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.     

Degradation of tissue-type plasminogen activator by human monocyte- derived macrophages is mediated by the mannose receptor and by the low- density lipoprotein receptor-related protein

The balance of tissue-type plasminogen activator (t-PA) production and degradation determines its concentration in blood and tissues. Disturbance of this balance may result in either increased or decreased proteolysis. In the present study, we identified the receptor systems involved in the degradation of t-PA by human monocytes/macrophages in culture. Monocytes were cultured and became macrophages within 2 days. At 4 degrees C, 125I-t-PA bound to macrophages with high (apparent dissociation constant [kd], 1 to 5 nmol/L) and low affinity (kd > 350 nmol/L). At 37 degrees C, the cells internalized and degraded t-PA via the high affinity binding sites, which were partially inhibited by mannan. The low affinity binding sites were 6-aminohexanoic acid- inhibitable and not involved in t-PA degradation. Degradation of t-PA was upregulated during differentiation of monocytes to macrophages. Dexamethasone further upregulated the mannan-inhibitable t-PA degradation. Lipopolysaccharide downregulated both mannan-inhibitable and non-mannan-inhibitable t-PA degradation. Non-mannan-inhibitable degradation was completely blocked by recombinant 39-kD receptor- associated protein (RAP, inhibitor of lipoprotein receptor-related protein [LRP]), whereas mannan-inhibitable degradation was blocked by the addition of a monoclonal antibody against the mannose receptor. No differences between the degradation of t-PA and functionally inactivated t-PA were observed. We conclude that human monocyte-derived macrophages are able to bind, internalize, and degrade t-PA. Degradation of t-PA does not require complex formation with plasminogen activator inhibitors. The macrophages use two independently regulated receptors, namely, the mannose receptor and LRP, for the uptake and degradation of t-PA.     

Systemic use of non‐biologic corticosteroids in orofacial diseases

Systemic non‐biologic agents have long been in clinical use in medicine – often with considerable efficacy, albeit with some adverse effects – as with all medications. With the advent of biologic agents, all of which currently are restricted to systemic use, there is a growing need to ensure which agents have the better therapeutic ratio. The non‐biologic agents (NBAs) include a range of agents, most especially the corticosteroids (corticosteroids). This study reviews the corticosteroids in systemic use in management of orofacial mucocutaneous diseases; subsequent studies discuss corticosteroid‐sparing agents used in the management of orofacial diseases, such as calcineurin inhibitors used to produce immunosuppression; purine synthetase inhibitors; and cytotoxic and other immunomodulatory agents.     

Review of processing and analysis methods for DNA methylation array data

The promise of epigenome-wide association studies and cancer-specific somatic DNA methylation changes in improving our understanding of cancer, coupled with the decreasing cost and increasing coverage of DNA methylation microarrays, has brought about a surge in the use of these technologies. Here, we aim to provide both a review of issues encountered in the processing and analysis of array-based DNA methylation data and a summary of the advantages of recent approaches proposed for handling those issues, focusing on approaches publicly available in open-source environments such as R and Bioconductor. We hope that the processing tools and analysis flowchart described herein will facilitate researchers to effectively use these powerful DNA methylation array-based platforms, thereby advancing our understanding of human health and disease.     

Gender-specific protective effect of hemoglobin on arsenic-induced skin lesions.

Chronic arsenic poisoning remains a public health crisis in Bangladesh. As arsenic has been shown to bind to human hemoglobin (Hb), hematologic mechanisms may play a role in the pathway through which arsenic exerts its toxicity. Two separate studies, a case-control and a cohort, were conducted to investigate the role of Hb in the development of arsenic-induced skin lesions. In the first, conditional logistic regression was used to investigate the effect of Hb on skin lesions among 900 case-control pairs from Pabna, Bangladesh, in which individuals were matched on gender, age, and location. In the second, mixed linear regression models were used to examine the association between toenail arsenic, urinary arsenic, and Hb within a cohort of 184 individuals from 50 families in the same region who did not have arsenic-induced skin lesions. Hb was significantly associated with skin lesions but this association was gender specific. In males, a 40% reduction in the odds of skin lesions occurred for every 1 g/dL increase in Hb (odds ratio, 0.60; 95% confidence interval, 0.49-0.73). No effect was observed for females (odds ratio, 1.16; 95% confidence interval, 0.92-1.46). In the cohort of 184 individuals, no associations between toenail arsenic or urinary arsenic species and Hb levels were observed. Low Hb levels may exacerbate the detrimental health effects of chronic arsenic poisoning. Whereas providing clean water remains the optimal solution to Bangladesh's problem of arsenic poisoning, improving nutrition and reducing iron-deficiency anemia may ameliorate negative health effects, such as skin lesions in individuals who have been exposed.     

Using electroactive substrates to pattern the attachment of two different cell populations

This report describes the development of an electroactive mask that permits the patterning of two different cell populations to a single substrate. This mask is based on a self-assembled monolayer of alkanethiolates on gold that could be switched from a state that prevents the attachment of cells to a state that promotes the integrin-mediated attachment of cells. Monolayers were patterned into regions having this electroactive monolayer and a second set of regions that were adhesive. After Swiss 3T3 fibroblasts had attached to the adhesive regions of this substrate, the second set of regions was activated electrically to permit the attachment of a second population of fibroblast cells. This method provides a general strategy for patterning the attachment of multiple cell types and will be important for studying heterotypic cell-cell interactions.     

Ketoacidosis at the diagnosis of type 1 (insulin dependent) diabetes mellitus is related to poor residual beta cell function. Childhood Diabetes in Finland Study Group

The determinants of the degree of metabolic decompensation at the diagnosis of type 1 (insulin dependent) diabetes mellitus (IDDM) and the possible role of diabetic ketoacidosis in the preservation and recovery of residual beta cell function were examined in 745 Finnish children and adolescents. Children younger than 2 years or older than 10 years of age were found to be more susceptible to diabetic ketoacidosis than children between 2 and 10 years of age (< 2 years: 53.3%; 2-10 years: 16.9%; > 10 years: 33.3%). Children from families with poor parental educational level had ketoacidosis more often than those from families with high parental educational level (24.4% v 16.9%). A serum C peptide concentration of 0.10 nmol/l or more was associated with a favourable metabolic situation. Low serum C peptide concentrations, high requirement of exogenous insulin, low prevalence of remission, and high glycated haemoglobin concentrations were observed during the follow up in the group of probands having diabetic ketoacidosis at the diagnosis of IDDM. Thus diabetic ketoacidosis at diagnosis is related to a decreased capacity for beta cell recovery after the clinical manifestation of IDDM in children.     

Aortic aneurysm complicating bacterial endocarditis in childhood

Bacterial endocarditis is an uncommon diagnosis in childhood with significant morbidity and mortality. Aortic aneurysm as a complication is well described in adults but there are few reports in the paediatric literature. Two children with bacterial endocarditis are described, whose illnesses were complicated by aortic aneurysm formation requiring surgical intervention.