The emergence of national electronic health record architectures in the United States and Australia: models, costs, and questions

Emerging electronic health record models present numerous challenges to health care systems, physicians, and regulators. This article provides explanation of some of the reasons driving the development of the electronic health record, describes two national electronic health record models (currently developing in the United States and Australia) and one distributed, personal model. The US and Australian models are contrasted in their different architectures ("pull" versus "push") and their different approaches to patient autonomy, privacy, and confidentiality. The article also discusses some of the professional, practical, and legal challenges that health care providers potentially face both during and after electronic health record implementation.     

Routes to transplant tolerance versus rejection; the role of cytokines

The alloimmune response can be divided into specific junctures where critical decisions between tolerance and immunity are made which define the outcome of the transplant. At these "decision nodes" various cytokines direct alloresponsive T cells to develop either a proinflammatory response aimed at graft destruction or an immunoregulatory response facilitating graft acceptance. This review will focus on the role of these cytokines in influencing the progression of an alloimmune response leading ultimately to either allograft survival or rejection.     

Development and Evaluation of an Interactive CD-ROM Refusal Skills Program to Prevent Youth Substance Use: “Refuse to Use”

An interactive CD-ROM program designed to reduce adolescent substance use was developed and evaluated. The program uses video vignettes to teach refusal skills and socially acceptable responses to substance use situations, specifically offers of marijuana. In a randomized pretest-to-posttest experiment with 74 public school students from six classes in three high schools, significant changes were observed at posttest on (1) the adolescent's personal efficacy to refuse the offer of marijuana, (2) the adolescent's intention to refuse marijuana if offered, and (3) the adolescent's perceptions of the social norms associated with substance use and the importance of respecting another's decision to refuse a drug offer. In addition, adolescents in the treatment condition were able to recall approximately 50% of the portrayed refusal strategies. Findings are discussed with regard to the potential benefits of an interactive multimedia approach for conducting substance use interventions.     

Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance

Therapeutic application of broadly reactive anti-T cell antibodies can lead not only to potent immunosuppression but also to profound and long-lived T cell depletion. We reasoned that a strategy that almost exclusively targets activated cytopathic donor reactive T cells and spares immunoregulatory networks might prove to be an exceptionally potent and highly selective means of producing long-term engraftment and tolerance. Herein we show that the combined administration of rapamycin and agonist IL-2- and antagonist IL-15-related cytolytic fusion proteins provides for long-term engraftment/tolerance in exceptionally stringent allotransplant models by (1) limiting the early expansion of activated T cells, (2) preserving and even exaggerating their subsequent apoptotic clearance, and (3) further amplifying the depletion of these activated T cells by antibody-dependent mechanisms, while (4) preserving CD4+CD25+ T cell-dependent immunoregulatory networks.     

A novel ELISpot method for adherent cells

The purpose of this study was to develop an enzyme-linked immunospot assay (ELISpot assay) that can be used with human adherent cells. While standard enzyme-linked immunosorbent assays (ELISAs) are available and widely used and ELISpot assays are used for nonadherent lymphocytes, no ELISpot assay has been developed for adherent cells. We used primary human fibroblasts from four different tissues (myometrium, lung, gingiva, and orbit), either unstimulated or interleukin (IL)-1beta-activated, to evaluate an ELISpot assay. Antibody pairs for IL-6 and IL-8 were used and results were compared to a standard ELISA. We found that we could reliably detect IL-6 and IL-8 spots with as few as 10 fibroblasts. Optimal cell numbers were 50 cells per well incubated for 8 h, although spots appeared as early as 2 h after incubation. Spots were absent when cells, primary, or secondary anti-cytokine antibodies were omitted from the protocol. Spot number and size can be ascertained using current automated ELISpot reader technology. The frequency of IL-6 and IL-8-producing human fibroblasts could also be determined. For example, 60% of the lung fibroblasts express IL-6, but IL-8 can be detected from only 40% of the cells. Approximately 80% of the human orbital fibroblasts make IL-6, whereas approximately 50% generate IL-8 following IL-1beta stimulation. These new findings show that fibroblasts from different human tissues display different frequencies of cytokine production and this further supports the concept of fibroblast diversity. The sensitivity of this new ELISpot assay is adequate for cytokine detection in just a few cells, unlike the standard ELISA. It should permit ascertaining the frequency of fibroblasts and other adherent cells that produce cytokines and, if desired, can be used in tandem with a standard ELISA to determine total cytokine produced. Moreover, the assay is suitable for normal human adherent cells that are often short-lived and difficult to cultivate.     

Lipophosphoglycan expression and virulence in Ricin-resistant variants of Leishmania major

Lipophosphoglycan (LPG) of Leishmania is a polymorphic molecule comprising an alkylglycerol anchor, a conserved oligosaccharide core and a species-specific polymer of oligosaccharide repeats joined by phosphodiester bonds. This molecule, together with the membrane polypeptide gp63, has been implicated as a parasite receptor for host macrophages. To examine the role of LPG in parasite infectivity glycosylation variants of Leishmania major were generated by chemical mutagenesis of a virulent cloned line V121 and variants with modified LPG selected using the galactose-specific lectin Ricinus communis II (RCA II). Twenty RCA II-resistant primary clones were generated. Analysis of LPG profile by immunoblotting using LPG-specific monoclonal and polyclonal antibodies revealed that some of the clones were LPG-deficient. Three clones that did not bind any LPG-specific antibodies but expressed normal levels of the M_r 63 000 glycoprotein (gp63), a second parasite receptor for host, were chosen for detailed studies.All three clones expressed, at least to some extent, a surface molecule which could be labeled by mild periodate oxidation and sodium borotritide and behaved like LPG by hydrophobic interaction chromatography. All clones also bound a well-characterized monoclonal antibody L157 directed to the core oligosaccharide of LPG, but did not bind another monoclonal antibody, CA7AE, to an epitope on a repeating unit shared by Leishmania donovani and L. major LPG. A third monoclonal antibody, 5E6, recognizing LPG on the surface of wild-type V121 promastigotes bound only to RCA II-resistant clone 3A2-C3 and was restricted to an internal structure. The LPG molecule that this clone expressed was a form of LPG by its chromatographic behavior and by its monosaccharide and alkylglycerol composition. Clone 3A2-C3 was the only one to infect mice in vivo and survive in macrophages in vitro, albeit at a much reduced rate compared to wild-type V121 promastigotes. The data suggest that some form of LPG may be necessary to ensure parasite infectivity.     

The putative role of fibroblasts in the pathogenesis of Graves' disease: evidence for the involvement of the insulin-like growth factor-1 receptor in fibroblast activation

Graves' disease when fully expressed affects the thyroid gland and connective tissues of the orbit and pretibium. While the glandular disease is relatively well-characterized, the pathogenesis of the orbital and dermal components remains enigmatic. In the following article, we review some of the evidence suggesting that fibroblast activation in Graves' disease might play an integral role in the tissue remodeling associated with ophthalmopathy. The thyrotropin receptor (TSHR) is expressed at low levels in several connective tissue depots and by their derivative fibroblasts, including those from the orbit. Little direct evidence currently links extra-thyroidal TSHR expression with Graves' disease. Very recent observations now implicate the insulin-like growth factor-1 receptor (IGF-1R) as a fibroblast activating antigen. When immunoglobulins from patients with the disease, with or without clinical ophthalmopathy, bind IGF-1R on the surface of fibroblasts, the receptor becomes activated and upregulates the expression of two T lymphocyte chemoattractants, IL-16 and RANTES. Thus, IGF-1R may represent a second self-antigen with a pathogenic role in extra-thyroidal Graves' disease.     

Water intake during the development of renal hypertension (2K-1C) in mice

For both practical and methodological reasons, mice have been the most widely employed species for development of transgenic and gene knockin and knockout animals. However, basic behavioral and physiology control and regulatory mechanisms in mice are not well characterized. To broaden our understanding of the processes maintaining body fluid and blood pressure homeostasis in the mouse, the objectives of this study were to evaluate voluntary water, and sodium intakes during the development of renal hypertension and to examine the relationship between hypertension and the quantities of water and salt ingested. In male, C57BL/6J mice, two-kidney, one-clip renal hypertension (2K-1C) was induced, and water and 1.8% NaCl intakes were monitored for 2 weeks. At the end of this period, all animals received arterial catheters for direct recording of blood pressure. The mice that received renal artery clips were sorted into hypertensive (152+/-4 mm Hg) and normotensive (122+/-2 mm Hg) groups and were compared to control (117+/-4 mm Hg) animals that underwent a sham renal clipping procedure. Hypertensive 2K-1C animals had significantly elevated water intake compared to control animals. On most of the postsurgical days, the normotensive 2K-1C animals did not display increased water intake in comparison to the control group. No significant effect was detected for 1.8% saline intake between any of the pairs of groups. In summary, the reduction of blood flow to a single kidney in the 2K-1C model of renal hypertension induces high blood pressure accompanied by sustained hyperdipsia in the mouse.     

Risks of AKI and Major Adverse Clinical Outcomes in Patients with Severe Acute Respiratory Syndrome or Coronavirus Disease 2019

BackgroundSevere acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) are closely related. The effect of AKI on the clinical outcomes of these two conditions is unclear.MethodsThis retrospective, territory-wide cohort study used an electronic public healthcare database in Hong Kong to identify patients with SARS or COVID-19 by diagnosis codes, virologic results, or both. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death.ResultsWe identified 1670 patients with SARS and 1040 patients with COVID-19 (median ages, 41 versus 35 years, respectively). Among patients with SARS, 26% met the primary endpoint versus 5.3% of those with COVID-19. Diabetes mellitus, abnormal liver function, and AKI were factors significantly associated with the primary endpoint among patients with either SARS or COVID-19. Among patients with SARS, 7.9%, 2.1%, and 3.7% developed stage 1, stage 2, and stage 3 AKI, respectively; among those with COVID-19, 6.6%, 0.4%, and 1.1% developed stage 1, stage 2, and stage 3 AKI, respectively. In both groups, factors significantly associated with AKI included diabetes mellitus and hypertension. Among patients with AKI, those with COVID-19 had a lower rate of major adverse clinical outcomes versus patients with SARS. Renal function recovery usually occurred within 30 days after an initial AKI event.ConclusionsAKI rates were higher among patients with SARS than those with COVID-19. AKI was associated with major adverse clinical outcomes for both diseases. Patients with diabetes mellitus and abnormal liver function were also at risk of developing severe consequences after SARS and COVID-19 infection.