunological responses of such cells. We confirm that these cells do express the 'memory phenotype', CD45Ro, in that depletion of such cells, but not of CD45Ra (virgin) cells, abrogates the immune response to malaria parasites. In an effort to define the genesis of these responses, numerous malaria-specific T cell clones have been generated from non-exposed individuals. These were tested for reactivity to a large panel of common bacterial, viral, and fungal pathogenic and non-pathogenic organisms. Most clones proliferated vigorously in response to one or more such organisms, while many clones demonstrated smaller but significant degrees of proliferation in response to many different organisms. Our data offers insights into the maintenance of immunological memory. All clones examined were CD3+, CD4+, CD8-, TCR alpha beta+, and TCR delta-. The ratio of TCR alpha beta+ to TCR delta+ cells among peripheral blood lymphocytes increased during polyclonal culture in the presence of parasite. The high frequency of such cells in peripheral blood (1/800-1/9000), and their response to a wide range of geographically different Plasmodium falciparum isolates and clones by both proliferation and lymphokine secretion (predominantly IFN-gamma) with a high degree of sensitivity (less than 1 parasite/microliters blood in some cases) suggests that these cells must be quickly activated following malaria infection. Their contribution to the outcome of the disease (protection/immunopathology) may be significant.

Animals↗
PubMed1987

Monoclonal antibodies that bind to the My23 human myeloid cell surface molecule: epitope analysis and antigen modulation studies.

It has previously been shown that the AML-2-23 monoclonal antibody (MoAb) reacts with a glycoprotein on differentiated myeloid cells. The antigen, My23, is released from these cells in culture and is also detectable in normal human plasma. We have now raised a panel of MoAbs against the soluble form of the antigen which reacts with monocytes and calcitriol-treated U937 and HL-60 myeloid cell lines, but not with lymphocytes or undifferentiated U937 and HL-60 cells. As with the AML-2-23 MoAb, the anti-My23 MoAbs immunoprecipitated a 50,000-55,000 protein from calcitriol treated HL-60 cells. Besides binding to cell surface My23, all eight MoAbs as well as the 63D3 MoAb reacted with crude and purified forms of soluble My23. A novel ELISA epitope analysis assay was developed to identify four distinct antigenic determinants on My23. Thus, the soluble and cell surface forms of My23 share several antigenic determinants and are biochemically very similar. Pooled anti-My23 caused selective patching, capping and clearing of My23 from the cell surface. My23 was not associated with cell surface, HLA-DR, HLA-A,B,C, beta 2-microglobulin or the Fc receptors for IgG or IgA. These anti-My23 MoAbs should be of importance in antigen functional studies and in clinical treatment protocols for patients with acute myelogenous leukemia. Furthermore, we have shown that a soluble myeloid differentiation antigen can serve as an effective immunogen for the preparation of MoAbs against important cell surface molecules thus obviating many problems inherent in the use of whole cells or detergent lysate-derived immunoprecipitates as immunogens.

Animals↗
PubMedDate not supplied

Remodeling of the coronary artery after vascular injury.

Vascular injury, such as angioplasty, induces a complex healing process that is analogous to generalized wound healing. Following initial injury, platelet thrombi and an acute inflammatory response occur, followed by cellular inhibition by monocytes/macrophages, proliferation of vascular smooth muscle cells, and extracellular matrix deposition. The injury repair concludes with organization of the matrix and reendothelialization. Recent studies suggest that restenosis or renarrowing after vascular injury is due to two components: a cellular proliferative process leading to intimal hyperplasia and remodeling of the vessel with a change in vessel geometry. Animal and clinical studies have shown that at least 60% of restenosis can be explained by unfavorable remodeling with vessel constriction rather than intimal hyperplasia. Although a number of factors appear to be associated with remodeling, alterations in extracellular matrix metabolism may be most important.

Angioplasty, Balloon↗