Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.     

Metabolic responses of the heart in acute myocardial infarction in man

Acute myocardial infarction evokes a characteristic neurohumoral response: Catecholamine release is increased, plasma contents of free fatty acids and glucose are elevated and glucose tolerance is diminished. To what degree the myocardium participates in this stress response was evaluated by sampling coronary sinus and arterial blood in 50 patients with acute transmural infarction. Studies were initiated an average of 8 hours after the clinical onset of infarction and were continued for up to 60 hours. A total of 173 separate metabolic studies were analyzed. Forty-one percent exhibited a pattern of predominant myocardial free fatty acid uptake (mean extraction ratio 24 percent) in the presence of elevated plasma free fatty acid and glucose contents (respective means 1,181 μmol/liter and 210 mg/100 ml). Myocardial extraction ratios for glucose, lactate and pyruvate were low (respective means 1.1, 4 and 11 percent). Twenty-one percent of the studies revealed normal myocardial metabolism and 18 percent showed enhanced carbohydrate uptake, as evidenced by increased myocardial extractions of lactate and pyruvate (respective means 42 percent) and of glucose (mean 5 percent). Plasma contents of glucose and free fatty acids were lower than in the predominant free fatty acid group (respective means 156 mg/100 ml and 743 μmol/liter). The remaining 20 percent of studies showed high plasma substrate contents and low myocardial substrate uptake suggesting metabolic breakdown. The free fatty acid metabolic pattern was observed in more than 50 percent of the studies performed at the time of or close to the occurrence of important clinical complications. Propranolol, 0.1 mg/kg intravenously, shifted myocardial substrate utilization from free fatty acids toward carbohydrates. The myocardial respiratory quotient increased from an average of 0.79 to 0.88 (P < 0.01).The study demonstrates that the metabolic patterns of the myocardium are influenced by the systemic response to stress. Beta adrenergic blockade changed substrate utilization of the myocardium, supporting the hypothesis that adrenergic activation plays an important role in these metabolic responses.     

Long term treatment of severe asthma with subcutaneous terbutaline

We have investigated the use of subcutaneous terbutaline in 17 patients with brittle asthma and five patients with chronic severe asthma. Twelve of the 17 patients with brittle asthma improved both subjectively and objectively (mean lowest daily PEF rising from 142 litres/min to 297 litres/min), with reduction in oral steroid dose, nebulized beta-agonist dose and number of hospital admissions. Both continuous infusion and 6-hourly divided dose regimens were equally effective. Only one of the five with chronic severe asthma showed any lasting response. Eighteen patients have continued to use subcutaneous terbutaline over long periods (2-40 months). Overall 11 patients suffered side-effects of usually minor degree, although one patient had to withdraw because of the development of painful subcutaneous nodules. We conclude that subcutaneous terbutaline delivered by infusion or by intermittent injections is a useful addition to the therapy of some patients with brittle asthma.     

The fate of the open canalicular system in surface and suspension- activated platelets

We have examined the movement of fibrinogen-gold (fgn-Au) complexes in platelets activated in suspension and by surface contact. Fgn-Au probes did not react with resting cells but were bound to the external membrane of platelets in suspension 5 seconds after addition of 1 U/mL of thrombin. At intervals over a period of 5 to 20 minutes, fgn-Au probes moved from the cell surface to peripheral and then deep channels of the open canalicular system (OCS). When platelets were surface activated by exposure to carbon-stabilized, formvar-coated grids for 5 to 20 minutes and then exposed to fgn-Au complexes for 5 minutes, probes were also observed in the OCS. At 5 minutes, over 40% of the platelets had concentrated fgn-Au in their OCS. Results after 10 minutes revealed 25% with gold-filled channels, 16% after 15 minutes, and 5% after 20 minutes. The decrease in frequency of OCS staining correlated with the increasing frequency of spread platelets, suggesting that tension produced by spreading may cause collapse of the OCS or that the OCS may evaginate onto the platelet during spreading. To evaluate the latter hypothesis, platelets were initially exposed to grids for 5 minutes and then incubated with fgn-Au for intervals of 5 to 20 minutes. The frequency of platelets with fgn-Au concentrated in the OCS was greatest at 5 minutes (44%) and decreased at the same rate as the frequency of spread platelets increased. Only 14.7% of the cells contained fgn-Au in the OCS after 20 minutes. These were primarily dendritic in form, while fully spread platelets rarely contained an OCS filled with the probe. The study indicates that fgn-Au particles are cleared to channels of the OCS independent of the mechanism of platelet activation. Fgn-Au that has been concentrated in the OCS at early stages of surface activation can be externalized during platelet spreading but remain internalized in suspension-activated cells. The OCS represents a membrane reservoir that can be evaginated onto the platelet surface during interaction with surfaces.     

Factors associated with potentially inappropriate medications use by the elderly according to Beers criteria 2003 and 2012

Background Potentially inappropriate medications (PIMs) should be avoided by the elderly because they possess a significant high risk for this population when a safer alternative is available. Therefore, the identification of prevalence and factors associated with PIMs should be considered as they provide valuable information that can be used to develop strategies to ensure patients’ safety. Objective To identify the prevalence and the clinical and socioeconomic–demographic factors that may be associated with PIMs use in the elderly, according to Beers criteria 2003 and its updated version 2012. And, as a secondary objective, a comparison between both criteria was performed. Setting Pharmacy of the Basic Health District Unit of the western district of Ribeirão Preto. Methods This cross-sectional observational study was conducted with the elderly, assisted by the Brazilian public health system. Data from patients were collected through a structured interview form. Beers criteria 2003 and 2012 were used to classify PIMs. The association between PIMs used and independent variables were analyzed by odds ratios. The differences between PIMs use according to Beers criteria 2003 and 2012 were analyzed by McNemar’s test and the agreement by kappa coefficient. Main outcome measure Prevalence and factors associated with PIMs use in Brazilian elderly outpatients. Results One thousand elderly patients were interviewed. High prevalence of PIMs use was observed, 48.0 and 59.2 % according to Beers criteria 2003 and 2012, respectively. The factors associated with PIMs use, common for both criteria, are female gender, self-medication, use of over the counter drugs, complaints related to adverse drug event, psychotropic medication, polypharmacy and some categories of drugs. PIMs use is different between Beers criteria 2003 and 2012 (McNemar’s test, p < 0.01), although a substantial agreement between these classifications was observed (kappa coefficient 0.635, 95% confidence intervals (0.588, 0.681). Conclusions Our study showed a high prevalence of PIMs use, which is associated with various clinical and social–demographic factors. When comparing both criteria through McNemar’s test, PIMs use was considered different. The differences may have occurred because medications with high prevalence of use in Brazil were included in Beers criteria 2012 .     

Virtual text and the growth of meaning in qualitative analysis

Qualitative researchers frequently analyze data in the form of narrative, such as responses to open-ended interview questions. Researchers acknowledge the validity of more than one interpretation of the same narratives but, to date, have offered little justification for multiple valid interpretations. A concept from literary theory, “the virtual text,” is presented to help explain the mechanism of multiple interpretations and provide a justification for their validity. An example from the first author's research is provided. © 1996 John Wiley & Sons, Inc.     

Functional evaluation of immunoregulatory molecules HLA-G,galectin-1, and IL-10 in people living with HIV

Objective(s):Investigate polymorphisms and expressions of human leukocyte antigen-G (HLA-G), galectin-1 (Gal-1), and interleukin-10 (IL-10) in people living with HIV (PLHIV) with and without comorbidities to help understanding the mechanisms involved in triggering these disorders in PLHIV and in their prognosis.Design:Here we evaluated the potential correlation between the genetic polymorphism and/or protein levels of HLA-G, Gal-1, and IL-10 with and without comorbidities of PLHIV.Methods:Two hundred HIV patients under antiretroviral treatment (83 with comorbidities and 117 without comorbidities) and 200 healthy individuals (controls) were genotyped, using PCR, for HLA-G 14-base pair polymorphism located at the 3’ untranslated region in exon 8 insertion/insertion (Ins/Ins: low HLA-G expression) or deletion/deletion (Del/Del: high HLA-G expression). Soluble levels of HLA-G (sHLA-G), Gal-1, and IL-10 were quantified by enzyme-linked immunosorbet assay.Results:HIV patients without comorbidities exhibited higher frequency of 14-base pair Del/Del genotype than HIV patients with comorbidities. As expected, HIV patients Ins/Ins with and without comorbidities produced less sHLA-G than controls. However, HIV patients Del/Del with comorbidities expressed sHLA-G more than controls and HIV patients Del/Del without comorbidities. Interestingly, patients that showed low levels sHLA-G, and presence of comorbidities, exhibited high Gal-1 serum levels. However, an increase in soluble levels of IL-10 in PLHIV was observed when compared to controls, especially in the PLHIV group without comorbidities suggesting, a protective role of IL-10 in the development of comorbidities.Conclusions:These data suggested that the high expression of sHLA-G and IL-10 or Gal-1 could be associated and could be associated with the development or not of comorbidities in PLHIV.