Monocyte NLRP3 inflammasome and interleukin-1β activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

Introduction: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1β secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers.

Lung Inflammation in alpha-1-antitrypsin deficient individuals with normal lung function.

Background: Alpha-1-antitrypsin deficient (AATD) individuals are prone to develop early age of onset chronic obstructive pulmonary disease (COPD) more severe than non-genetic COPD. Here, we investigated the characteristics of lower respiratory tract of AATD individuals prior to the onset of clinically significant COPD.

Methods: Bronchoalveolar lavage was performed on 22 AATD with normal lung function and 14 healthy individuals.

Comparison of chlordecone and estradiol effects on splenic T-cells in (NZBxNZW)F(1) mice.

Previous studies have shown that treatment of ovariectomized females with 17-beta estradiol (E2) accelerates the development of autoimmunity in the (NZBxNZW)F(1) murine lupus model. Treatment with estrogenic organochlorine pesticides (OCPs) such as chlordecone produces a similar effect. Although it is reasonable to postulate that the effects of chlordecone and related OCPs on autoimmunity are due to their estrogenic effects, this has not been clearly demonstrated.

Angiotensin-(1-7) as an antihypertensive, antifibrotic target.

Over the past two decades, enormous progress has been made in understanding the possible physiological significance of alternate renin-angiotensin system processing pathways and angiotensin fragments, such as angiotensin (Ang)-(1-7). Evidence from in vivo and ex vivo studies in humans and various animal models suggests a possible role for this heptapeptide in blood pressure regulation, although the mechanisms involved are most likely indirect, involving some combination of bradykinin and nitric oxide signaling. In contrast, a growing body of in vivo and in vitro evidence supports direct cardioprotective (antihypertrophic, antifibrotic) actions of Ang-(1-7).

Focal adhesion kinase expression in human neuroblastoma: immunohistochemical and real-time PCR analyses.

Purpose: The focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase important in signaling between cells and their extracellular matrix. Studies have shown that FAK expression is up-regulated in several human tumors and is related to tumor progression. We recently found an increase in p125(FAK) expression in human neuroblastoma cells lines and wished to determine its expression in human neuroblastoma specimens and evaluate for a possible correlation between p125(FAK) expression and known prognostic factors for neuroblastoma.

Diminished prolactin from chlordecone treatment in ovariectomized (NZBxNZW)F(1) mice.

In murine models of systemic lupus erythematosus (SLE), administration of either prolactin or estradiol (E2) increases autoimmunity, and there is evidence that elevated prolactin in response to E2 administration may contribute substantially to E2 effects. Hormonal influence on SLE can extend to environmental agents, as demonstrated by the ability of estrogenic organochlorine pesticides such as chlordecone to accelerate the development of lupus in female (NZBxNZW)F(1) mice. In order to evaluate a potential role for prolactin in chlordecone effects on SLE, it was necessary to first determine whether treatment with chlordecone, like E2, results in elevated prolactin levels.

Acceleration of autoimmunity by organochlorine pesticides: a comparison of splenic B-cell effects of chlordecone and estradiol in (NZBxNZW)F1 mice.

The weakly estrogenic organochlorine pesticide chlordecone can accelerate the development of systemic lupus erythematosus (SLE) in ovariectomized (NZBxNZW)F1 mice, with a shortened time to appearance of autoantibodies and disease similar to that produced by treatment with the sex hormone 17beta-estradiol (E2). It is unclear whether chlordecone and E2 share the same pathways in mediating this effect. The effects of chlordecone and E2 treatment on splenic germinal center (GC) and marginal zone B cells were examined.

Comparison of chlordecone effects on autoimmunity in (NZBxNZW) F(1) and BALB/c mice.

It has been shown previously that chronic treatment with relatively low doses of chlordecone accelerates the development of systemic lupus erythematosus (SLE) in ovariectomized female (NZBxNZW) F(1) mice. In this study, the effect of chronic chlordecone treatment on SLE was evaluated in ovary-intact female (NZBxNZW) F(1) mice, as well as in female mice from a strain that is not lupus-prone, BALB/c. Chlordecone was administered chronically via implanted sustained-release pellets, and mice were monitored over time for the appearance of elevated autoantibodies (anti-dsDNA and anti-chromatin) and for the development of renal impairment, both indicators of SLE.

Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice.

The effect of the inducible forms of 70 kDa heat shock protein (Hsp70i) on acetaminophen (APAP) hepatotoxicity was assessed in an Hsp70i knockout mouse model. Absence of the Hsp70i protein in liver was verified by monitoring Hsp levels in knockout and control mice after heat stress (41.5 degrees C water bath immersion for 30 min).

Manipulating heat shock protein expression in laboratory animals.

Upregulation of heat shock proteins (Hsps) has been observed to impart resistance to a wide variety of physical and chemical insults. Elucidation of the role of Hsps in cellular defense processes depends, in part, on the ability to manipulate Hsp expression in laboratory animals. Simple methods of inducing whole body hyperthermia, such as warm water immersion or heating pad application, are effective in producing generalized expression of Hsps.

Heat shock proteins and acquired resistance to uranium nephrotoxicity.

Previous studies have demonstrated that prior exposures to uranium can produce acquired resistance to uranium nephrotoxicity. In this study, the potential role for heat shock proteins (Hsps) in acquired resistance to uranium nephrotoxicity was explored. Pretreatment of male Sprague-Dawley rats with a conditioning dose of uranyl acetate (5 mg/kg, i.

Pediatric sand aspiration: case report and literature review.

Sand aspiration is a rare but life-threatening event that occurs in the pediatric and adult populations after cave-ins or near drownings. We report the case of a 10-year-old boy who suffered from aspiration of particulate matter after being buried in sand. In addition, we performed a literature review regarding similar cases and their treatment of aspiration of significant amounts of particulate matter.

VEGF receptors are differentially expressed by neuroblastoma cells in culture.

Background/purpose: Vascular endothelial growth factor (VEGF) is best known for its angiogenic properties, but its mitogenic capacity may be more important for tumorigenesis. The ability of VEGF to induce specific biologic activities may be dependent on the amount and type of VEGF receptors present. The authors hypothesize that neuroblastoma cells express specific VEGF receptors and that their expression may be altered when the cells are exposed to differing cytokines and culture environments.

Differential expression of Bcl-2 and Bax may enhance neuroblastoma survival.

Background/purpose: Aggressive tumors may alter their expression of Bcl-2 proteins to decrease apoptosis and increase survival. The authors reported previously that neuroblastoma cells have diminished apoptosis when placed in coculture with hepatocytes to stimulate a metastatic environment. It was hypothesized that the expression of proapoptotic (Bax) and prosurvival (Bcl-2 and Mcl-1) proteins would be altered in neuroblastoma cells grown in a cell culture model of metastatic neuroblastoma.

Measurement of arsenic bioavailability in soil using a primate model.

Several studies have shown limited absorption of arsenic from soils. This has led to increased interest in including measurements of arsenic relative bioavailability from soils in the calculation of risks to human health posed by arsenic-contaminated sites. Most of the information in the literature regarding arsenic bioavailability from soils comes from studies of mining and smelter sites in the western United States.

Significance of asymmetric sites in choosing siderophores as deferration agents.

The syntheses of the microbial iron chelators L-fluviabactin, its unnatural enantiomer, D-fluviabactin, L-homofluviabactin, and L-agrobactin, are described. The key steps involve the selective bis-acylation of the terminal nitrogens of norspermidine, spermidine, or homospermidine with 2,3-bis(benzyloxy)benzoic acid in the presence of 1,1-carbonyldiimidazole, followed by coupling of the N-hydroxysuccinimide ester of CBZ-protected L- or D-threonine with the central nitrogen. The effectiveness of each of these ligands in supporting the growth of Paracoccus denitrificans in a low-iron environment and the ability of these compounds to promote iron uptake are evaluated.

Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives.

A new means of accessing N(1)-cyclopropylmethyl-N(11)-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N(1)-cyclopropylmethyl-2,10-dihydroxy-N(11)-ethylnorspermine [(2R,10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N(1),N(11)-diethylnorspermine (DENSPM) or (2R,10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)(2)DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives.

"Physician, heal thyself": how teaching holistic medicine differs from teaching CAM.

The term complementary and alternative medicine (CAM) has been adopted to describe a system of health care not generally recognized as part of mainstream medical practice. It is often conflated with an older term, holistic medicine, which can briefly be defined as the art and science of healing the whole person-body, mind, and spirit-in relation to that person's community and environment. Coursework in CAM is now offered in at least two thirds of U.

Polyamine analogue antidiarrheals: a structure-activity study.

The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals.

Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives.

The synthesis of four hydroxylated polyamine analogues, (2R, 10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine, (2S,10S)-N(1), N(11)-diethyl-2,10-dihydroxynorspermine, (3S,12S)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, and (3R,12R)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[(2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2,3-epoxypropyl]-N-ethyl trifluoromethanesulfonamide to N,N'-dibenzyl-1,3-diaminopropane.

Immunochemical comparison of 3'-hydroxyacetanilide and acetaminophen binding in mouse liver.

The hepatotoxicity of the analgesic acetaminophen is believed to be mediated by covalent binding to critical proteins. Radiolabeled 3'-hydroxyacetanilide, a regioisomer of acetaminophen, covalently binds to proteins at levels similar to those of acetaminophen, but without toxicity. Covalent binding has recently been detected by Western blot to a 50-kDa microsomal protein that comigrated with CYP2E1 and was accompanied by a loss of the CYP2E1 activity.

Protection against hepatotoxicity by a single dose of amphetamine: the potential role of heat shock protein induction.

Amphetamine has been shown previously to increase levels of the inducible 70-kDa heat shock protein (hsp70i) in mouse liver. In the present study, the hepatic concentrations of a variety of hsps in livers of mice pretreated with amphetamine (15 mg/kg, i.p.

Differential heat shock protein induction by acetaminophen and a nonhepatotoxic regioisomer, 3'-hydroxyacetanilide, in mouse liver.

The effect of acetaminophen (APAP) and 3'-hydroxyacetanilide (AMAP) on heat shock protein (hsp) induction in mouse liver was examined using Western blotting and immunohistochemistry. Western blots from APAP (200 mg/kg i.p.

Effects of prenatal ethanol exposure on parvalbumin-expressing GABAergic neurons in the adult rat medial septum.

Exposure of human fetuses to ethanol often results in the fetal alcohol syndrome. Animal models of fetal alcohol syndrome have been developed and used to examine the consequences of prenatal ethanol exposure on the central nervous system. The objective of this study was to determine the long-term effects of prenatal ethanol exposure on parvalbumin-expressing (PA+) GABAergic neurons of the rat medial septum.

Ca(2+)-ATPases in the cochlear duct.

Differing levels of the Ca(2+)-ATPase enzymes that reside on the plasma membrane (PM) and on the endoplasmic reticulum (ER) were identified in individual rat cochlear tissues by the use of a semi-quantitative enzyme-linked immunosorbent assay (ELISA). Unlike other studies, a specific antibody to PM Ca(2+)-ATPase was used to detect significantly greater levels (about 2x) of PM Ca(2+)-ATPase in the stria vascularis (SV) than that in the spiral ligament (SL) and organ of Corti (OC) tissues. Similarly, levels of ER Ca(2+)-ATPase were also significantly higher in the SV than in the SL and OC tissues.