S100A8 promotes migration and infiltration of inflammatory cells in acute anterior uveitis

PubMed Central

Wang, Yuqin; Zhang, Zuhui; Zhang, Laihe; Li, Xinxin; Lu, Rui; Xu, Peipei; Zhang, Xuhong; Dai, Mali; Dai, Xiaodan; Qu, Jia; Lu, Fan; Chi, Zailong

2016-01-01

Uveitis, the pathologic condition of inflammation of the uvea, frequently leads to severe vision loss and blindness. S100A8 is a calcium-binding protein which mainly expresses in granulocytes and monocytes and plays a prominent role in the regulation of inflammatory processes and immune response. Here, we determined the role of S100A8-positive cells in acute anterior uveitis (AAU) and keratitis. In rat models of endotoxin (lipopolisaccharide, LPS) -induced uveitis (EIU) and keratitis, S100A8-positive granulocytes and monocytes increased significantly in the iris-ciliary body and cornea as well as in the blood. Interestingly, Glucocorticoids slightly increased S100A8 levels in leukocytes, but reduced its presence significantly in the iris-ciliary body after LPS injection. Moreover, inhibition of NF-kB activation remarkably suppressed both progression of AAU and total S100A8 levels in leukocytes and the iris-ciliary body after LPS administration. Additionally, S100A8 protein level was also found to be elevated in the serum of AAU patients parallel with the progression of AAU through the designated clinical stages. Thus, S100A8 plays a pivotal role in the processes of AAU through involvement in migration and infiltration of S100A8-positive cells. Our findings suggest that serum levels of S100A8 protein can be used to monitor inflammatory activity in AAU. PMID:27786310

S100A8 promotes migration and infiltration of inflammatory cells in acute anterior uveitis.

PubMed

Wang, Yuqin; Zhang, Zuhui; Zhang, Laihe; Li, Xinxin; Lu, Rui; Xu, Peipei; Zhang, Xuhong; Dai, Mali; Dai, Xiaodan; Qu, Jia; Lu, Fan; Chi, Zailong

2016-10-27

Uveitis, the pathologic condition of inflammation of the uvea, frequently leads to severe vision loss and blindness. S100A8 is a calcium-binding protein which mainly expresses in granulocytes and monocytes and plays a prominent role in the regulation of inflammatory processes and immune response. Here, we determined the role of S100A8-positive cells in acute anterior uveitis (AAU) and keratitis. In rat models of endotoxin (lipopolisaccharide, LPS) -induced uveitis (EIU) and keratitis, S100A8-positive granulocytes and monocytes increased significantly in the iris-ciliary body and cornea as well as in the blood. Interestingly, Glucocorticoids slightly increased S100A8 levels in leukocytes, but reduced its presence significantly in the iris-ciliary body after LPS injection. Moreover, inhibition of NF-kB activation remarkably suppressed both progression of AAU and total S100A8 levels in leukocytes and the iris-ciliary body after LPS administration. Additionally, S100A8 protein level was also found to be elevated in the serum of AAU patients parallel with the progression of AAU through the designated clinical stages. Thus, S100A8 plays a pivotal role in the processes of AAU through involvement in migration and infiltration of S100A8-positive cells. Our findings suggest that serum levels of S100A8 protein can be used to monitor inflammatory activity in AAU.

Botulinum toxin-induced acute anterior uveitis in a patient with Behçet's disease under infliximab treatment: a case report.

PubMed

Sasajima, Hirofumi; Yagi, Syunsuke; Osada, Hiromu; Zako, Masahiro

2017-05-04

Injections of lipopolysaccharide in animal models generate acute anterior uveitis (also known as endotoxin-induced uveitis), but the effects of lipopolysaccharide injection are unknown in humans. We describe an unusual case in which acute anterior uveitis was dramatically activated subsequent to botulinum toxin injection in a patient with Behçet's disease but the acute anterior uveitis was satisfactorily attenuated by infliximab. A 53-year-old Japanese man had normal ocular findings at his regularly scheduled appointment. He had been diagnosed as having incomplete-type Behçet's disease 11 years before. Three years after the diagnosis he was given systemic infusions of 5 mg/kg infliximab every 8 weeks and he had not experienced a uveitis attack for 8 years with no treatment other than infliximab. Two days after the eye examination, he received intracutaneous botulinum toxin injections to treat axillary hyperhidrosis on both sides. Three hours after the injections, he noted rapidly increasing floaters in his right eye. Four days after the injections, his right eye showed severe acute anterior uveitis with deteriorated aqueous flare and anterior vitreous opacity. He received his scheduled infliximab injection, and the right acute anterior uveitis immediately attenuated. Botulinum toxin may have clinical effects similar to those of lipopolysaccharide in endotoxin-induced uveitis models. To the best of our knowledge, this is the first report to suggest that botulinum toxin may trigger acute anterior uveitis, although the precise mechanism is still unclear.

Topically applied standardized aqueous extract of Curcuma longa Linn. suppresses endotoxin-induced uveal inflammation in rats.

PubMed

Agarwal, Renu; Gupta, S K; Agarwal, Puneet; Srivastava, Sushma

2013-10-01

Aqueous extract of C. longa when administered 4 h after induction of E. coli lipopolysaccharide-induced uveitis in rats showed significantly suppressed inflammation with a significantly lower mean clinical grade, histopathological grade and aqueous humor (AH) protein level compared to vehicle treated group. Although, prednisolone group showed significantly lower clinical grade, histopathological grades and AH protein levels compared to C. longa group, TNF-alpha levels did not differ significantly. Moreover, when the aqueous extract was administered starting from 3 days before induction of uveitis, the mean clinical and histopathological grade as well as AH protein and TNF-alpha levels were comparable to C. longa group when treatment was administered 4 h after induction of uveitis. It is concluded that topically applied standardized aqueous extract of C. longa suppresses endotoxin-induced uveitis in rats by reducing TNF-alpha activity.

Drug-induced uveitis

PubMed Central

2013-01-01

A number of medications have been associated with uveitis. This review highlights both well-established and recently reported systemic, topical, intraocular, and vaccine-associated causes of drug-induced uveitis, and assigns a quantitative score to each medication based upon criteria originally described by Naranjo and associates. PMID:23522744

Experimental arthritis and uveitis in rats associated with Mycobacterium butyricum.

PubMed

Petty, R E; Hunt, D W; Mathers, D M; McCormick, A Q; Barker, H; Southwood, T R; Corson, L

1994-08-01

To determine if the anterior uveitis associated with adjuvant arthritis (AA) in the rat can be passively transferred with arthritis to syngeneic recipients using spleen cells or T cell lines prepared from animals given complete Freund's adjuvant (CFA) and Mycobacterium butyricum (M. butyricum) in incomplete Freund's adjuvant (IFA). Spleen cells from Lewis or Lewis SsN rats given IFA, CFA, type I collagen in IFA (CI-IFA), or type II collagen in IFA (CII-IFA) were administered to naive rats or rats treated with pertussis toxin or bacterial endotoxin. Three CD4+ T cell lines, propagated from CFA injected rats and maintained in vitro with M. butyricum (M-1), bovine proteoglycan (PR-1) or an extract of M. butyricum (MBE-1) were administered to naive or immunosuppressed rats. The arthritogenic and uveitogenic properties of these cell preparations and intradermal MBE-IFA, CII-IFA and intraperitoneal (ip) M. butyricum without adjuvant were evaluated. Uveitis was observed in 15/69 (22%) arthritic rats given CFA. Spleen cells prepared from CFA injected rats caused arthritis in 55 (82%) and uveitis in 2 (3%) of 67 cell recipients. Uveitis occurred in 2/6 cell recipients pretreated with bacterial endotoxin. Neither uveitis nor arthritis was observed in rats given IFA (0/6) or spleen cells prepared from rats given IFA (0/27), CI-IFA (0/6), or CII-IFA (0/28). CII-IFA produced polyarthritis in 5/6 rats, but no uveitis. CII-IFA induced arthritis associated uveitis in 1/15 animals receiving spleen cells from rats given CII-IFA, but not those given CI-IFA (0/3) or IFA (0/13). Uveitis was observed in one recipient of the M-1 T cell line and in 2 recipients of the PR-1 T cell line. Immunization with 400 micrograms of MBE-IFA induced uveitis but not arthritis in 3/11 animals. The MBE specific T cell line was neither arthritogenic nor uveitogenic. A high frequency (5/6) of uveitis accompanied arthritis in male Lewis rats given ip M. butyricum. Arthritis occurred in 4/10 female Lewis

Anti-inflammatory effect of Heliotropium indicum Linn on lipopolysaccharide-induced uveitis in New Zealand white rabbits.

PubMed

Kyei, Samuel; Koffuor, George Asumeng; Ramkissoon, Paul; Ameyaw, Elvis Ofori; Asiamah, Emmanuel Akomanin

2016-01-01

To investigate the anti-inflammatory effect of an aqueous whole plant extract of Heliotropium indicum (HIE) on endotoxin-induced uveitis in New Zealand white rabbits. Clinical signs of uveitis including flares, iris hyperemia and miosis, were sought for and scored in 1.0 mg/kg lipopolysaccharide (LPS) -induced uveitic rabbits treated orally with HIE (30-300 mg/kg), prednisolone (30 mg/kg), or normal saline (10 mL/kg). The number of polymorphonuclear neutrophils infiltrating, the protein concentration, as well as levels of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and monocyte chemmoattrant protein-1 (MCP-1) in the aqueous humor after the various treatments were also determined. A histopathological study of the anterior uveal was performed. The extract and prednisolone-treatment significantly reduced (P≤0.001) both the clinical scores of inflammation (1.0-1.8 compared to 4.40±0.40 in the normal saline-treated rabbits) and inflammatory cells infiltration. The level of protein, and the concentrations of TNF-α, PGE2 and MCP-1 in the aqueous humor were also significantly reduced (P≤0.001). Histopathological studies showed normal uveal morphology in the HIE and prednisolone-treated rabbits while normal saline-treated rabbits showed marked infiltration of inflammatory cells. The HIE exhibits anti-inflammatory effect on LPS-induced uveitis possibly by reducing the production of pro-inflammatory mediators.

MitoQ administration prevents endotoxin-induced cardiac dysfunction.

PubMed

Supinski, G S; Murphy, M P; Callahan, L A

2009-10-01

Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6'-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg x kg(-1) x day(-1)), saline + MitoQ (500 microM), or both endotoxin and MitoQ. At 48 h animals were killed and hearts were removed for determination of either cardiac mitochondrial function (using polarography) or cardiac pressure generation (using the Langendorf technique). We found that endotoxin induced reductions in mitochondrial state 3 respiration rates, the respiratory control ratio, and ATP generation. Moreover, MitoQ administration prevented each of these endotoxin-induced abnormalities, P < 0.001. We also found that endotoxin produced reductions in cardiac pressure-generating capacity, reducing the systolic pressure-diastolic relationship. MitoQ also prevented endotoxin-induced reductions in cardiac pressure generation, P < 0.01. One potential link between mitochondrial and contractile dysfunction is caspase activation; we found that endotoxin increased cardiac levels of active caspases 9 and 3 (P < 0.001), while MitoQ prevented this increase (P < 0.01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction.

MitoQ administration prevents endotoxin-induced cardiac dysfunction

PubMed Central

Murphy, M. P.; Callahan, L. A.

2009-01-01

Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6′-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg·kg−1·day−1), saline + MitoQ (500 μM), or both endotoxin and MitoQ. At 48 h animals were killed and hearts were removed for determination of either cardiac mitochondrial function (using polarography) or cardiac pressure generation (using the Langendorf technique). We found that endotoxin induced reductions in mitochondrial state 3 respiration rates, the respiratory control ratio, and ATP generation. Moreover, MitoQ administration prevented each of these endotoxin-induced abnormalities, P < 0.001. We also found that endotoxin produced reductions in cardiac pressure-generating capacity, reducing the systolic pressure-diastolic relationship. MitoQ also prevented endotoxin-induced reductions in cardiac pressure generation, P < 0.01. One potential link between mitochondrial and contractile dysfunction is caspase activation; we found that endotoxin increased cardiac levels of active caspases 9 and 3 (P < 0.001), while MitoQ prevented this increase (P < 0.01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction. PMID:19657095

Anti-inflammatory effect of Heliotropium indicum Linn on lipopolysaccharide-induced uveitis in New Zealand white rabbits

PubMed Central

Kyei, Samuel; Koffuor, George Asumeng; Ramkissoon, Paul; Ameyaw, Elvis Ofori; Asiamah, Emmanuel Akomanin

2016-01-01

AIM To investigate the anti-inflammatory effect of an aqueous whole plant extract of Heliotropium indicum (HIE) on endotoxin-induced uveitis in New Zealand white rabbits. METHODS Clinical signs of uveitis including flares, iris hyperemia and miosis, were sought for and scored in 1.0 mg/kg lipopolysaccharide (LPS) -induced uveitic rabbits treated orally with HIE (30-300 mg/kg), prednisolone (30 mg/kg), or normal saline (10 mL/kg). The number of polymorphonuclear neutrophils infiltrating, the protein concentration, as well as levels of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and monocyte chemmoattrant protein-1 (MCP-1) in the aqueous humor after the various treatments were also determined. A histopathological study of the anterior uveal was performed. RESULTS The extract and prednisolone-treatment significantly reduced (P≤0.001) both the clinical scores of inflammation (1.0-1.8 compared to 4.40±0.40 in the normal saline-treated rabbits) and inflammatory cells infiltration. The level of protein, and the concentrations of TNF-α, PGE2 and MCP-1 in the aqueous humor were also significantly reduced (P≤0.001). Histopathological studies showed normal uveal morphology in the HIE and prednisolone-treated rabbits while normal saline-treated rabbits showed marked infiltration of inflammatory cells. CONCLUSION The HIE exhibits anti-inflammatory effect on LPS-induced uveitis possibly by reducing the production of pro-inflammatory mediators. PMID:27162723

Antibacterial and anti-inflammatory activity of traditional Chinese herb pairs, Angelica sinensis and Sophora flavescens.

PubMed

Han, Chunchao; Guo, Jianyou

2012-06-01

The purpose of the present study was to investigate the antibacterial and anti-inflammatory activity of Angelica sinensis extract (AE), Sophora flavescens extract (SE), and herb pair A. sinensis and S. flavescens extract (HPE). Endotoxin-induced uveitis (EIU) was induced in rats by a footpad injection of lipopolysaccharide. The anti-inflammatory potential of AE, SE, and HPE in the regulation of nuclear factor kappa B (NF-κB), maleic dialdehyde (MDA), polymorphonuclear cells (PMN), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α), adhesion molecule (ICAM-1), and cyclooxygenase-2 (COX-2) was determined by ELISA and immunohistochemistry. HPE showed strong antibacterial activity at all tested concentrations (1.25, 2.5, and 5 μg/ml) to Escherichia coli, Staphylococcus aureus, and Shigella Castellani and Chalmers. HPE significantly inhibited EIU-induced upregulation of NF-κB activation and the production of IL-1β, TNF-α, iNOS, ICAM-1, and COX-2. Moreover, HPE suppressed MDA and infiltration of PMN. The study supports the hypothesis that the antipimple and anti-eczema activities of Dangguikushen compound recipe are attributed to herb pairs, A. sinensis and S. flavescens, used in combination.

Anti-inflammatory effects of fermented and non-fermented Sophora flavescens: a comparative study.

PubMed

Han, Chun-chao; Wei, Hong; Guo, Jianyou

2011-10-26

The roots of Sophora flavescens (Leguminosae) have been used in East Asian countries as an herbal medicine and a food ingredient for thousands of years. The aim of the present study was to investigate the effects of S. flavescens fermentation on endotoxin-induced uveitis (EIU) in rats. EIU was induced in rats via a footpad injection of lipopolysaccharide (LPS). Immediately after the LPS inoculation, fermented and non-fermented extracts of S. flavescens (FSE and NFSE, respectively) were administered orally, and the aqueous humor was collected from both eyes 24 hours later. The anti-inflammatory effects of FSE and NFSE were examined in terms of regulation of nuclear factor kappa B (NF-κB) activation and the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), intercellular cell adhesion molecule (ICAM)-1, and cyclooxygenase-2 (COX-2). The regulation of maleic dialdehyde (MDA) levels and polymorphonuclear cell (PMN) infiltration by FSE and NFSE were also examined. Treatment with FSE significantly inhibited LPS-induced increases in IL-1β and TNF-α production and the expression of iNOS, ICAM-1 and COX-2. Moreover, FSE suppressed LPS-induced NF-κB activation, and reduced both MDA levels and infiltration by PMN. These results indicate that solid state fermentation may enhance the anti-inflammatory effects of S. flavescens.

Effects of blue honeysuckle (Lonicera caerulea L.) extract on lipopolysaccharide-induced inflammation in vitro and in vivo.

PubMed

Jin, Xue-Hai; Ohgami, Kazuhiro; Shiratori, Kenji; Suzuki, Yukari; Koyama, Yoshikazu; Yoshida, Kazuhiko; Ilieva, Iliyana; Tanaka, Tsuneo; Onoe, Kazunori; Ohno, Shigeaki

2006-05-01

The aim of the present study was to investigate the effects of blue honeysuckle extract (BHE), which contains high level of phenolic compounds, on endotoxin-induced uveitis (EIU). Male Lewis rats were randomly divided into 5 groups with 14 rats in each (eight rats for collection of aqueous humor, six rats for histologic examination). EIU was induced by a footpad injection of lipopolysaccharide (LPS). 1, 10, or 100 mg of BHE was injected intravenously immediately after LPS injection. The aqueous humor was collected at 24 h after LPS injection, the number of infiltrating cells, protein concentration, nitric oxide (NO), tumor necrosis factor (TNF)-alpha, and prostaglandin (PG)-E2 levels in the aqueous humor were determined. Some eyes were enucleated for histologic examination and immunohistochemical analysis. Immunohistochemical staining with a monoclonal antibody against activated nuclear factor (NF)-kappaB was performed to evaluate the effect of BHE on NF-kappaB activation. To further clarify the anti-inflammatory effect, RAW264.7 cells (a mouse macrophage cell line) were stimulated with LPS in the presence or absence of BHE and its major phenolics, cyanidin 3-glucoside (C3G), cyanidin 3-rutinoside (C3R), chlorogenic acid (CA). Expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were analyzed by Western blot method. BHE treatment significantly reduced the inflammatory cell infiltration, the protein concentration, the levels of NO, TNF-alpha and PGE2 in the aqueous humor and improved histologic status of the ocular tissue. The number of activated NF-kappaB-positive cells was lower in the iris-ciliary body treated with BHE at 3 h after LPS injection. BHE significantly suppressed the production of NO, PGE2 and TNF-alpha in the culture medium as well as the expression of iNOS and COX-2 by LPS-stimulated RAW264.7 cells in a dose-dependent fashion. C3G, C3R and CA showed no or weak inhibitory effects on the level of inflammatory mediators and the

Binding of /sup 125/I-labeled endotoxin to bovine, canine, and equine platelets and endotoxin-induced agglutination of canine platelets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meyers, K.M.; Boehme, M.; Inbar, O.

Endotoxin from Escherichia coli O127:B8, Salmonella abortus-equi and S minnesota induced clumping of some canine platelets (PLT) at a final endotoxin concentration of 1 microgram/ml. Endotoxin-induced clumping of canine PLT was independent of PLT energy-requiring processes, because clumping was observed with canine PLT incubated with 2-deoxy-D-glucose and antimycin A. The PLT responded to adenosine diphosphate before, but not after, incubation with the metabolic inhibitors. Endotoxin induced a slight and inconsistant clumping of bovine and equine PLT at high (mg/ml) endotoxin concentration. High-affinity binding sites could not be demonstrated on canine, bovine, and equine PLT, using /sup 125/I-labeled E coli O127:B8more » endotoxin. Nonspecific binding was observed and appeared to be due primarily to an extraneous coat on the PLT surface that was removed by gel filtration. The endotoxin that was bound to PLT did not appear to modify PLT function. An attempt to identify plasma proteins that bound physiologically relevant amounts of endotoxin was not successful. The significance of the endotoxin-induced clumping or lack of it on the pathophysiology of endotoxemia is discussed.« less

Anti-inflammatory effects of fermented and non-fermented Sophora flavescens: a comparative study

PubMed Central

2011-01-01

Background The roots of Sophora flavescens (Leguminosae) have been used in East Asian countries as an herbal medicine and a food ingredient for thousands of years. The aim of the present study was to investigate the effects of S. flavescens fermentation on endotoxin-induced uveitis (EIU) in rats. Methods EIU was induced in rats via a footpad injection of lipopolysaccharide (LPS). Immediately after the LPS inoculation, fermented and non-fermented extracts of S. flavescens (FSE and NFSE, respectively) were administered orally, and the aqueous humor was collected from both eyes 24 hours later. The anti-inflammatory effects of FSE and NFSE were examined in terms of regulation of nuclear factor kappa B (NF-κB) activation and the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), intercellular cell adhesion molecule (ICAM)-1, and cyclooxygenase-2 (COX-2). The regulation of maleic dialdehyde (MDA) levels and polymorphonuclear cell (PMN) infiltration by FSE and NFSE were also examined. Results Treatment with FSE significantly inhibited LPS-induced increases in IL-1β and TNF-α production and the expression of iNOS, ICAM-1 and COX-2. Moreover, FSE suppressed LPS-induced NF-κB activation, and reduced both MDA levels and infiltration by PMN. Conclusion These results indicate that solid state fermentation may enhance the anti-inflammatory effects of S. flavescens. PMID:22026927

Endotoxin-Induced Structural Transformations in Liquid Crystalline Droplets

NASA Astrophysics Data System (ADS)

Lin, I.-Hsin; Miller, Daniel S.; Bertics, Paul J.; Murphy, Christopher J.; de Pablo, Juan J.; Abbott, Nicholas L.

2011-06-01

The ordering of liquid crystals (LCs) is known to be influenced by surfaces and contaminants. Here, we report that picogram per milliliter concentrations of endotoxin in water trigger ordering transitions in micrometer-size LC droplets. The ordering transitions, which occur at surface concentrations of endotoxin that are less than 10-5 Langmuir, are not due to adsorbate-induced changes in the interfacial energy of the LC. The sensitivity of the LC to endotoxin was measured to change by six orders of magnitude with the geometry of the LC (droplet versus slab), supporting the hypothesis that interactions of endotoxin with topological defects in the LC mediate the response of the droplets. The LC ordering transitions depend strongly on glycophospholipid structure and provide new designs for responsive soft matter.

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

PubMed Central

Echeverría, César; Montorfano, Ignacio; Tapia, Pablo; Riedel, Claudia; Cabello-Verrugio, Claudio

2014-01-01

During endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor β1 (TGF-β1) and TGF-β2. However, whether TGF-β1 and TGF-β2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-β receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-β production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-β1 and TGF-β2. Endotoxin-treated ECs induced the expression and secretion of TGF-β1 and TGF-β2. TGF-β1 and TGF-β2 downregulation inhibited the endotoxin-induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins α-SMA and fibronectin. Thus, endotoxin induces the production of TGF-β1 and TGF-β2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-β secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases. PMID:24935972

Endotoxin-induced endothelial fibrosis is dependent on expression of transforming growth factors β1 and β2.

PubMed

Echeverría, César; Montorfano, Ignacio; Tapia, Pablo; Riedel, Claudia; Cabello-Verrugio, Claudio; Simon, Felipe

2014-09-01

During endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor β1 (TGF-β1) and TGF-β2. However, whether TGF-β1 and TGF-β2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-β receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-β production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-β1 and TGF-β2. Endotoxin-treated ECs induced the expression and secretion of TGF-β1 and TGF-β2. TGF-β1 and TGF-β2 downregulation inhibited the endotoxin-induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins α-SMA and fibronectin. Thus, endotoxin induces the production of TGF-β1 and TGF-β2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-β secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Dexamethasone inhibits endotoxin-induced coagulopathy in human lungs.

PubMed

Bartko, J; Schoergenhofer, C; Schwameis, M; Buchtele, N; Wojta, J; Schabbauer, G; Stiebellehner, L; Jilma, B

2016-12-01

Essentials Glucocorticoids are associated with an increased risk of thrombosis. Healthy volunteers received dexamethasone or placebo in an endotoxin lung instillation model. Dexamethasone suppressed thrombin generation in bronchoalveolar lavage. Glucocorticoids inhibit endotoxin induced pulmonary coagulopathy. Background Activation of local and systemic coagulation is a common finding in patients with pneumonia. There is evidence that glucocorticoids have procoagulant activity in the circulation, particularly in the context of inflammation. The effects of glucocorticoids on local pulmonary coagulation have not yet been investigated. Objective To use a human model of lung inflammation based on the local instillation of endotoxin in order to investigate whether glucocorticoids alter pulmonary coagulation. Methods Twenty-four healthy volunteers were randomized to receive either dexamethasone or placebo in a double-blind trial. Endotoxin was instilled via bronchoscope into right or left lung segments, followed by saline into the contralateral site. Six hours later, a bilateral bronchoalveolar lavage (BAL) was performed and coagulation parameters were measured. Results Endotoxin induced activation of coagulation in the bronchoalveolar compartment: the level of prothrombin fragment 1 + 2 (F 1 + 2 ) was increased three-fold (248 pmol L -1 , 95% confidence interval [CI] 43-454 versus 743 pmol L -1 , 95% CI 437-1050) and the level of thrombin-antithrombin complex (TATc) was increased by ~ 50% (31 μg L -1 , 95% CI 18-45 versus 49 μg L -1 , 95% CI 36-61) as compared with saline-challenged segments. Dexamethasone reduced F 1 + 2 (284 pmol L -1 , 95% CI 34-534) and TATc (9 μg L -1 , 95% CI 0.7-17) levels almost to those measured in BAL fluid from the saline-instilled segments in the placebo group. Dexamethasone even profoundly reduced F 1 + 2 levels (80%) in saline-instilled lung segments (50 pmol L -1 , 95% CI 12-87). In contrast, dexamethasone had no effect on systemic F 1

Tumor necrosis factor and interleukin 1 as mediators of endotoxin-induced beneficial effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urbaschek, R.; Urbaschek, B.

Bacterial lipopolysaccharides or endotoxins are known to induce tumor necrosis; enhanced nonspecific resistance to bacterial, viral, and parasitic infections and to radiation sickness; and tolerance to lethal doses of endotoxin. These beneficial effects are achieved by pretreatment with minute amounts of endotoxin. Recombinant tumor necrosis factor (TNF) and interleukin 1 (IL-1) are among the mediators capable of invoking radioprotection or resistance to the consequences of cecal ligation and puncture. Both cytokines are potent inducers of serum colony-stimulating factor (CSF) in C3H/HeJ mice (low responders to endotoxin). The number of splenic granulocyte-macrophage precursors was found to increase 5 days after injectionmore » of TNF in these mice. Although with IL-1 no increase in the number of granulocyte-macrophage colonies occurred in culture in the presence of serum CSF, a marked stimulation was observed when TNF was added. This stimulation of myelopoiesis observed in vivo and in vitro may be related to the radioprotective effect of TNF. The data presented suggest that TNF and IL-1 released after injection of endotoxin participate in the mediation of endotoxin-induced enhancement of nonspecific resistance and stimulation of hematopoiesis. 76 references.« less

Protection against endotoxin-induced foetal resorption in mice by desferrioxamine and ebselen.

PubMed Central

Gower, J. D.; Baldock, R. J.; O'Sullivan, A. M.; Doré, C. J.; Coid, C. R.; Green, C. J.

1990-01-01

Endotoxin was administered to mice on their 13th day of pregnancy at doses which caused the resorption of approximately 50% of the implanted foetuses. The iron chelator desferrioxamine was found to significantly inhibit the percentage of resorptions induced by endotoxin in a dose-dependent manner. The highest dose of desferrioxamine (5 mg) given intravenously 30 min prior to, immediately after, and 4 and 24 h after endotoxin inoculation, reduced the percentage of resorptions from 56.9 to 17.9%. Administration of the novel selenium-containing compound ebselen, which is both an antioxidant and an inhibitor of leukotriene synthesis, was also found to significantly protect against endotoxin-induced foetal resorptions, reducing the percentage of resorbed foetuses from 52.9 to 26.0% when given at a dose of 50 mg/kg (s.c.) at the time of endotoxin inoculation and 24 and 48 h following. Both these compounds also significantly reduced the increase in spleen weights observed when the mice were given endotoxin. These results provide evidence that the iron-catalysed production of hydroxyl radicals from other oxygen-derived species and the formation of leukotrienes play an important role in the mechanism by which endotoxin causes foetal resorptions in the mouse. PMID:2205283

Allergen endotoxins induce T-cell-dependent and non-IgE-mediated nasal hypersensitivity in mice.

PubMed

Iwasaki, Naruhito; Matsushita, Kazufumi; Fukuoka, Ayumi; Nakahira, Masakiyo; Matsumoto, Makoto; Akasaki, Shoko; Yasuda, Koubun; Shimizu, Takeshi; Yoshimoto, Tomohiro

2017-01-01

Allergen-mediated cross-linking of IgE on mast cells/basophils is a well-recognized trigger for type 1 allergic diseases such as allergic rhinitis (AR). However, allergens may not be the sole trigger for AR, and several allergic-like reactions are induced by non-IgE-mediated mechanisms. We sought to describe a novel non-IgE-mediated, endotoxin-triggered nasal type-1-hypersensitivity-like reaction in mice. To investigate whether endotoxin affects sneezing responses, mice were intraperitoneally immunized with ovalbumin (OVA), then nasally challenged with endotoxin-free or endotoxin-containing OVA. To investigate the role of T cells and mechanisms of the endotoxin-induced response, mice were adoptively transferred with in vitro-differentiated OVA-specific T H 2 cells, then nasally challenged with endotoxin-free or endotoxin-containing OVA. Endotoxin-containing, but not endotoxin-free, OVA elicited sneezing responses in mice independent from IgE-mediated signaling. OVA-specific T H 2 cell adoptive transfer to mice demonstrated that local activation of antigen-specific T H 2 cells was required for the response. The Toll-like receptor 4-myeloid differentiation factor 88 signaling pathway was indispensable for endotoxin-containing OVA-elicited rhinitis. In addition, LPS directly triggered sneezing responses in OVA-specific T H 2-transferred and nasally endotoxin-free OVA-primed mice. Although antihistamines suppressed sneezing responses, mast-cell/basophil-depleted mice had normal sneezing responses to endotoxin-containing OVA. Clodronate treatment abrogated endotoxin-containing OVA-elicited rhinitis, suggesting the involvement of monocytes/macrophages in this response. Antigen-specific nasal activation of CD4 + T cells followed by endotoxin exposure induces mast cell/basophil-independent histamine release in the nose that elicits sneezing responses. Thus, environmental or nasal residential bacteria may exacerbate AR symptoms. In addition, this novel phenomenon might

Endotoxin induces fibrosis in vascular endothelial cells through a mechanism dependent on transient receptor protein melastatin 7 activity.

PubMed

Echeverría, Cesar; Montorfano, Ignacio; Hermosilla, Tamara; Armisén, Ricardo; Velásquez, Luis A; Cabello-Verrugio, Claudio; Varela, Diego; Simon, Felipe

2014-01-01

The pathogenesis of systemic inflammatory diseases, including endotoxemia-derived sepsis syndrome, is characterized by endothelial dysfunction. It has been demonstrated that the endotoxin lipopolysaccharide (LPS) induces the conversion of endothelial cells (ECs) into activated fibroblasts through endothelial-to-mesenchymal transition mechanism. Fibrogenesis is highly dependent on intracellular Ca2+ concentration increases through the participation of calcium channels. However, the specific molecular identity of the calcium channel that mediates the Ca2+ influx during endotoxin-induced endothelial fibrosis is still unknown. Transient receptor potential melastatin 7 (TRPM7) is a calcium channel that is expressed in many cell types, including ECs. TRPM7 is involved in a number of crucial processes such as the conversion of fibroblasts into activated fibroblasts, or myofibroblasts, being responsible for the development of several characteristics of them. However, the role of the TRPM7 ion channel in endotoxin-induced endothelial fibrosis is unknown. Thus, our aim was to study whether the TRPM7 calcium channel participates in endotoxin-induced endothelial fibrosis. Using primary cultures of ECs, we demonstrated that TRPM7 is a crucial protein involved in endotoxin-induced endothelial fibrosis. Suppression of TRPM7 expression protected ECs from the fibrogenic process stimulated by endotoxin. Downregulation of TRPM7 prevented the endotoxin-induced endothelial markers decrease and fibrotic genes increase in ECs. In addition, TRPM7 downregulation abolished the endotoxin-induced increase in ECM proteins in ECs. Furthermore, we showed that intracellular Ca2+ levels were greatly increased upon LPS challenge in a mechanism dependent on TRPM7 expression. These results demonstrate that TRPM7 is a key protein involved in the mechanism underlying endotoxin-induced endothelial fibrosis.

The role of endotoxin in grain dust-induced lung disease.

PubMed

Schwartz, D A; Thorne, P S; Yagla, S J; Burmeister, L F; Olenchock, S A; Watt, J L; Quinn, T J

1995-08-01

To identify the role of endotoxin in grain dust-induced lung disease, we conducted a population-based, cross-sectional investigation among grain handlers and postal workers. The study subjects were selected by randomly sampling all grain facilities and post offices within 100 miles of Iowa City. Our study population consisted of 410 grain workers and 201 postal workers. Grain workers were found to be exposed to higher concentrations of airborne dust (p = 0.0001) and endotoxin (p = 0.0001) when compared with postal workers. Grain workers had a significantly higher prevalence of work-related (cough, phlegm, wheezing, chest tightness, and dyspnea) and chronic (usual cough or phlegm production) respiratory symptoms than postal workers. Moreover, after controlling for age, gender, and cigarette smoking status, work-related respiratory symptoms were strongly associated with the concentration of endotoxin in the bioaerosol in the work setting. The concentration of total dust in the bioaerosol was marginally related to these respiratory problems. After controlling for age, gender, and cigarette smoking status, grain workers were found to have reduced spirometric measures of airflow (FEV1, FEV1/FVC, and FEF25-75) and enhanced airway reactivity to inhaled histamine when compared with postal workers. Although the total dust concentration in the work environment appeared to have little effect on these measures of airflow obstruction, higher concentrations of endotoxin in the bioaerosol were associated with diminished measures of airflow and enhanced bronchial reactivity. Our results indicate that the concentration of endotoxin in the bioaerosol may be particularly important in the development of grain dust-induced lung disease.

Blockade by fenspiride of endotoxin-induced neutrophil migration in the rat.

PubMed

Cunha, F Q; Boukili, M A; da Motta, J I; Vargaftig, B B; Ferreira, S H

1993-07-06

Fenspiride, an antiinflammatory drug with low anti-cyclooxygenase activity, administered orally at 60-200 mg/kg inhibited neutrophil migration into peritoneal and air pouches cavities as well as exudation into peritoneal cavities induced by endotoxin but not induced by carrageenin. Up to 100 microM, fenspiride failed to inhibit the in vitro release of a neutrophil chemotactic activity by endotoxin-stimulated macrophages and the in vivo migration into the peritoneal cavities induced by the supernatant of those macrophages. The release of tumour necrosis factor by stimulated macrophages was inhibited by fenspiride in a dose-dependent manner. These results suggest that the antiinflammatory effects of fenspiride are associated with the inhibition of the tumour necrosis factor release by resident macrophages.

Primed Mycobacterial Uveitis (PMU): Histologic and Cytokine Characterization of a Model of Uveitis in Rats.

PubMed

Pepple, Kathryn L; Rotkis, Lauren; Van Grol, Jennifer; Wilson, Leslie; Sandt, Angela; Lam, Deborah L; Carlson, Eric; Van Gelder, Russell N

2015-12-01

The purpose of this study was to compare the histologic features and cytokine profiles of experimental autoimmune uveitis (EAU) and a primed mycobacterial uveitis (PMU) model in rats. In Lewis rats, EAU was induced by immunization with interphotoreceptor binding protein peptide, and PMU was induced by immunization with a killed mycobacterial extract followed by intravitreal injection of the same extract. Clinical course, histology, and the cytokine profiles of the aqueous and vitreous were compared using multiplex bead fluorescence immunoassays. Primed mycobacterial uveitis generates inflammation 2 days after intravitreal injection and resolves spontaneously 14 days later. CD68+ lymphocytes are the predominant infiltrating cells and are found in the anterior chamber, surrounding the ciliary body and in the vitreous. In contrast to EAU, no choroidal infiltration or retinal destruction is noted. At the day of peak inflammation, C-X-C motif ligand 10 (CXCL10), IL-1β, IL-18, and leptin were induced in the aqueous of both models. Interleukin-6 was induced 2-fold in the aqueous of PMU but not EAU. Cytokines elevated in the aqueous of EAU exclusively include regulated on activation, normal T cell expressed and secreted (RANTES), lipopolysaccharide-induced CXC chemokine (LIX), growth-related oncogene/keratinocyte chemokine (GRO/KC), VEGF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and IL-17A. In the vitreous, CXCL10, GRO/KC, RANTES, and MIP-1α were elevated in both models. Interleukin-17A and IL-18 were elevated exclusively in EAU. Primed mycobacterial uveitis generates an acute anterior and intermediate uveitis without retinal involvement. Primed mycobacterial uveitis has a distinct proinflammatory cytokine profile compared with EAU, suggesting PMU is a good complementary model for study of immune-mediated uveitis. CXCL10, a proinflammatory cytokine, was increased in the aqueous and vitreous of both models and may be a

Effect of thalidomide on endotoxin-induced decreases in activity and expression of hepatic cytochrome P450 3A2.

PubMed

Ueyama, Jun; Nadai, Masayuki; Zhao, Ying Lan; Kanazawa, Hiroaki; Takagi, Kenji; Kondo, Takaaki; Takagi, Kenzo; Wakusawa, Shinya; Abe, Fumie; Saito, Hiroko; Miyamoto, Ken-Ichi; Hasegawa, Takaaki

2008-08-01

Thalidomide has been reported to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) that are involved in the down-regulation of hepatic cytochrome P450 (CYP) induced by endotoxin. In the present study, we investigated the effects of thalidomide on endotoxin-induced decreases in the activity and expression of hepatic CYP3A2 in rats. Thalidomide (50 mg/kg) was administered orally 22 h and 2 h before intraperitoneal injection of endotoxin (1 mg/kg). Twenty-four hours after the injection of endotoxin, antipyrine clearance experiments were conducted, in which the rats were sacrificed and protein levels of hepatic CYP3A2 were measured. There were no significant differences in the histopathological changes in the liver between the endotoxin-treated and endotoxin plus thalidomide-treated rats. Thalidomide had no effect on the systemic clearance of antipyrine, which is a proper indicator for hepatic CYP3A2 activity, whereas it enhanced endotoxin-induced decrease in the systemic clearance of antipyrine. Western blot analysis revealed that thalidomide had no effect on the protein levels of hepatic CYP3A2, whereas it enhanced the down-regulation of hepatic CYP3A2 by endotoxin. However, there were no significant differences in the concentrations of TNF-alpha and NO in plasma between the endotoxin-treated and endotoxin plus thalidomide-treated rats. The present findings suggest that thalidomide enhances endotoxin-induced decreases in the activity and expression of hepatic CYP3A2.

Fingolimod against endotoxin-induced fetal brain injury in a rat model.

PubMed

Yavuz, And; Sezik, Mekin; Ozmen, Ozlem; Asci, Halil

2017-11-01

Fingolimod is a sphingosine-1-phosphate receptor modulator used for multiple sclerosis treatment and acts on cellular processes such as apoptosis, endothelial permeability, and inflammation. We hypothesized that fingolimod has a positive effect on alleviating preterm fetal brain injury. Sixteen pregnant rats were divided into four groups of four rats each. On gestational day 17, i.p. endotoxin was injected to induce fetal brain injury, followed by i.p. fingolimod (4 mg/kg maternal weight). Hysterotomy for preterm delivery was performed 6 h after fingolimod. The study groups included (i) vehicle controls (i.p. normal saline only); (ii) positive controls (endotoxin plus saline); (iii) saline plus fingolimod; and (iv) endotoxin plus fingolimod treatment. Brain tissues of the pups were dissected for evaluation of interleukin (IL)-6, caspase-3, and S100β on immunohistochemistry. Maternal fingolimod treatment attenuated endotoxin-related fetal brain injury and led to lower immunoreactions for IL-6, caspase-3, and S100β compared with endotoxin controls (P < 0.0001 for all comparisons). Antenatal maternal fingolimod therapy had fetal neuroprotective effects by alleviating preterm birth-related fetal brain injury with inhibitory effects on inflammation and apoptosis. © 2017 Japan Society of Obstetrics and Gynecology.

Proteome Dynamics in Biobanked Horse Peripheral Blood Derived Lymphocytes (PBL) with Induced Autoimmune Uveitis.

PubMed

Hauck, Stefanie M; Lepper, Marlen F; Hertl, Michael; Sekundo, Walter; Deeg, Cornelia A

2017-10-01

Equine recurrent uveitis is the only spontaneous model for recurrent autoimmune uveitis in humans, where T cells target retinal proteins. Differences between normal and autoaggressive lymphocytes were identified in this study by analyzing peripheral blood derived lymphocytes (PBL) proteomes from the same case with interphotoreceptor retinoid binding protein induced uveitis sampled before (Day 0), during (Day 15), and after uveitic attack (Day 23). Relative protein abundances of PBL were investigated in a quantitative, label-free differential proteome analysis in cells that were kept frozen for 14 years since the initial experiment. Quantitative data could be acquired for 2632 proteins at all three time points. Profound changes (≥2-fold change) in PBL protein abundance were observed when comparing Day 0 with 15, representing acute inflammation (1070 regulated proteins) and Day 0 with 23 (cessation; 1571 regulated). Significant differences applied to proteins with functions in integrin signaling during active uveitis, involving "Erk and pi-3 kinase are necessary for collagen binding in corneal epithelia," "integrins in angiogenesis," and "integrin-linked kinase signaling" pathways. In contrast, at cessation of uveitic attack, significantly changed proteins belonged to pathways of "nongenotropic androgen signaling," "classical complement pathway," and "Amb2 integrin signaling." Several members of respective pathways were earlier shown to be changed in naturally occurring uveitis, underscoring the significance of these findings here and proofing the value of the induced model in mimicking spontaneous autoimmune uveitis. All MS data have been deposited to the ProteomeXchange consortium via the PRIDE partner repository (dataset identifier PXD005580). © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Primed Mycobacterial Uveitis (PMU): Histologic and Cytokine Characterization of a Model of Uveitis in Rats

PubMed Central

Pepple, Kathryn L.; Rotkis, Lauren; Van Grol, Jennifer; Wilson, Leslie; Sandt, Angela; Lam, Deborah L.; Carlson, Eric; Van Gelder, Russell N.

2015-01-01

Purpose The purpose of this study was to compare the histologic features and cytokine profiles of experimental autoimmune uveitis (EAU) and a primed mycobacterial uveitis (PMU) model in rats. Methods In Lewis rats, EAU was induced by immunization with interphotoreceptor binding protein peptide, and PMU was induced by immunization with a killed mycobacterial extract followed by intravitreal injection of the same extract. Clinical course, histology, and the cytokine profiles of the aqueous and vitreous were compared using multiplex bead fluorescence immunoassays. Results Primed mycobacterial uveitis generates inflammation 2 days after intravitreal injection and resolves spontaneously 14 days later. CD68+ lymphocytes are the predominant infiltrating cells and are found in the anterior chamber, surrounding the ciliary body and in the vitreous. In contrast to EAU, no choroidal infiltration or retinal destruction is noted. At the day of peak inflammation, C-X-C motif ligand 10 (CXCL10), IL-1β, IL-18, and leptin were induced in the aqueous of both models. Interleukin-6 was induced 2-fold in the aqueous of PMU but not EAU. Cytokines elevated in the aqueous of EAU exclusively include regulated on activation, normal T cell expressed and secreted (RANTES), lipopolysaccharide-induced CXC chemokine (LIX), growth-related oncogene/keratinocyte chemokine (GRO/KC), VEGF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and IL-17A. In the vitreous, CXCL10, GRO/KC, RANTES, and MIP-1α were elevated in both models. Interleukin-17A and IL-18 were elevated exclusively in EAU. Conclusions Primed mycobacterial uveitis generates an acute anterior and intermediate uveitis without retinal involvement. Primed mycobacterial uveitis has a distinct proinflammatory cytokine profile compared with EAU, suggesting PMU is a good complementary model for study of immune-mediated uveitis. CXCL10, a proinflammatory cytokine, was increased in the aqueous and

Altered macrophage arachidonic acid metabolism induced by endotoxin tolerance: characterization and mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rogers, T.S.

Altered macrophage arachidonic acid (AA) metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase and cyclooxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e., endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT) C/sub 4/D/sub 4/ and prostaglandin (PG) E/sub 2/ production by tolerant cells was greater than that by non-tolerant controls (p <0.001). However, A23187-stimulated i6-keto PGF/sub 1a/more » levels were lower in tolerant macrophages compared to controls (P < 0.05). iL TC/sub 4/D/sub 4/ production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in non-tolerant cells. Synthesis of iLTB/sub 4/ by control macrophages was stimulated by endotoxin (p <0.01). The effect of tolerance on factors that affect AA release was investigated by measuring /sup 14/C-AA incorporation and release and phospholipase A/sub 2/ activity« less

A Myeloid Hypoxia-inducible Factor 1α-Krüppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis*

PubMed Central

Mahabeleshwar, Ganapati H.; Qureshi, Muhammad Awais; Takami, Yoichi; Sharma, Nikunj; Lingrel, Jerry B.; Jain, Mukesh K.

2012-01-01

Although Gram-positive infections account for the majority of cases of sepsis, the molecular mechanisms underlying their effects remains poorly understood. We investigated how cell wall components of Gram-positive bacteria contribute to the development of sepsis. Experimental observations derived from cultured primary macrophages and the cell line indicate that Gram-positive bacterial endotoxins induce hypoxia-inducible factor 1α (HIF-1α) mRNA and protein expression. Inoculation of live or heat-inactivated Gram-positive bacteria with macrophages induced HIF-1 transcriptional activity in macrophages. Concordant with these results, myeloid deficiency of HIF-1α attenuated Gram-positive bacterial endotoxin-induced cellular motility and proinflammatory gene expression in macrophages. Conversely, Gram-positive bacteria and their endotoxins reduced expression of the myeloid anti-inflammatory transcription factor Krüppel-like transcription factor 2 (KLF2). Sustained expression of KLF2 reduced and deficiency of KLF2 enhanced Gram-positive endotoxins induced HIF-1α mRNA and protein expression in macrophages. More importantly, KLF2 attenuated Gram-positive endotoxins induced cellular motility and proinflammatory gene expression in myeloid cells. Consistent with these results, mice deficient in myeloid HIF-1α were protected from Gram-positive endotoxin-induced sepsis mortality and clinical symptomatology. By contrast, myeloid KLF2-deficient mice were susceptible to Gram-positive sepsis induced mortality and clinical symptoms. Collectively, these observations identify HIF-1α and KLF2 as critical regulators of Gram-positive endotoxin-mediated sepsis. PMID:22110137

Uveitis in horses induced by interphotoreceptor retinoid-binding protein is similar to the spontaneous disease.

PubMed

Deeg, Cornelia A; Thurau, Stephan R; Gerhards, Hartmut; Ehrenhofer, Marion; Wildner, Gerhild; Kaspers, Bernd

2002-09-01

Equine recurrent uveitis (ERU) is an inflammatory eye disease with high similarity to uveitis in man. It is the only spontaneous animal model for uveitis and the most frequent eye disease in horses affecting up to 10% of the population. To further investigate the pathophysiology of ERU we now report the establishment of an inducible uveitis model in horses. An ERU-like disease was elicited in seven out of seven horses by injection of interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. Control horses did not develop uveitis. The disease model is characterized by a highly reproducible disease course and recurrent episodes with an identical time course elicited in all horses by repeated IRBP injections. The histology revealed the formation of lymphoid follicle-like structures in the eyes and an intraocular infiltration dominated by CD3(+) lymphocytes, morphological patterns typical for the spontaneous disease. Antigen-specific T cell proliferation of PBL was monitored prior to clinical uveitis and during disease episodes. An initial T cell response to IRBP-derived peptides was followed by epitope spreading to S-antigen-derived peptides in response to subsequent immunizations. Thus, horse experimental uveitis represents a valuable disease model for comparative studies with the spontaneous disease and the investigation of immunomodulatory therapeutic approaches after onset of the disease.

Inhaled endotoxin and organic dust particulates have synergistic proinflammatory effects in equine heaves (organic dust-induced asthma).

PubMed

Pirie, R S; Collie, D D S; Dixon, P M; McGorum, B C

2003-05-01

Equine heaves is a naturally occurring organic dust-induced asthma characterized by airway neutrophilia, mucus hypersecretion and obstructive lung dysfunction. However, the relative role of different dust components in disease severity remains unclear. This study investigated the relative contribution of inhaled endotoxin and organic dust particulates (mainly mould spores) in inducing heaves in heaves-susceptible horses. Control and heaves-susceptible horses received inhalation challenges with hay dust suspension (HDS) before and after lipopolysaccharide (LPS) depletion. Heaves-susceptible horses also received inhalation challenge with HDS particulates with and without the addition of LPS and were housed in two separate dusty environments during which mould and endotoxin exposure was measured. The airway inflammatory and functional response to each challenge was measured. Depletion of endotoxin from HDS attenuated the airway neutrophilia and abrogated the airway dysfunction induced in heaves horses by inhaled HDS. The airway response was re-established by adding back LPS to the depleted HDS, confirming that the attenuation in airway response was due specifically to endotoxin depletion. Interestingly, the magnitude of alteration in airway response following endotoxin depletion and add-back was greater than that which could be attributed solely to endotoxin per se, indicating that the LPS activity was enhanced by the other dust components. Consistent with this possibility, washed particulates harvested from HDS enhanced the airway response to inhaled LPS in heaves horses. Heaves horses given two different hay/straw challenges had a significantly different severity of airway inflammation and dysfunction, despite airborne dust and endotoxin concentrations in the horses' breathing zones being similar. Although inhaled endotoxin appears not to be the only determinant of disease severity in heaves, it does contribute significantly to the induction of airway inflammation

Effects of endotoxin induced lung injury and exercise in goats/sheep. Final report, 1 February 1992-2 June 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mundie, T.G.

This study was designed the effects of exercise performed on animals already injured with E. coli endotoxin. This would tell us whether exercise makes the lung injury worse. It would also tell us how much exercise performance is impaired. These studies were designed to give further insights into the underlying causes of acute lung injury. Premature termination of the study prevented completion of the research project. It appeared from the limited experimentation conducted that maximal exercise was impaired by endotoxin-induced lung injury. Conclusions regarding exacerbation of endotoxin-induced lung injury cannot be made.... Acute lung injury, Maximal exercise, Endotoxin.

Endotoxin-induced shock in the rat. A role for C5a.

PubMed Central

Smedegård, G.; Cui, L. X.; Hugli, T. E.

1989-01-01

Administration of endotoxin from gram-negative bacteria to rats results in systemic hypotension, an increased hematocrit, and decreased numbers of circulating leukocytes (polymorphonuclear), monocytes, and platelets. These potentially lethal physiologic changes may be partially attributed to complement activation and generation of anaphylatoxins by the endotoxin (LPS). We demonstrated an elevation in the plasma levels of both C3a and C5a in LPS-treated rats. Injection of 5 micrograms C5ades Arg (rat) into rats produced effects similar to those induced by LPS, including decreased mean arterial pressure (systemic hypotension) and decreased numbers of circulating polymorphonuclear leukocytes, monocytes, and platelets. Unlike the response to LPS, C5a did not increase the hematocrit, indicating little effect on vascular permeability at the doses used. When LPS-treated animals were pretreated with F(ab')2 fragments of rabbit anti-rat C5a, no changes were measured in the circulating cell counts compared with LPS alone; however a significant improvement in the mean arterial pressure and a decrease in hematocrit was observed. We conclude that LPS-induced (septic) shock in the rat may result, in part, from the effects of complement activation and particularly from the generation of C5a. The influence of C5a on the LPS effect in the rat appears to enhance both the hypotensive (mean arterial pressure) and vascular permeability (hematocrit) responses. These results appear to support and confirm earlier observations that anti-human C5a increased survival in a septic-shock monkey model by eliminating circulating C5a and presumably thereby reducing the effects of endotoxin on blood pressure. Our results demonstrate that C5a plays a significant role in the hemodynamic changes associated with endotoxin-induced shock. Neutralization of C5a with specific antibodies may reduce the hypotensive response to endotoxin sufficiently to prevent lethal septic shock both in animals and in man

Budesonide inhalation ameliorates endotoxin-induced lung injury in rabbits

PubMed Central

Gao, Wei

2015-01-01

Acute respiratory distress syndrome (ARDS) is a serious clinical problem that has a 30–50% mortality rate. Budesonide has been used to reduce lung injury. This study aims to investigate the effects of nebulized budesonide on endotoxin-induced ARDS in a rabbit model. Twenty-four rabbits were randomized into three groups. Rabbits in the control and budesonide groups were injected with endotoxin. Thereafter, budesonide or saline was instilled, ventilated for four hours, and recovered spontaneous respiratory. Peak pressure, compliance, and PaO2/FiO2 were monitored for 4 h. After seven days, PaO2/FiO2 ratios were measured. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells, and percentage of neutrophils in BALF were evaluated. TNF-α, IL-1β, IL-8, and IL-10 in BALF were detected. Lung histopathologic injury and seven-day survival rate of the three groups were recorded. Peak pressure was downregulated, but compliance and PaO2/FiO2 were upregulated by budesonide. PaO2/FiO2 ratios significantly increased due to budesonide. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells and percentage of neutrophils in BALF decreased in the budesonide group. TNF-α, IL-1β, and IL-8 levels decreased in BALF, while IL-10 levels increased in the budesonide group. Lung injuries were reduced and survival rate was upregulated by budesonide. Budesonide effectively ameliorated respiratory function, attenuated endotoxin-induced lung injury, and improved the seven-day survival rate. PMID:25956681

Budesonide inhalation ameliorates endotoxin-induced lung injury in rabbits.

PubMed

Gao, Wei; Ju, Nanying

2015-12-01

Acute respiratory distress syndrome (ARDS) is a serious clinical problem that has a 30-50% mortality rate. Budesonide has been used to reduce lung injury. This study aims to investigate the effects of nebulized budesonide on endotoxin-induced ARDS in a rabbit model. Twenty-four rabbits were randomized into three groups. Rabbits in the control and budesonide groups were injected with endotoxin. Thereafter, budesonide or saline was instilled, ventilated for four hours, and recovered spontaneous respiratory. Peak pressure, compliance, and PaO2/FiO2 were monitored for 4 h. After seven days, PaO2/FiO2 ratios were measured. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells, and percentage of neutrophils in BALF were evaluated. TNF-α, IL-1β, IL-8, and IL-10 in BALF were detected. Lung histopathologic injury and seven-day survival rate of the three groups were recorded. Peak pressure was downregulated, but compliance and PaO2/FiO2 were upregulated by budesonide. PaO2/FiO2 ratios significantly increased due to budesonide. Wet-to-dry weight ratios, total protein, neutrophil elastase, white blood cells and percentage of neutrophils in BALF decreased in the budesonide group. TNF-α, IL-1β, and IL-8 levels decreased in BALF, while IL-10 levels increased in the budesonide group. Lung injuries were reduced and survival rate was upregulated by budesonide. Budesonide effectively ameliorated respiratory function, attenuated endotoxin-induced lung injury, and improved the seven-day survival rate. © 2015 by the Society for Experimental Biology and Medicine.

Human papilloma virus vaccine associated uveitis.

PubMed

Holt, Henry D; Hinkle, David M; Falk, Naomi S; Fraunfelder, Frederick T; Fraunfelder, Frederick W

2014-03-01

To report a possible association between human papilloma virus (HPV) vaccination and uveitis. Spontaneous reports from the National Registry of Drug-Induced Ocular Side effects, World Health Organization and Food and Drug Administration were collected on uveitis associated with human papilloma virus vaccination. A MEDLINE search was performed using keywords "uveitis," "iritis," "iridocyclitis," "human papilloma virus," "Cervarix", and "Gardasil." Data garnered from spontaneous reports included the age, gender, adverse drug reaction (ADR), date of administration, concomitant administration of other vaccinations, time until onset of ADR, other systemic reactions, and dechallenge and rechallenge data. A total of 24 case reports of uveitis associated with human papilloma virus vaccination were identified, all cases were female, and the median age was 17. Median time from HPV vaccination to reported ADR was 30 days (range 0-476 days). According to World Health Organization criteria, the relationship between human papilloma virus vaccination and uveitis is "possible." Causality assessments are based on the time relationship of drug administration, uveitis development and re-challenge data. Clinicians should be aware of a possible bilateral uveitis and papillitis following HPV vaccination.

[Disseminated intravascular coagulation induced by endotoxin in rabbits: effect of treatment with t-PA and urokinase].

PubMed

Paloma, M J; Páramo, J A; Rifón, J; Rocha, E

1992-12-01

To assess the therapeutic efficacy of agents capable of stimulating the fibrinolytic system, such as tissue plasminogen activator (t-PA) and urokinase (UK) on endotoxin-induced disseminated intravascular coagulation (DIC) in the rabbit. DIC was induced by intravenous administration of endotoxin, 20 micrograms/kg/hr during 6 hr. Four different groups were established: a) control group, receiving only saline solution; b) t-PA group receiving 0.2 mg/kg; c) t-PA group receiving 0.7 mg/kg, and d) UK group, which was given 3,000 IU/kg/hr for 6 hr. Blood samples were drawn before and after 2 hr and 6 hr of endotoxin administration. Platelet count, and fibrinogen, factor XII and antithrombin III concentrations, were assessed in each sample. Mean, standard deviation and percentage of increase or decrease with respect to the basal value, this considered 100%, were used to evaluate the findings. For comparison of values, Student's t and Mann Whitney's U were used; the Fisher test was used for mortality studies. No statistical differences appeared for any of the values in the rabbits under basal conditions. The rabbits in the control group developed DIC. No doses of t-PA modified the changes appearing in blood coagulation. UK reduced the fibrinogen and factor XII consumption induced by endotoxin. The mortality rate in the control group reached 70%. High-dose t-PA decreased such figure to 50%, while low-dose t-PA or UK failed to reduce mortality. High-dose t-PA has beneficial effects on endotoxin-induced DIC in rabbits. UK failed to achieve such effect at the doses given in this experimental DIC model.

SUPPRESSION OF ALLERGIC UVEITIS BY 6-MERCAPTOPURINE

PubMed Central

Wirostko, E.; Halbert, S. P.

1962-01-01

Experimental uveitis in rabbits was induced by single intraocular antigen injection. Treatment with 6-MP for 14 days suppressed the allergic inflammation and antibody response. A good correlation was demonstrated between the degree of uveitis and the antibody titer. PMID:14001284

Involvement of sympathetic nervous system and brown fat in endotoxin-induced fever in rats.

PubMed

Jepson, M M; Millward, D J; Rothwell, N J; Stock, M J

1988-11-01

The object of this study was to assess the role of brown adipose tissue (BAT) and the sympathetic nervous system in the rise in heat production associated with endotoxin-induced fever. Oxygen consumption (VO2) was found to be significantly increased (28%) over a 4-h period after two doses of endotoxin (Escherichia coli lipopolysaccharide, 0.3 mg/100 g body wt) given 24 h apart. Injection of a mixed beta-adrenoceptor antagonist (propranolol) reduced VO2 by 14% in endotoxin-treated rats, whereas the selective beta 1- (atenolol) or beta 2- (ICI 118551) antagonists suppressed VO2 by 10%. These drugs did not affect VO2 in control animals. BAT thermogenic activity assessed from measurements of in vitro mitochondrial guanosine 5'-diphosphate (GDP) binding was elevated by 54% in interscapular BAT and by 171% in other BAT depots. Surgical denervation of one lobe of the interscapular depot prevented these responses. Endotoxin failed to stimulate GDP binding in rats fed protein-deficient diets. This may have been because BAT thermogenic activity was already elevated in control rats fed these diets or because endotoxin caused a marked suppression of food intake in the protein-deficient animals. The results indicate that sympathetic activation of BAT is involved in the thermogenic responses to endotoxin and that these can be modified by dietary manipulation.

Lamotrigine-induced tubulointerstitial nephritis and uveitis-atypical Cogan syndrome.

PubMed

Kolomeyer, Anton M; Kodati, Shyam

2015-12-01

To report a case of lamotrigine-induced tubulointerstitial nephritis and uveitis (TINU)-atypical Cogan syndrome. Case report. A 16-year-old boy with traumatic brain injury and seizures presented to the emergency department with facial swelling, rash, and back pain several days after increasing lamotrigine dose secondary to a breakthrough seizure. Creatinine, urine β2 microglobulin, and eosinophils were elevated. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme, and complement were normal. Renal biopsy showed acute granulomatous tubulointerstitial nephritis. Lamotrigine was discontinued, intravenous steroids were initiated, and the patient was discharged on Ativan and prednisone. Subsequently, he was diagnosed with bilateral anterior uveitis (vision 20/30 bilaterally) and started on prednisolone and cyclopentolate. Two months later, he developed a branch retinal artery occlusion in the right eye (vision 20/70) and bilateral ocular hypertension for which timolol-brimonidine and dorzolamide were added. Neuroimaging and hypercoagulability workup was unremarkable. Vision and intraocular pressure improved, while uveitis remained recalcitrant. Several months later, the patient developed central serous retinopathy in the right eye (vision 20/30). Prednisone was stopped but restarted due to methotrexate intolerance. A month later, he reported dizziness and was diagnosed with severe bilateral sensorineural hearing loss. Brain magnetic resonance imaging showed foci of perivascular, subcortical, and cochlear enhancement. Transtympanic Decadron injections and infliximab infusions were initiated. At the final visit, vision remained at 20/30 with trace anterior chamber reaction bilaterally while on timolol-brimonidine, dorzolamide, and prednisolone. An idiosyncratic drug reaction should be considered in the differential diagnosis of TINU-atypical Cogan syndrome.

Endotoxin Inhalation Alters Lung Development in Neonatal Mice

PubMed Central

Kulhankova, Katarina; George, Caroline L.S.; Kline, Joel N.; Darling, Melissa; Thorne, Peter S.

2012-01-01

Background Childhood asthma is a significant public health problem. Epidemiologic evidence suggests an association between childhood asthma exacerbations and early life exposure to environmental endotoxin. Although the pathogenesis of endotoxin-induced adult asthma is well studied, questions remain about the impact of environmental endotoxin on pulmonary responsiveness in early life. Methods We developed a murine model of neonatal/juvenile endotoxin exposures approximating those in young children and evaluated the lungs inflammatory and remodeling responses. Results Persistent lung inflammation induced by the inhalation of endotoxin in early life was demonstrated by the influx of inflammatory cells and pro-inflammatory mediators to the airways and resulted in abnormal alveolarization. Conclusions Results of this study advance the understanding of the impact early life endotoxin inhalation has on the lower airways, and demonstrates the importance of an experimental design that approximates environmental exposures as they occur in young children. PMID:22576659

Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in vascular permeability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, E.J.; Cook, J.A.; Spicer, K.M.

Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites. It was hypothesized that EFAD rats would manifest decreased vascular permeability changes during endotoxemia as a consequence of reduced arachidonic acid metabolism. To test this hypothesis, changes in hematocrit (HCT) and mesenteric localization rate of technetium-labeled human serum albumin (99mTc-HSA) and red blood cells (99mTc-RBC) were assessed in EFAD and normal rats using gamma-camera imaging. Thirty minutes after Salmonella enteritidis endotoxin, EFAD rats exhibited less hemoconcentration as determined by % HCT than normal rats. Endotoxin caused a less severe change inmore » permeability index in the splanchnic region in EFAD rats than in normal rats (1.2 +/- 0.6 x 10(-3)min-1 vs. 4.9 +/- 1.7 x 10(-3)min-1 respectively, P less than 0.05). In contrast to 99mTc-HSA, mesenteric localization of 99mTc-RBC was not changed by endotoxin in control or EFAD rats. Supplementation with ethyl-arachidonic acid did not enhance susceptibility of EFAD rats to endotoxin-induced splanchnic permeability to 99mTc-HSA. Leukotrienes have been implicated as mediators of increased vascular permeability in endotoxin shock. Since LTC3 formation has been reported to be increased in EFA deficiency, we hypothesized that LTC3 may be less potent than LTC4. Thus the effect of LTC3 on mean arterial pressure and permeability was compared to LTC4 in normal rats. LTC3-induced increases in peak mean arterial pressure were less than LTC4 at 10 micrograms/kg (39 +/- 5 mm Hg vs. 58 +/- 4 mm Hg respectively, P less than 0.05) and at 20 micrograms/kg (56 +/- 4 mm Hg vs. 75 +/- 2 mm Hg respectively, P less than 0.05). LY171883 (30 mg/kg), an LTD4/E4 receptor antagonist, attenuated the pressor effect of LTC4, LTD4, and LTC3.« less

Multiple Sclerosis-related Uveitis: Does MS Treatment Affect Uveitis Course?

PubMed

Jouve, Léa; Benrabah, Rabah; Héron, Emmanuel; Bodaghi, Bahram; Le Hoang, Phuc; Touitou, Valérie

2017-06-01

Few data are available regarding the optimal treatment of multiple sclerosis (MS)-related uveitis. The aim of this study was to describe clinical features of MS-associated uveitis and determine how MS treatment affects the course of uveitis. Retrospective, multicenter study. Patients were divided into two groups according to the use (group 2) or not (group 1) of immunomodulatory drugs. Characteristics of uveitis and treatment were reviewed. A total of 68 eyes from 36 patients (17 in group 1 and 19 in group 2) were included. All patients were treated with topical and/or systemic steroids for uveitis. Uveitis occurred 1-17 years prior to neurologic symptoms in 78% of patients. Uveitis was more severe in group 2 (p<0.05), with a tendency toward a higher rate of chronic uveitis (p = 0.06). MS-related uveitis has often a favorable evolution. Patients on interferon-beta have more severe and chronic uveitis. As far as we are concerned, interferon-beta given on the sole indication of uveitis is not recommended. If steroid-sparing agent is required for intraocular inflammation, immunosuppressive drugs should be considered.

Effect of a 5-lipoxygenase inhibitor on endotoxin-induced pulmonary dysfunction in awake sheep.

PubMed

Kuratomi, Y; Lefferts, P L; Christman, B W; Parker, R E; Smith, W G; Mueller, R A; Snapper, J R

1993-02-01

We studied the effects of a 5-lipoxygenase inhibitor, SC-45662, on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. Each sheep was studied with endotoxin alone, SC-45662 alone, and endotoxin after SC-45662 pretreatment. Endotoxin did not cause consistent increases in plasma or lung lymph concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood from sheep before and after treatment with SC-45662 demonstrated no inhibition of cyclooxygenase metabolism but an approximately 80% inhibition of LTB4 production. At drug concentrations obtained in vivo, SC-45662 did not significantly inhibit in vitro A23187-stimulated whole blood thromboxane B2 production but did inhibit LTB4 production from ionophore-stimulated sheep granulocytes. SC-45662 attenuated the early changes in lung mechanics and pulmonary hypertension but did not attenuate the later increase in lung fluid and solute exchange observed after endotoxemia. We conclude that 5-lipoxygenase products are not measurably involved in the later increase in lung fluid and solute exchange observed after endotoxemia in sheep.

Pasteurella haemolytica A1-Derived Leukotoxin and Endotoxin Induce Intracellular Calcium Elevation in Bovine Alveolar Macrophages by Different Signaling Pathways

PubMed Central

Hsuan, S. L.; Kannan, M. S.; Jeyaseelan, S.; Prakash, Y. S.; Sieck, G. C.; Maheswaran, S. K.

1998-01-01

Leukotoxin and endotoxin derived from Pasteurella haemolytica serotype 1 are the primary virulence factors contributing to the pathogenesis of lung injury in bovine pneumonic pasteurellosis. Activation of bovine alveolar macrophages with endotoxin or leukotoxin results in the induction of cytokine gene expression, with different kinetics (H. S. Yoo, S. K. Maheswaran, G. Lin, E. L. Townsend, and T. R. Ames, Infect. Immun. 63:381–388, 1995; H. S. Yoo, B. S. Rajagopal, S. K. Maheswaran, and T. R. Ames, Microb. Pathog. 18:237–252, 1995). Furthermore, extracellular Ca2+ is required for leukotoxin-induced cytokine gene expression. However, the involvement of Ca2+ in endotoxin effects and the precise signaling mechanisms in the regulation of intracellular Ca2+ by leukotoxin and endotoxin are not known. In fura-2-acetoxymethyl ester-loaded alveolar macrophages, intracellular Ca2+ regulation by leukotoxin and endotoxin was studied by video fluorescence microscopy. Leukotoxin induced a sustained elevation of intracellular Ca2+ in a concentration-dependent fashion by influx of extracellular Ca2+ through voltage-gated channels. In the presence of fetal bovine serum, endotoxin elevated intracellular Ca2+ even in the absence of extracellular Ca2+. Leukotoxin-induced intracellular Ca2+ elevation was inhibited by pertussis toxin, inhibitors of phospholipases A2 and C, and the arachidonic acid analog 5,8,11,14-eicosatetraynoic acid. Intracellular Ca2+ elevation by endotoxin was inhibited by inhibitors of phospholipase C and protein tyrosine kinase, but not by pertussis toxin, or the arachidonic acid analog. To the best of our knowledge, this is the first report of Ca2+ signaling by leukotoxin through a G-protein-coupled mechanism involving activation of phospholipases A2 and C and release of arachidonic acid in bovine alveolar macrophages. Ca2+ signaling by endotoxin, on the other hand, involves activation of phospholipase C and requires tyrosine phosphorylation. The

Pasteurella haemolytica A1-derived leukotoxin and endotoxin induce intracellular calcium elevation in bovine alveolar macrophages by different signaling pathways.

PubMed

Hsuan, S L; Kannan, M S; Jeyaseelan, S; Prakash, Y S; Sieck, G C; Maheswaran, S K

1998-06-01

Leukotoxin and endotoxin derived from Pasteurella haemolytica serotype 1 are the primary virulence factors contributing to the pathogenesis of lung injury in bovine pneumonic pasteurellosis. Activation of bovine alveolar macrophages with endotoxin or leukotoxin results in the induction of cytokine gene expression, with different kinetics (H. S. Yoo, S. K. Maheswaran, G. Lin, E. L. Townsend, and T. R. Ames, Infect. Immun. 63:381-388, 1995; H. S. Yoo, B. S. Rajagopal, S. K. Maheswaran, and T. R. Ames, Microb. Pathog. 18:237-252, 1995). Furthermore, extracellular Ca2+ is required for leukotoxin-induced cytokine gene expression. However, the involvement of Ca2+ in endotoxin effects and the precise signaling mechanisms in the regulation of intracellular Ca2+ by leukotoxin and endotoxin are not known. In fura-2-acetoxymethyl ester-loaded alveolar macrophages, intracellular Ca2+ regulation by leukotoxin and endotoxin was studied by video fluorescence microscopy. Leukotoxin induced a sustained elevation of intracellular Ca2+ in a concentration-dependent fashion by influx of extracellular Ca2+ through voltage-gated channels. In the presence of fetal bovine serum, endotoxin elevated intracellular Ca2+ even in the absence of extracellular Ca2+. Leukotoxin-induced intracellular Ca2+ elevation was inhibited by pertussis toxin, inhibitors of phospholipases A2 and C, and the arachidonic acid analog 5,8,11,14-eicosatetraynoic acid. Intracellular Ca2+ elevation by endotoxin was inhibited by inhibitors of phospholipase C and protein tyrosine kinase, but not by pertussis toxin, or the arachidonic acid analog. To the best of our knowledge, this is the first report of Ca2+ signaling by leukotoxin through a G-protein-coupled mechanism involving activation of phospholipases A2 and C and release of arachidonic acid in bovine alveolar macrophages. Ca2+ signaling by endotoxin, on the other hand, involves activation of phospholipase C and requires tyrosine phosphorylation. The differences in

Gender Difference in Bacteria Endotoxin-Induced Inflammatory and Anorexic Responses.

PubMed

Kuo, Shiu-Ming

2016-01-01

Inflammation-related anorexic response has been observed in systemic diseases as well as in localized infection and is an important issue in patient care. We tested the hypothesis that upon the same endotoxin exposure, males have more severe inflammatory responses and thus suffer from more negative effect on appetite. Ten-week old male and female mice were compared in their plasma levels of pro-inflammatory cytokines after a body weight-based i.p. injection of bacterial endotoxin lipopolysaccharide. Male mice consistently showed significantly higher levels of IL6 and TNFα than female mice. The difference was observed starting at 3 hours after the systemic endotoxin exposure. It was independent of the level of endotoxin dosage and of the genotype of the anti-inflammatory cytokine, IL10. Interestingly, endotoxin-injected male mice also had significantly higher plasma IL10 levels compared to the female mice. Pre-puberty young mice showed no gender differences in the plasma levels of IL6, TNFα and IL10. Their cytokine levels were mostly between that of the adult males and females. Consistent with the higher inflammatory response in male mice, the endotoxin exposure also led to significantly more appetite loss in male mice at a range of doses in two strains of mice. Saline injection in the absence of endotoxin affected neither the cytokine levels nor the appetite. Although a direct mechanistic link between inflammation parameters and appetite was not addressed here, the results support that male gender could be a risk factor for higher pro-inflammatory cytokines and anorexic response after the endotoxin exposure.

Influence of E. coli endotoxin on ACTH induced adrenal cell steroidogenesis.

PubMed

Garcia, R; Viloria, M D; Municio, A M

1985-03-01

The effect of endotoxin (lipopolysaccharide from E. coli) on isolated adrenocortical cells was examined. Lipopolysaccharide decreased the ACTH-induced steroidogenesis. This effect was shown by all corticotropin concentrations studied, and the longer the incubation time, the higher the effect produced. The rate of decrease of ACTH-induced steroidogenesis was dependent on the concentration of lipopolysaccharide in the medium. Binding of [125I]ACTH to adrenocortical cells was modified by lipopolysaccharide; this modification was related to a decrease of the ACTH-induced steroidogenesis. This effect supports the hypothesis of a direct interaction between lipopolysaccharide and the cell membrane with a concomitant distortion of the cell surface affecting the ACTH receptor sites of their environment. [14C]Lipopolysaccharide binds to isolated adrenocortical cells. Binding specificity was investigated by competitive experiments in the presence of various types of endotoxins, polypeptide hormones and proteins. Unlabelled lipopolysaccharide from the same bacterial strain and isolated under identical conditions than the labelled lipopolysaccharide exerted the strongest inhibitory activity. Unlabelled lipopolysaccharide of various strains different from that originating the labelled lipopolysaccharide exerted the less displacement. It would imply a certain kind of specificity but the decrease in the binding of lipopolysaccharide produced by ACTH and glucagon suggests the existence of non-specific interactions between lipopolysaccharide and cell membrane.

Effect of postponed treatment with an anti-tumour necrosis factor (TNF) F(ab')2 fragment on endotoxin-induced cytokine and neutrophil responses in chimpanzees.

PubMed Central

van der Poll, T; Levi, M; ten Cate, H; Jansen, J; Biemond, B J; Haagmans, B L; Eerenberg, A; van Deventer, S J; Hack, C E; ten Cate, J W

1995-01-01

TNF is considered to be an intermediate factor in endotoxin-induced release of other cytokines and endotoxin-induced neutrophil degranulation. Little is known about the effect of postponed treatment with anti-TNF in primate endotoxin models. To assess the effect of delayed treatment with anti-TNF in endotoxaemia, six healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin (4 ng/kg). In three of these animals the administration of endotoxin was followed after 30 min by a bolus i.v. injection of the anti-TNF F(ab')2 fragment MAK 195F (0.1 mg/kg). Post-treatment with MAK 195F completely prevented the appearance of TNF activity in serum elicited by endotoxin, and markedly reduced the rises in the serum concentrations of IL-6 and IL-8. In addition, the endotoxin-induced increases in the type I and type II soluble TNF receptors were also profoundly inhibited by MAK 195F, suggesting that TNF is involved in the release of its own soluble receptors in endotoxaemia. Neutrophilic leucocytosis was not affected by MAK 195F. In contrast, MAK 195F did significantly abrogate neutrophil degranulation, as measured by the plasma concentrations of lactoferrin. These results indicate that treatment with anti-TNF 30 min after the administration of endotoxin is still effective in attenuating the induction of the cytokine network and of neutrophil degranulation. PMID:7697917

[New etiological concepts in uveitis].

PubMed

Bodaghi, B

2005-05-01

Uveitis remains an important cause of visual impairment, particularly in young patients. Idiopathic forms of intraocular inflammation should no longer be regarded as a presumed clinical entity, and the ophthalmologist must reconsider the specific etiology of primary uveitis when the clinical examination does not yield a definitive diagnosis or when the course of the disease on corticosteroids remains atypical. Laboratory tests based on serum analysis have limited value and should not be considered as diagnostic proof in different clinical presentations. The diagnostic management of infectious uveitis has been greatly improved by the use of molecular techniques applied to ocular fluids and tissues. Polymerase chain reaction (PCR) technology is a powerful tool that should be proposed in atypical cases of uveitis or retinitis of unclear but potentially infectious origin. This strategy is a major step before using unconventional and new immunomodulatory agents such as anti-TNF-alpha molecules. Under strict experimental conditions including adequate testing to rule out a possible contamination, PCR and its variants have changed our practical approach to intraocular inflammatory disorders and have provided new details for the understanding of infectious uveitis. The concept of pathogen-induced intraocular inflammation can be revisited in the light of molecular data obtained after anterior chamber paracentesis or diagnostic vitrectomy.

Pediatric Uveitis.

PubMed

Chan, Nicole Shu-Wen; Choi, Jessy; Cheung, Chui Ming Gemmy

2018-01-01

Pediatric uveitis differs from adult-onset uveitis and is a topic of special interest because of its diagnostic and therapeutic challenges. Children with uveitis are often asymptomatic and the uveitis is often chronic, persistent, recurrent, and resistant to conventional treatment. Anterior uveitis is the most common type of uveitis in children; the prevalence of intermediate, posterior, and panuveitis varies geographically and among ethnic groups. Regarding etiology, most cases of pediatric uveitis are idiopathic but can be due to systemic inflammatory disorders, infections, or a manifestation of masquerade syndrome. Ocular complications include cataracts, hypotony or glaucoma, band keratopathy, synechiae formation, macular edema, optic disc edema, choroidal neovascular membranes, and retinal detachment. These complications are often severe, leading to irreversible structural damage and significant visual disability due to delayed presentation and diagnosis, persistent chronic inflammation from suboptimal treatment, topical and systemic corticosteroid dependence, and delayed initiation of systemic disease‒modifying agents. Treatment for noninfectious uveitis is a stepwise approach starting with corticosteroids. Immunomodulatory therapy should be initiated in cases where quiescence cannot be achieved without steroid dependence. Patients should be monitored regularly for complications of uveitis along with systemic and ocular adverse effects from treatments. The goals are to achieve steroid-free durable remission, to reduce the risk of sight-threatening complications from the uncontrolled ocular inflammation, and to avoid the impact of lifelong burden of visual loss on the child and their family. Multidisciplinary management will ensure holistic care of affected children and improve the support for their families. Copyright 2018 Asia-Pacific Academy of Ophthalmology.

TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation

PubMed Central

Tauseef, Mohammad; Knezevic, Nebojsa; Chava, Koteswara R.; Smith, Monica; Sukriti, Sukriti; Gianaris, Nicholas; Obukhov, Alexander G.; Vogel, Stephen M.; Schraufnagel, Dean E.; Dietrich, Alexander; Birnbaumer, Lutz; Malik, Asrar B.

2012-01-01

Lung vascular endothelial barrier disruption and the accompanying inflammation are primary pathogenic features of acute lung injury (ALI); however, the basis for the development of both remains unclear. Studies have shown that activation of transient receptor potential canonical (TRPC) channels induces Ca2+ entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca2+ signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca2+ entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6 renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. TRPC6 induces Ca2+ entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca2+ entry mediated by TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the interaction of myeloid differentiation factor 88 and IL-1R–associated kinase 4, which are required for NF-κB activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca2+ entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin. PMID:23045603

N-acetylcysteine attenuates endotoxin-induced leukocyte-endothelial cell adhesion and macromolecular leakage in vivo.

PubMed

Schmidt, H; Schmidt, W; Müller, T; Böhrer, H; Gebhard, M M; Martin, E

1997-05-01

To determine the influence of N-acetylcysteine on endotoxin-induced leukocyte-endothelial cell adhesion, vascular leakage, and venular microhemodynamics. Randomized, blinded, controlled trial. Experimental laboratory. Thirty male Wistar rats. After pretreatment with N-acetylcysteine (150 mg/kg; n = 40; group A) or 0.9% saline solution (n = 10; group B) animals were given an intravenous infusion of endotoxin (Escherichia coli lipopolysaccharide 026:B6; 2 mg/kg/hr) over 120 mins. Animals in the control group (n = 10; group C) received a volume-equivalent infusion of 0.9% saline solution. Leukocyte adherence, red cell velocity (VRBC), vessel diameters, venular wall shear rate, and macromolecular leakage were determined in mesenteric postcapillary venules using in vivo videomicroscopy at baseline and at 30, 50, 90, and 120 mins after the start of the endotoxin challenge. Endotoxin exposure induced a marked increase in adherent leukocytes (group B: baseline, 391 +/- 24 cells/mm2; 120 mins, 1268 +/- 131 cells/mm2; p < .01). N-acetylcysteine pretreatment attenuated the adherence of leukocytes during endotoxemia (baseline, 366 +/- 28 cells/mm2; 120 mins, 636 +/- 49 cells/mm2; p < .01 vs. baseline; p < .01 vs. group B). Leukocyte adherence in control animals (group C) did not increase significantly. Administration of N-acetylcysteine did not influence the decrease in VRBC observed during endotoxemia. In group B1 VRBC decreased during the infusion of endotoxin from 2.0 +/- 0.2 mm/sec at baseline to 1.1 +/- 0.2 mm/ sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C), and in group A from 2.2 +/- 0.2 mm/sec to 1.1 +/- 0.1 mm/sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C). In group C, VRBC remained unchanged (baseline, 1.7 +/- 0.2 mm/sec; at 120 mins, 1.5 +/- 0.2 mm/sec). The venular diameters remained unchanged in all groups during the entire study period. After 120 mins, the venular wall shear rate decreased from 502 +/- 62 secs-1 at baseline to 272

Etanercept in methotrexate-resistant JIA-related uveitis.

PubMed

Saeed, Muhammad Usman; Raza, Syed Hamid; Goyal, Sudeshna; Cleary, Gavin; Newman, William David; Chandna, Arvind

2014-01-01

We report our results with systemic Etanercept in patients with juvenile idiopathic arthritis in a joint ophthalmology-rheumatology clinic at a tertiary hospital. Patients with JIA on Etanercept were identified from a dedicated uveitis database. A retrospective review of electronic and paper-based patient records was performed. Nine patients with JIA and current or previous treatment with Etanercept were identified, including six females and three males. Five patients with previous or current uveitis were noted. A further four were under observation for uveitis and required Etanercept for their joint disease. All nine patients had previously been taking Methotrexate, which had a suboptimal response in controlling arthritis or uveitis. Six out of nine patients did not show any uveitis activity at their last follow-up. Eyes of three patients still show signs of active inflammation in the anterior chamber (two on Etanercept and one off Etanercept). Severely impaired visual acuity (PL) was recorded in both eyes of one patient with long-standing persistent uveitis. Moderate visual loss in one eye of one patient was seen. The remaining seven patients did not show any significant loss of vision. Intraocular inflammation was not induced in any patient started on Etanercept. Etanercept may be useful in controlling JIA-related uveitis or arthritis in a pediatric patient when Methotrexate has had a suboptimal response in controlling the inflammatory activity.

Adherent endotoxin on dental implant surfaces: a reappraisal.

PubMed

Morra, Marco; Cassinelli, Clara; Bollati, Daniele; Cascardo, Giovanna; Bellanda, Marco

2015-02-01

Osteoimmunology is the crosstalk between cells from the immune and skeletal systems, suggesting a role of pro-inflammatory cytokines in the stimulation of osteoclast activity. Endotoxin or bacterial challenges to inflammatory cells are directly relevant to dental implant pathologies involving bone resorption, such as osseointegration failure and peri-implantitis. While the endotoxin amount on implant devices is regulated by standards, it is unknown whether commercially available dental implants elicit different levels of adherent-endotoxin stimulated cytokines. The objective of this work is to develop a model system and evaluate endotoxin-induced expression of pro-inflammatory cytokine genes relevant to osteoclast activation on commercially available dental implants. Murine J774-A1 macrophages were cultured on Ti disks with different level of lipopolysaccharide (LPS) contamination to define the time-course of the inflammatory response to endotoxin, as evaluated by reverse transcription polymerase chain reaction analysis. The developed protocol was then used to measure adherent endotoxin on commercially available packaged and sterile dental implants in the "as-implanted" condition. Results show that tested dental implants induce variable expression of endotoxin-stimulated genes, sometimes above the level expected to promote bone resorption in vivo. Results are unaffected by the specific surface treatment; rather, they likely reflect care in cleaning and packaging protocols. In conclusion, expression of genes that enhance osteoclast activity through endotoxin stimulation of inflammatory cells is widely different on commercially available dental implants. A reappraisal of the clinical impact of adherent endotoxins on dental (and bone) implant devices is required in light of increasing knowledge on crosstalk between cells from the immune and skeletal systems.

Uveitis and Gender: The Course of Uveitis in Pregnancy

PubMed Central

Chiam, Nathalie P. Y.; Lim, Lyndell L. P.

2014-01-01

The hormonal and immunological changes in pregnancy have a key role in maintaining maternal tolerance of the semiallogeneic foetus. These pregnancy-associated changes may also influence the course of maternal autoimmune diseases. Noninfectious uveitis tends to improve during pregnancy. Specifically, uveitis activity tends to ameliorate from the second trimester onwards, with the third trimester being associated with the lowest disease activity. The mechanism behind this phenomenon is likely to be multifactorial and complex. Possible mechanisms include Th1/Th2 immunomodulation, regulatory T-cell phenotype plasticity, and immunosuppressive cytokines. This clearly has management implications for patients with chronic sight threatening disease requiring systemic treatment, as most medications are not recommended during pregnancy due to lack of safety data or proven teratogenicity. Given that uveitis activity is expected to decrease in pregnancy, systemic immunosuppressants could be tapered during pregnancy in these patients, with flare-ups being managed with local corticosteroids till delivery. In the postpartum period, as uveitis activity is expected to rebound, patients should be reviewed closely and systemic medications recommenced, depending on uveitis activity and the patient's breastfeeding status. This review highlights the current understanding of the course of uveitis in pregnancy and its management to help guide clinicians in managing their uveitis patients during this special time in life. PMID:24683491

Characterization of uveitis induced by use of a single intravitreal injection of bacterial lipopolysaccharide in cats.

PubMed

Del Sole, María J; Sande, Pablo H; Felipe, Antonio E; Fernandez, Diego C; Keller Sarmiento, María I; Aba, Marcelo A; Rosenstein, Ruth E

2008-11-01

To investigate the use of a single intravitreal injection of bacterial lipopolysaccharide (LPS) to experimentally induce uveitis in cats. 7 young male European shorthair cats that were considered physically and ophthalmologically healthy. In each cat, LPS was injected intravitreally into 1 eye; the contralateral eye was injected with the preparation vehicle. During a period of 45 days, both eyes were evaluated by means of clinical evaluation; assessment of the integrity of the blood-aqueous humor barrier (determined via measurement of protein concentration and cell content in samples of aqueous humor); functional analysis (via electroretinography); and following euthanasia, histologic examination of the retinas. In LPS-treated eyes, several clinical signs were observed until day 45 after injection. Compared with vehicle-treated eyes, intraocular pressure was significantly lower and protein concentration and the number of infiltrating cells were significantly higher in LPS-treated eyes. Mean amplitudes of scotopic electroretinographic a- and b-waves were significantly reduced in eyes injected with LPS, compared with findings in eyes injected with vehicle. At 45 days after injection, LPS-induced alterations in photoreceptors and the middle portion of the retina were detected histologically. Results indicated that a single intravitreal injection of LPS in eyes of cats induced clinical, biochemical, functional, and histologic changes that were consistent with the main features of naturally occurring uveitis. This technique may be a useful tool in the investigation of new treatment strategies for uveitis in cats.

Attenuation by intravenous 2-chloroadenosine of acute lung injury induced by live escherichia coli or latex particles added to endotoxin in the neutropenic state.

PubMed

Sakamaki, Fumio; Ishizaka, Akitoshi; Urano, Tetsuya; Sayama, Koichi; Nakamura, Hidetoshi; Terashima, Takeshi; Waki, Yasuhiro; Soejima, Kenzo; Tasaka, Sadatomo; Sawafuji, Makoto; Kobayashi, Kouichi; Yamaguchi, Kazuhiro; Kanazawa, Minoru

2003-08-01

Although neutrophil depletion can reduce the level of acute lung injury (ALI) induced by Escherichia coli endotoxin, that induced by live E coli cannot be attenuated even in neutropenia. This suggests that live E coli cause ALI by way of an mechanism independent of circulating neutrophil. Tumor necrosis factor-alpha (TNF-alpha), which is released from monocytes and macrophages, is a proinflammatory cytokine that is recognized as a central mediator of several forms of inflammation. In this controlled experimental study, we examined the effects of an adenosine-receptor agonist, 2-chloroadenosine (2CA), that has suppressive effects on various cell types and TNF-alpha, on endotoxin plus latex particles, and on ALI induced by live E coli in the neutropenic state. We studied 42 guinea pigs rendered neutropenic by means of intraperitoneal cyclophosphamide administration. Experimental groups consisted of (1) a saline-solution control group; (2) an endotoxin (0.2 mg/kg)-treated group; (3) a group treated with endotoxin plus 2CA (10 micro g/kg); (4) a group treated with latex (2 x 10(9)/kg); (5) a group exposed to endotoxin and latex; (6) a group exposed to endotoxin, latex, and 2CA; (7) a group exposed to E coli (2 x 10(9)/kg); and (8) a group exposed to E coli and 2CA. The injection of endotoxin alone in neutropenic animals did not increase the indexes of ALI (lung tissue/plasma ratio [T/P] and lung wet weight/dry weight ratio [W/D], calculated with the use of iodine 125-labeled albumin). In contrast, these indexes were increased in the endotoxin-and-latex groups compared with those of the control group. ALI in the endotoxin-and-latex group was attenuated by intravenous 2CA. The intravenous injection of live E coli also caused increases in T/P, W/D, and plasma TNF-alpha, but thse were limited by 2CA. In summary, ALI induced by latex particles added to endotoxin and live E coli in the neutropenic state was attenuated by 2CA, suggesting a partial contribution of various cell

ALLERGEN PROVOCATION AUGMENTS ENDOTOXIN-INDUCED NASAL INFLAMMATION IN ATOPIC ASTHMATICS

EPA Science Inventory

Background: Recent epidemiologic and in vivo studies have suggested that inhaled endotoxin plays an important role in asthma pathogenesis.
Objective: The present study examines the effect of nasal allergen provocation on subsequent endotoxin challenges in subjects with atopi...

Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model

PubMed Central

2013-01-01

Introduction The acute respiratory distress syndrome (ARDS), affects up to 150,000 patients per year in the United States. We and other groups have demonstrated that bone marrow derived mesenchymal stromal stem cells prevent ARDS induced by systemic and local administration of endotoxin (lipopolysaccharide (LPS)) in mice. Methods A study was undertaken to determine the effects of the diverse populations of bone marrow derived cells on the pathophysiology of ARDS, using a unique ex-vivo swine preparation, in which only the ventilated lung and the liver are perfused with autologous blood. Six experimental groups were designated as: 1) endotoxin alone, 2) endotoxin + total fresh whole bone marrow nuclear cells (BMC), 3) endotoxin + non-hematopoietic bone marrow cells (CD45 neg), 4) endotoxin + hematopoietic bone marrow cells (CD45 positive), 5) endotoxin + buffy coat and 6) endotoxin + in vitro expanded swine CD45 negative adherent allogeneic bone marrow cells (cultured CD45neg). We measured at different levels the biological consequences of the infusion of the different subsets of cells. The measured parameters were: pulmonary vascular resistance (PVR), gas exchange (PO2), lung edema (lung wet/dry weight), gene expression and serum concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6. Results Infusion of freshly purified autologous total BMCs, as well as non-hematopoietic CD45(-) bone marrow cells significantly reduced endotoxin-induced pulmonary hypertension and hypoxemia and reduced the lung edema. Also, in the groups that received BMCs and cultured CD45neg we observed a decrease in the levels of IL-1β and TNF-α in plasma. Infusion of hematopoietic CD45(+) bone marrow cells or peripheral blood buffy coat cells did not protect against LPS-induced lung injury. Conclusions We conclude that infusion of freshly isolated autologous whole bone marrow cells and the subset of non-hematopoietic cells can suppress the acute humoral and physiologic

Infectious Uveitis

PubMed Central

2015-01-01

Infectious uveitis is one of the most common and visually devastating causes of uveitis in the US and worldwide. This review provides a summary of the identification, treatment, and complications associated with certain forms of viral, bacterial, fungal, helminthic, and parasitic uveitis. In particular, this article reviews the literature on identification and treatment of acute retinal necrosis due to herpes simplex virus, varicella virus, and cytomegalovirus. While no agreed-upon treatment has been identified, the characteristics of Ebola virus panuveitis is also reviewed. In addition, forms of parasitic infection such as Toxoplasmosis and Toxocariasis are summarized, as well as spirochetal uveitis. Syphilitic retinitis is reviewed given its increase in prevalence over the last decade. The importance of early identification and treatment of infectious uveitis is emphasized. Early identification can be achieved with a combination of maintaining a high suspicion, recognizing certain clinical features, utilizing multi-modal imaging, and obtaining specimens for molecular diagnostic testing. PMID:26618074

Morphine induced exacerbation of sepsis is mediated by tempering endotoxin tolerance through modulation of miR-146a

PubMed Central

Banerjee, Santanu; Meng, Jingjing; Das, Subhas; Krishnan, Anitha; Haworth, Justin; Charboneau, Richard; Zeng, Yan; Ramakrishnan, Sundaram; Roy, Sabita

2013-01-01

Development of tolerance to endotoxin prevents sustained hyper inflammation during systemic infections. Here we report for the first time that chronic morphine treatment tempers endotoxin tolerance resulting in persistent inflammation, septicemia and septic shock. Morphine was found to down-regulate endotoxin/LPS induced miR-146a and 155 in macrophages. However, only miR-146a over expression, but not miR-155 abrogates morphine mediated hyper-inflammation. Conversely, antagonizing miR-146a (but not miR-155) heightened the severity of morphine-mediated hyper-inflammation. These results suggest that miR-146a acts as a molecular switch controlling hyper-inflammation in clinical and/or recreational use of morphine. PMID:23756365

The use of topical honey in the treatment of corneal abrasions and endotoxin-induced keratitis in an animal model.

PubMed

Uwaydat, Sami; Jha, Purushottam; Tytarenko, Ruslana; Brown, Harry; Wiggins, Michael; Bora, Puran S; Bora, Nalini S

2011-09-01

 To investigate the effect of topically applied honey on intact corneas, surgically induced corneal abrasions and endotoxin induced keratitis. The effect of honey on the cornea was investigated by application of honey on intact corneas, wounded corneas and endotoxin-induced keratitis in Lewis rats. The corneas were wounded by creating an epithelial defect using a surgical blade, and the keratitis was induced by topically applying Pseudomonas aeruginosa endotoxin to scarified corneas. After treatment rats were sacrificed and cornea harvested in each case. Corneas were processed for paraffin embedding for histological and immuno-fluorescence staining. Corneas were also harvested and processed for total ribonucleic acid (RNA) isolation for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for various growth factors and inflammatory chemokines/cytokines).  Histological analysis revealed that no inflammation or morphological changes occurred after honey treatment in naive intact corneas. Vascular endothelial growth factor (VEGF) levels were also not altered after honey treatment. Topical application of honey to injured corneas resulted in faster epithelial healing and decreased expression of VEGF, transforming growth factor beta (TGF-β), interferon gamma (IFN-γ), interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-α) in injured corneas. Our results also established that honey treatment reduced the inflammation in endotoxin-induced keratitis by reducing the levels of angiogenic factors (VEGF and TGF-β), inflammatory cytokines (IL-12) and chemokines (CC chemokine receptor 5(CCR-5)).  Short term use of honey on intact corneas can be safe. Honey has anti-angiogenic and anti-inflammatory properties that can be explored in several corneal inflammatory and infectious conditions.

Equine recurrent uveitis--a spontaneous horse model of uveitis.

PubMed

Deeg, Cornelia A; Hauck, Stefanie M; Amann, Barbara; Pompetzki, Dirk; Altmann, Frank; Raith, Albert; Schmalzl, Thomas; Stangassinger, Manfred; Ueffing, Marius

2008-01-01

Equine recurrent uveitis (ERU) is an autoimmune disease that occurs with a high prevalence (10%) in horses. ERU represents the only reliable spontaneous model for human autoimmune uveitis. We already identified and characterized novel autoantigens (malate dehydrogenase, recoverin, CRALBP) by analyzing the autoantibody-binding pattern of horses affected by spontaneous recurrent uveitis (ERU) to the retinal proteome. CRALBP also seems to be relevant to human autoimmune uveitis. Proteomic screening of vitreous and retinal samples from ERU diseased cases in comparison to healthy controls has led to the identification of a series of differentially regulated proteins, which are functionally linked to the immune system and the maintenance of the blood-retinal barrier. 2008 S. Karger AG, Basel.

Expression of cyclin D{sub 1} during endotoxin-induced aleveolar type II cell hyperplasia in rat lung and the detection of apoptotic cells during the remodeling process

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tesfaigzi, J.; Wood, M.B.; Johnson, N.F.

Our studies have shown that endotoxin intratracheally instilled into the rat lung induces proliferation of alveolar type II cells. In that study, the alveolar type II cells. In that study, the alveolar type II cell hyperplasia occurred 2 d after instillation of endotoxin and persisted for a further 2 d. After hyperplasia, the lung remodeled and returned to a normal state within 24-48 h. Understanding the mechanisms involved in the remodeling process of this transient hyperplasia may be useful to identify molecular changes that are altered in neoplasia. The purpose of the present study was to corroborate induction of epithelialmore » cell hyperplasia by endotoxin and to delineate mechanisms involved in tissue remodeling after endotoxin-induced alveolar type II cell hyperplasia. In conclusion, immonostaining with cyclin D1 and cytokeratin shows that endotoxin induced epithelial cell proliferation and resulted in hyperplasia in the lung which persisted through 4 d post-instillation.« less

Apigenin Alleviates Endotoxin-Induced Myocardial Toxicity by Modulating Inflammation, Oxidative Stress, and Autophagy

PubMed Central

Li, Fang; Lang, Fangfang; Zhang, Huilin; Xu, Liangdong; Wang, Yidan; Zhai, Chunxiao

2017-01-01

Apigenin, a component in daily diets, demonstrates antioxidant and anti-inflammatory properties. Here, we intended to explore the mechanism of apigenin-mediated endotoxin-induced myocardial injury and its role in the interplay among inflammation, oxidative stress, and autophagy. In our lipopolysaccharide- (LPS-) induced myocardial injury model, apigenin ameliorated cardiac injury (lactate dehydrogenase (LDH) and creatine kinase (CK)), cell death (TUNEL staining, DNA fragmentation, and PARP activity), and tissue damage (cardiac troponin I (cTnI) and cardiac myosin light chain-1 (cMLC1)) and improved cardiac function (ejection fraction (EF) and end diastolic left ventricular inner dimension (LVID)). Apigenin also alleviated endotoxin-induced myocardial injury by modulating oxidative stress (nitrotyrosine and protein carbonyl) and inflammatory cytokines (TNF-α, IL-1β, MIP-1α, and MIP-2) along with their master regulator NFκB. Apigenin modulated redox homeostasis, and its anti-inflammatory role might be associated with its ability to control autophagy. Autophagy (determined by LAMP1, ATG5, and p62), its transcriptional regulator transcription factor EB (TFEB), and downstream target genes including vacuolar protein sorting-associated protein 11 (Vps11) and microtubule-associated proteins 1A/1B light chain 3B (Map1lc3) were modulated by apigenin. Thus, our study demonstrated that apigenin may lead to potential development of new target in sepsis treatment or other myocardial oxidative and/or inflammation-induced injuries. PMID:28828145

Apigenin Alleviates Endotoxin-Induced Myocardial Toxicity by Modulating Inflammation, Oxidative Stress, and Autophagy.

PubMed

Li, Fang; Lang, Fangfang; Zhang, Huilin; Xu, Liangdong; Wang, Yidan; Zhai, Chunxiao; Hao, Enkui

2017-01-01

Apigenin, a component in daily diets, demonstrates antioxidant and anti-inflammatory properties. Here, we intended to explore the mechanism of apigenin-mediated endotoxin-induced myocardial injury and its role in the interplay among inflammation, oxidative stress, and autophagy. In our lipopolysaccharide- (LPS-) induced myocardial injury model, apigenin ameliorated cardiac injury (lactate dehydrogenase (LDH) and creatine kinase (CK)), cell death (TUNEL staining, DNA fragmentation, and PARP activity), and tissue damage (cardiac troponin I (cTnI) and cardiac myosin light chain-1 (cMLC1)) and improved cardiac function (ejection fraction (EF) and end diastolic left ventricular inner dimension (LVID)). Apigenin also alleviated endotoxin-induced myocardial injury by modulating oxidative stress (nitrotyrosine and protein carbonyl) and inflammatory cytokines (TNF- α , IL-1 β , MIP-1 α , and MIP-2) along with their master regulator NF κ B. Apigenin modulated redox homeostasis, and its anti-inflammatory role might be associated with its ability to control autophagy. Autophagy (determined by LAMP1, ATG5, and p62), its transcriptional regulator transcription factor EB (TFEB), and downstream target genes including vacuolar protein sorting-associated protein 11 (Vps11) and microtubule-associated proteins 1A/1B light chain 3B (Map1lc3) were modulated by apigenin. Thus, our study demonstrated that apigenin may lead to potential development of new target in sepsis treatment or other myocardial oxidative and/or inflammation-induced injuries.

SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE

EPA Science Inventory

SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE. D. M. Brass, J. D. Savov, *S. H. Gavett, ?C. George, D. A. Schwartz. Duke Univ Medical Center Durham, NC, *U.S. E.P.A. Research Triangle Park, NC, ?Univ of Iowa,...

The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis.

PubMed

Chung, Ki Wung; Kim, Kyung Mok; Choi, Yeon Ja; An, Hye Jin; Lee, Bonggi; Kim, Dae Hyun; Lee, Eun Kyeong; Im, Eunok; Lee, Jaewon; Im, Dong Soon; Yu, Byung Pal; Chung, Hae Young

2017-07-03

Macroautophagy/autophagy is a central mechanism by which cells maintain integrity and homeostasis, and endotoxin-induced autophagy plays important roles in innate immunity. Although TLR4 stimulation mediated by lipopolysaccharide (LPS) also upregulates autophagy in hepatocytes and liver, its physiological role remains elusive. The objective of this study was to determine the role of LPS-induced autophagy in the regulation of liver lipid metabolism. LPS treatment (5 mg/kg) increased autophagy, as detected by LC3 conversion and transmission electron microscopy (TEM) analysis in C57BL6 mouse livers. AC2F hepatocytes also showed increased autophagic flux after LPS treatment (1 μg/ml). To investigate the role of LPS-induced autophagy further, liver lipid metabolism changes in LPS-treated mice and fasted controls were compared. Interestingly, LPS-treated mice showed less lipid accumulation in liver than fasted mice despite increased fatty acid uptake and lipid synthesis-associated genes. In vitro analysis using AC2F hepatocytes demonstrated LPS-induced autophagy influenced the degradation of lipid droplets. Inhibition of LPS-induced autophagy using bafilomycin A 1 or Atg7 knockdown significantly increased lipid accumulation in AC2F hepatocytes. In addition, pretreatment with chloroquine aggravated LPS-induced lipid accumulation and inflammation in C57BL6 mouse livers. The physiological importance of autophagy was verified in LPS-treated young and aged rats. Autophagic response was diminished in LPS-treated aged rats and lipid metabolism was impaired during sepsis, indicating autophagy response is important for regulating lipid metabolism after endotoxin challenge. Our findings demonstrate endotoxin-induced autophagy is important for the regulation of lipid metabolism, and suggest that autophagy helps maintain lipid metabolism homeostasis during sepsis.

Airborne endotoxin in fine particulate matter in Beijing

NASA Astrophysics Data System (ADS)

Guan, Tianjia; Yao, Maosheng; Wang, Junxia; Fang, Yanhua; Hu, Songhe; Wang, Yan; Dutta, Anindita; Yang, Junnan; Wu, Yusheng; Hu, Min; Zhu, Tong

2014-11-01

Endotoxin is an important biological component of particulate matter (PM) which, upon inhalation, can induce adverse health effects, and also possibly complicate the diseases in combination with other pollutants. From 1 March 2012 to 27 February 2013 we collected air samples using quartz filters daily for the quantification of airborne endotoxin and also fine PM (PM2.5) in Beijing, China. The geometric means for endotoxin concentration and the fraction of endotoxin in PM were 0.65 EU/m3 (range: 0.10-75.02) and 10.25 EU/mg PM2.5 (range: 0.38-1627.29), respectively. The endotoxin concentrations were shown to vary greatly with seasons, typically with high values in the spring and winter seasons. Temperature and relative humidity, as well as concentrations of sulfur dioxide and nitrogen oxides were found to be significantly correlated with airborne endotoxin concentrations (p < 0.05). Additionally, positive correlations were also detected between endotoxin concentrations and natural sources of Na+, K+, Mg2+, and F-, while negative correlations were observed between endotoxin concentrations and anthropogenic sources of P, Co, Zn, As, and Tl. Oxidative potential analysis revealed that endotoxin concentrations were positively correlated with reactive oxygen species (ROS), but not dithiothreitol (DTT) of PM. This study provided the first continuous time series of airborne endotoxin concentrations in Beijing, and identifies its potential associations with atmospheric factors. The information developed here can assist in the assessment of health effects of air pollution in Beijing.

Current trends in endotoxin detection and analysis of endotoxin-protein interactions.

PubMed

Dullah, Elvina Clarie; Ongkudon, Clarence M

2017-03-01

Endotoxin is a type of pyrogen that can be found in Gram-negative bacteria. Endotoxin can form a stable interaction with other biomolecules thus making its removal difficult especially during the production of biopharmaceutical drugs. The prevention of endotoxins from contaminating biopharmaceutical products is paramount as endotoxin contamination, even in small quantities, can result in fever, inflammation, sepsis, tissue damage and even lead to death. Highly sensitive and accurate detection of endotoxins are keys in the development of biopharmaceutical products derived from Gram-negative bacteria. It will facilitate the study of the intermolecular interaction of an endotoxin with other biomolecules, hence the selection of appropriate endotoxin removal strategies. Currently, most researchers rely on the conventional LAL-based endotoxin detection method. However, new methods have been and are being developed to overcome the problems associated with the LAL-based method. This review paper highlights the current research trends in endotoxin detection from conventional methods to newly developed biosensors. Additionally, it also provides an overview of the use of electron microscopy, dynamic light scattering (DLS), fluorescence resonance energy transfer (FRET) and docking programs in the endotoxin-protein analysis.

Endotoxin-induced mortality in rats is reduced by nitrones

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamburger, S.A.; McCay, P.B.

The goal of these investigations was to determine if nitrone spin-trapping agents can alter mortality associated with endotoxemia in the rat. Reactive free radicals attack nitrone spin-trapping agents forming relatively reactive, persistent free radical spin adducts. We administered 85 mM (10 ml/kg) of alpha-phenyl N-tert-butyl nitrone (PBN), alpha-4-pyridyl-N-oxide N-tert-butyl nitrone (4-POBN), 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), or vehicle (saline i.p.) 30 min before endotoxin (25 mg/kg i.p.) or vehicle to Sprague-Dawley (SD) or Holtzman virus-free (HVF) rats (n = 10-17/group). All vehicle-treated rats receiving endotoxin were dead by 1 day. At 7 days, 83% of PBN-treated SD, 42% of PBN- or POBN-treated HVF,more » and 25% of DMPO-treated HVF rats were alive. The difference in survival of PBN-treated animals between strains may reflect the higher susceptibility of HVF rats to endotoxin. The observed reduction in mortality may be related to the well-established capacity of spin-trapping agents to capture reactive free radicals that may be generated in target tissues in response to endotoxin, and that would otherwise react with cell components and produce tissue injury.« less

Effect of endotoxin and radio-detoxified endotoxin on the serum T4 level of rats and response of their thyroid gland to exogenous TSH

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bertok, L.; Nagy, S.U.

Experiments were performed to demonstrate that, while the shock-inducing dose of parent (toxic) endotoxin significantly decreases the serum T4 level of rats and inhibits the T4 response given to exogenous thyroid stimulating hormone (TSH), the radio-detoxified (/sup 60/Co-gamma, 150 kGy) endotoxin preparation does not inhibit the response to exogenous TSH. It also decreases serum T4 level to a lesser extent than untreated endotoxin.

Immunization of cows with novel core glycolipid vaccine induces anti-endotoxin antibodies in bovine colostrum.

PubMed

Cross, Alan S; Karreman, Hubert J; Zhang, Lei; Rosenberg, Zeil; Opal, Steven M; Lees, Andrew

2014-10-21

Translocation of gut-derived Gram-negative bacterial (GNB) lipopolysaccharide (LPS, or endotoxin) is a source of systemic inflammation that exacerbates HIV, cardiovascular and gastrointestinal diseases and malnutrition. The oral administration of bovine colostrum (BC) reduces endotoxemia in patients with impaired gut barrier function. Consequently, BC enriched in antibodies to LPS may ameliorate endotoxemia-related morbidities. We developed a detoxified J5 LPS/group B meningococcal outer membrane protein (J5dLPS/OMP) vaccine that induces antibodies against a highly conserved core region of LPS and protects against heterologous GNB infection. We now examine the ability of this vaccine to elicit anti-core endotoxin antibodies in BC. Two cohorts of pregnant cows were immunized with this vaccine in combination with FICA (Cohort 1) or Emulsigen-D (Cohort 2) adjuvants. Antibody responses to the J5 core LPS antigen were measured in both serum and colostrum and compared to antibody levels elicited by a commercially available veterinary vaccine (J5 Bacterin) comprised of heat-killed Escherichia coli O111, J5 mutant bacteria, from which the J5 LPS was purified. The J5dLPS/OMP vaccine induced high titers of serum IgG antibody to J5 LPS in all seven cows. Both IgG and to a lesser extent IgA anti-J5 LPS antibodies were generated in the colostrum. The J5dLPS/OMP vaccine was significantly more immunogenic in mice than was the J5 Bacterin. BC enriched in anti-J5 LPS antibody reduced circulating endotoxin levels in neutropenic rats, a model of "leaky gut". The J5dLPS/OMP vaccine elicits high titers of serum anti-endotoxin antibodies in cows that is passed to the colostrum. This BC enriched in anti-core LPS antibodies has the potential to reduce endotoxemia and ameliorate endotoxin-related systemic inflammation in patients with impaired gut barrier function. Since this vaccine is significantly more immunogenic than the J5 Bacterin vaccine, this J5dLPS/OMP vaccine might prove to be

[Therapy of intermediate uveitis].

PubMed

Doycheva, D; Deuter, C; Zierhut, M

2014-12-01

Intermediate uveitis is a form of intraocular inflammation in which the vitreous body is the major site of inflammation. Intermediate uveitis is primarily treated medicinally and systemic corticosteroids are the mainstay of therapy. When recurrence of uveitis or side effects occur during corticosteroid therapy an immunosuppressive treatment is required. Cyclosporine A is the only immunosuppressive agent that is approved for therapy of uveitis in Germany; however, other immunosuppressive drugs have also been shown to be effective and well-tolerated in patients with intermediate uveitis. In severe therapy-refractory cases when conventional immunosuppressive therapy has failed, biologics can be used. In patients with unilateral uveitis or when the systemic therapy is contraindicated because of side effects, an intravitreal steroid treatment can be carried out. In certain cases a vitrectomy may be used.

Presentation of suspected pediatric uveitis.

PubMed

Saeed, Muhammad Usman; Raza, Syed Hamid; Goyal, Sudeshna; Cleary, Gavin; Newman, William David; Chandna, Arvind

2014-01-01

Presentation of suspected pediatric uveitis: Pediatric uveitis is usually managed in specialized ophthalmic centers in the UK. Meaningful data acquisition in these clinics may be helpful in clinical governance, and healthcare planning in a specialty that is gradually changing due to changes in treatment choices. Retrospective analysis of prospectively acquired data in the Liverpool pediatric uveitis database was performed. Analysis of our data, based on 147 patients, with a mean age of 10 years, indicated a female to male ratio of 2:1. 99% of patients were Caucasian. Our data indicates 86% of all patients attending the uveitis clinic were diagnosed with juvenile idiopathic arthritis, followed by intermediate uveitis 5% and idiopathic uveitis 4%. 46% of patients required treatment. Systemic treatment included methotrexate (34%), prednisolone (14%), etanercept (6%), ciclosporin (6%), mycophenolate (3%), and infliximab (1%). Severe visual loss (defined by counting fingers or below vision) was seen in 10 eyes despite appropriately treated chronic uveitis. Our data shows uveitis-related ocular morbidity in a predominantly pediatric Caucasian population. Patients with severe and chronic uveitis may experience significant uveitis-related complications and subsequent visual loss despite aggressive treatment.

Antimicrobial-induced endotoxin and cytokine activity in an in vitro model of septicemia in foals.

PubMed

Bentley, Adrienne P; Barton, Michelle H; Lee, Margie D; Norton, Natalie A; Moore, James N

2002-05-01

To determine which antimicrobials that are used to treat neonatal foals with septicemia attributable to Escherichia coli will minimize endotoxin release from bacteria and subsequent activity of inflammatory mediators while maintaining bactericidal efficacy. Blood samples from 10 healthy foals. Escherichia coli isolates A and B were isolated from 2 septicemic foals, and minimal inhibitory concentrations (MIC) were determined for 9 antimicrobials. Five of these antimicrobials were tested in vitro at 2 and 20 times their respective MIC. Whole blood or mononuclear cells grown in tissue-culture media were incubated with 105 colony-forming units of E. coli and each antimicrobial or saline (0.9% NaCl) solution. After 6 hours, number of viable bacteria remaining was determined, and supernatant was tested for endotoxin and tumor necrosis activity. Testing in whole blood was compromised by bactericidal effects of the blood itself. In mononuclear cell suspensions, each antimicrobial significantly reduced the number of viable bacteria to low or undetectable amounts. Antimicrobials did not differ significantly in efficacy of bacterial killing. Amikacin used alone or in combination with ampicillin resulted in significantly less endotoxin activity than did ampicillin, imipenem, or ceftiofur alone. There was a correlation between TNF-alpha and endotoxin activity. Aminoglycosides appear less likely to induce endotoxemia and TNF-alpha synthesis during bactericidal treatment of E. coli septicemia, compared with beta-lactam antimicrobials. Use of ampicillin, imipenem, or ceftiofur in the treatment of septicemic neonatal foals should be accompanied by appropriate treatment for endotoxemia.

Uveitis induced by programmed cell death protein 1 inhibitor therapy with nivolumab in metastatic melanoma patient.

PubMed

Kanno, Hiroaki; Ishida, Kyoko; Yamada, Wataru; Nishida, Takashi; Takahashi, Nobumichi; Mochizuki, Kiyofumi; Mizuno, Yuki; Matsuyama, Kanako; Takahashi, Tomoko; Seishima, Mariko

2017-11-01

Nivolumab, a new immune checkpoint inhibitor, binds to programmed cell death-protein 1 receptors on T cell, blockades binding of its ligands, and augments the immunologic reaction against tumor cells. Augmented immune response, however, may lead to immune-related adverse events. Herein we describe a rare case of bilateral anterior uveitis induced by nivolumab treatment for metastatic melanoma. A 54-year-old woman presented with mild conjunctival redness and blurred vision two months after initiating nivolumab treatment. Ophthalmological examination revealed bilateral non-granulomatous anterior uveitis. The flare values in the anterior chamber were monitored as an objective inflammatory index during nivolumab therapy and clinical time course was reported in this paper. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Temperament influences endotoxin-induced changes in rectal temperature, sickness behavior, and plasma epinephrine concentrations in bulls

USDA-ARS?s Scientific Manuscript database

This study was designed to determine the influence of temperament on endotoxin (lipopolysaccharide; LPS) induced changes in body temperature and the secretion of cortisol and epinephrine. Purebred Brahman bulls were selected based on temperament score (average of exit velocity, EV, and pen score, PS...

Cyclooxygenase-2 expression in the eyes of cats with and without uveitis.

PubMed

Sim, Zhi Hui; Pinard, Chantale L; Plattner, Brandon L; Bienzle, Dorothee

2018-01-01

OBJECTIVE To characterize the distribution and intensity of cyclooxygenase (COX)-2 expression in the eyes of cats with and without uveitis and to determine whether COX-2 expression is correlated with severity of inflammation. SAMPLES Archived ocular tissue specimens from 51 cats with and 10 cats without ocular disease. PROCEDURES Specimens from only 1 eye were evaluated for each cat. Specimens were stained with H&E stain or immunohistochemical stain for detection of COX-2 and reviewed. For each eye, the type, severity, and distribution of inflammation and the distribution and intensity of COX-2 expression were determined for the uvea and other ocular tissues. Correlation between COX-2 expression and inflammation severity was also assessed. RESULTS COX-2 was not expressed in any nondiseased eye. Of the 51 diseased eyes, 20 had histologic evidence of lymphocytic-plasmacytic uveitis, 13 had neutrophilic uveitis, 11 had diffuse iris melanoma with uveitis, and 7 had diffuse iris melanoma without uveitis. Of the 44 eyes with uveitis, COX-2 was detected in the uvea of 16, including 11 eyes with lymphocytic-plasmacytic uveitis, 4 with neutrophilic uveitis, and 1 with diffuse iris melanoma-induced uveitis. Inflammation was severe, moderate, or mild in 10, 5, and 1 of those eyes, respectively. Cyclooxygenase-2 was detected in the cornea of 21 eyes with uveitis and 1 eye with diffuse iris melanoma without uveitis. Uveitis severity was positively correlated with COX-2 expression in both the uvea and cornea. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that COX-2 is an inflammatory mediator in feline uveitis but not diffuse iris melanoma.

Immunological and pathological investigations in equine experimental uveitis.

PubMed

Simeonova, Galina P; Krastev, Svetozar Z; Simeonov, Radostin S

2016-12-01

The pathogenic mechanism of equine recurrent uveitis (ERU) is still poorly defined and many variations between experimental animal models and spontaneous disease exist. The aim of our study was to investigate if Th17 cell-mediated response plays role in the pathogenesis of the used experimental model in horses and to reveal its pathological findings. Experimental uveitis was induced in 6 healthy horses. The concentrations of retinal autoantigen CRALBP and IL-17 were measured using ELISA in aqueous humor and vitreous body of the 12 inflamed eyes as well as in 12 control non-inflamed eyes taken from 6 horses in slaughter house. After centrifugation of the two eye media, smears were prepared and cytological investigation was performed. Tissue specimens were taken from all eye globes and were submitted to histopathological investigation. CRALBP and IL-17 concentrations were significantly elevated in eye media of horses with experimental uveitis in comparison with controls. Cytological and histopathological findings corresponded to the changes characteristic of chronic immune-mediated inflammation with mononuclear cell infiltration of uvea, choroid, retina, and eye media as well as severe retinal destruction. Our study demonstrated the involvement of the retinal autoantigen CRALBP as well as IL-17 in the pathogenesis of experimental uveitis in horses. These findings suggests that this experimental uveitis in horses may serve as a suitable animal model for investigation of IL-17- mediated immune response during spontaneous autoimmune uveitis in horses as well as in humans.

Uveitis in children.

PubMed

Angeles-Han, Sheila T; Rabinovich, Consuelo Egla

2016-09-01

The review provides updates on novel risk markers for the development of pediatric inflammatory uveitis and a severe disease course, on treatment of refractory disease, and on the measurement of visual outcomes. There are several new genetic markers, biomarkers, and clinical factors that may influence a child's uveitis disease course. It is important to identify children at risk for poor visual outcomes and who are refractory to traditional therapy. Racial disparities have recently been reported. We describe agents of potential benefit. In addition, we discuss the importance of patient reported outcomes in this population. Uveitis can lead to vision-threatening complications. Timely and aggressive treatment of children identified to be at risk for a severe uveitis course may lead to improved outcomes.

The effect of endotoxin on heart rate dynamics in diabetic rats.

PubMed

Meamar, Morvarid; Dehpour, Tara; Mazloom, Roham; Sharifi, Fatemeh; Raoufy, Mohammad R; Dehpour, Ahmad R; Mani, Ali R

2015-05-01

The effect of endotoxin on heart rate variability (HRV) was assessed in diabetic and controls rats using a telemetric system. Endotoxin induced a reduction in sample entropy of cardiac rhythm in control animals. However, this effect was significantly blunted in streptozotocin-induced diabetic rats. Since uncoupling of cardiac pacemaker from cholinergic control is linked to reduced HRV in endotoxemia, chronotropic responsiveness to cholinergic stimulation was assessed in isolated atria. Endotoxemia was associated with impaired responsiveness to carbacholine in control rats. However, endotoxemia did not impair cholinergic responsiveness in diabetic atria. These findings corroborates with development of endotoxin tolerance in diabetic rats. Copyright © 2014 Elsevier B.V. All rights reserved.

Endotoxin exposure, serum vitamin D, asthma and wheeze outcomes.

PubMed

Mendy, Angelico; Cohn, Richard D; Thorne, Peter S

2016-05-01

Endotoxin has been shown to induce neutrophilic asthma and wheeze after binding toll-like receptor 4 to produce pro-inflammatory cytokines. Animal models have demonstrated that vitamin D might inhibit lipopolysaccharide-induced cytokines. However, whether endotoxin exposure and serum vitamin D deficiency interact to affect asthma and wheeze in humans has never been investigated in an epidemiological study. Joint associations of house dust endotoxin and vitamin D with asthma and wheeze were examined using logistic regression adjusted for covariates in 5924 US participants of the National Health and Nutrition Examination Survey (NHANES). Interactions were assessed on the multiplicative as well as additive scale using the relative excess risk, the attributable portion due to additive interaction, and the synergy index. The median endotoxin concentration was 19.1 EU/mg. Prevalence of vitamin D inadequacy (20-30 ng/ml) and deficiency (<20 ng/ml) were respectively 42.9 and 33.4%. The combination of high endotoxin and low vitamin D was associated with current asthma (OR: 1.56, 95% CI: 1.09, 2.23), wheeze in the past 12 months (OR: 1.72, 95% CI: 1.10, 3.71), recurrent wheeze (OR: 1.97, 95% CI: 1.00, 4.00), asthma diagnosis or recurrent wheeze (OR: 1.88, 95% CI: 1.33, 2.66), and current asthma or recurrent wheeze (OR:1.81, 95% CI: 1.23, 2.68) when compared to low endotoxin and normal vitamin D. The interactions between the exposures were not significant on the multiplicative or additive scale for any of the outcomes. Combination of high endotoxin exposure and low vitamin D increases the odds of asthma and wheeze, but the exposures do not interact or modify each other's effect in the NHANES cohort. Copyright © 2016 Elsevier Ltd. All rights reserved.

Uveitis in Children

PubMed Central

Angeles-Han, Sheila T.; Rabinovich, C. Egla

2016-01-01

Purpose of review This review provides updates on novel risk markers for the development of pediatric inflammatory uveitis and a severe disease course, on treatment of refractory disease, and on the measurement of visual outcomes. Recent findings There are several new genetic markers, biomarkers and clinical factors that may influence a child’s uveitis disease course. It is important to identify children at risk for poor visual outcomes and who are refractory to traditional therapy. Racial disparities have recently been reported. We describe agents of potential benefit. In addition, we discuss the importance of patient reported outcomes in this population. Summary Uveitis can lead to vision threatening complications. Timely and aggressive treatment of children identified to be at risk for a severe uveitis course may lead to improved outcomes. PMID:27328333

Uveitis in patients with autoimmune hepatitis.

PubMed

Lim, Lyndell L; Scarborough, John D; Thorne, Jennifer E; Graham, Elizabeth; Kempen, John H; Mackensen, Friederike; Nguyen, Quan Dong; Prabriputaloong, Tisha; Read, Russell W; Suhler, Eric B; Schwartz, Jonathan M; Smith, Justine R

2009-02-01

To report seven cases of uveitis occurring in patients with autoimmune hepatitis (AIH), raising the possibility that uveitis may be an extrahepatic feature of AIH. Multicenter, retrospective, observational case series of patients with AIH and uveitis. One index case was identified at Oregon Health & Science University. Further cases were identified by a web-based survey of members of the American Uveitis Society, the International Uveitis Study Group, the Proctor Foundation mailing list server, and the First SUN International Workshop. Respondents were asked to provide clinical information about uveitis phenotype, AIH features, and treatment. Clinical information was obtained for seven individuals (four females and three males; age range, seven to 67 years) who suffered from AIH and uveitis. Average duration of follow-up was 5.5 years. All patients had chronic, persistent bilateral uveitis that was anterior (n = 3), intermediate (n = 1), or pan (n = 3) in location. Every patient had complications arising from his or her uveitis, including cataract (n = 5), glaucoma (n = 3), cystoid macular edema (n = 3), and posterior synechiae (n = 3). Final visual acuities ranged from 20/16 to hand movements. To treat the uveitis and/or AIH, the majority of patients required oral prednisone and all seven patients were treated with systemic immunosuppression. Despite the small size of this study, our findings suggest an association between AIH and uveitis. The uveitis is chronic, bilateral, and associated with sight-threatening complications, necessitating systemic immunosuppression in some individuals.

Biosensor of endotoxin and sepsis

NASA Astrophysics Data System (ADS)

Shao, Yang; Wang, Xiang; Wu, Xi; Gao, Wei; He, Qing-hua; Cai, Shaoxi

2001-09-01

To investigate the relation between biosensor of endotoxin and endotoxin of plasma in sepsis. Method: biosensor of endotoxin was designed with technology of quartz crystal microbalance bioaffinity sensor ligand of endotoxin were immobilized by protein A conjugate. When a sample soliton of plasma containing endotoxin 0.01, 0.03, 0.06, 0.1, 0.5, 1.0Eu, treated with perchloric acid and injected into slot of quartz crystal surface respectively, the ligand was released from the surface of quartz crystal to form a more stable complex with endotoxin in solution. The endotoxin concentration corresponded to the weight change on the crystal surface, and caused change of frequency that occurred when desorbed. The result was biosensor of endotoxin might detect endotoxin of plasma in sepsis, measurements range between 0.05Eu and 0.5Eu in the stop flow mode, measurement range between 0.1Eu and 1Eu in the flow mode. The sensor of endotoxin could detect the endotoxin of plasm rapidly, and use for detection sepsis in clinically.

Pinealitis accompanying equine recurrent uveitis.

PubMed Central

Kalsow, C M; Dwyer, A E; Smith, A W; Nifong, T P

1993-01-01

There is no direct verification of pineal gland involvement in human uveitis. Specimens of pineal tissue are not available during active uveitis in human patients. Naturally occurring uveitis in horses gives us an opportunity to examine tissues during active ocular inflammation. We examined the pineal gland of a horse that was killed because it had become blind during an episode of uveitis. The clinical history and histopathology of the eyes were consistent with post-leptospiral equine recurrent uveitis. The pineal gland of this horse had significant inflammatory infiltration consisting mainly of lymphocytes with some eosinophils. This observation of pinealitis accompanying equine uveitis supports the animal models of experimental autoimmune uveoretinitis with associated pinealitis and suggests that the pineal gland may be involved in some human uveitides. Images PMID:8435400

Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization

PubMed Central

Sherry, Christina L.; Kim, Stephanie S.; Dilger, Ryan N.; Bauer, Laura L.; Moon, Morgan L.; Tapping, Richard I.; Fahey, George C.; Tappenden, Kelly A.; Freund, Gregory G.

2010-01-01

Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1βand TNF-αin the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-γwhen compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1β, TNF-α, IFN-γ, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages. PMID:20138982

[Mycotic keratitis with uveitis cause by Scedosporium apiospermum].

PubMed

Firdová, M; Tkácová, E; Jesenská, Z; Minová, M

1997-08-01

Mycotic Keratitis with Induced Uveitis Caused by Scedosporium Apiospermum. In the work the case of mycotic keratitis with induced uveitis is descriped. Affected is young healthy woman working in a fruit and vegetable store. Affection arised on cornea in the area of previous erosion. Current antibiotics did not have any effect on the affection after repeated negative cultivative examinations. The culture of fibrous mikromycete was gained out of cultivation done on Sabouraud's glucose agar and was identified as Scedosporium apiospermum. This is the first case of mycotic eye infection of this etiology in our conditions. The patient reacted successfully on miconazol treatment. The finding on cornea equals vascularized leucoma, visual acuity is 5/50. In the future perforative keratoplastic is planned.

Diagnostic yield of heat shock protein 70 (HSP-70) and anti-HSP-70 in Behcet-induced uveitis.

PubMed

Sahebari, M; Hashemzadeh, K; Mahmoudi, M; Saremi, Z; Mirfeizi, Z

2013-06-01

Heat shock proteins (HSPs) are intracellular proteins with pro- and anti-inflammatory actions, playing an important role in the pathogenesis of Behcet's disease (BD). Diagnosis of BD uveitis in early stages is still problematic, thus this study was undertaken to determine diagnostic values of serum HSP- and anti-HSP-70 in BD uveitis. Serum levels of HSP- and anti-HSP-70 were measured in 53 patients with BD (26 with and 27 without uveitis). In control group, 25 age- and sex-matched idiopathic uveitis patients were enrolled consecutively. Both groups had no medical problems save uveitis at the time of sampling. Confounders like medications were analysed subsequently. HSP- and anti-HSP-70 values were measured by commercial ELISA kits. Data were analysed by spss 11.5 and medcalc 11.5.1 software. The Mean HSP-70 serum levels were different among aforementioned subgroups (P = 0.001, anova). They were elevated in BD uveitis compared with BD without uveitis (4.84 ± 4.21 versus 2.24 ± 2.08 ng/ml; P = 0.045). HSP-70 in sera of BD uveitis was also higher than that parameter in patients with idiopathic uveitis (4.84 ± 4.21 versus 2.37 ± 3.30 ng/ml; P = 0.001; cut-off point value 1.0 9 ng/ml, 95% CI 0.61-0.86, P = 0.0002, ß = 0.06). However, there was not any statistical difference among those groups in the serum anti-HSP-70 levels (P = 0.63, anova). Multiple regression analysis demonstrated that among different confounders, only prednisolone increases and BD uveitis decreases HSP-70 levels independently. This prospective cross-sectional study suggested that HSP-70 serum level is impressed over the course of BD uveitis, and it could be utilized to diagnose or predict developing it. © 2013 The Authors. Scandinavian Journal of Immunology © 2013 Blackwell Publishing Ltd.

Impact of ghrelin on vitreous cytokine levels in an experimental uveitis model

PubMed Central

Turgut, Burak; Gül, Fatih Cem; Dağli, Ferda; Ilhan, Nevin; Özgen, Metin

2013-01-01

Background The purpose of this study was to investigate the effect of intraperitoneal ghrelin on vitreous levels of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α) and to compare its effects with those of intraperitoneal infliximab in an experimental uveitis model. Methods Twenty-four male rats were assigned to four groups of six rats in each. All the rats, except for those in group 1 (controls), were injected intravitreally with concanavalin A to induce experimental uveitis. Rats in group 2 (sham) were not given any treatment after uveitis was induced. Rats in group 3 were given intraperitoneal infliximab 0.5 mg/100 mL on days 0, 1, 3, 5, and 7 following induction of uveitis on day 14 of the study. Rats in group 4 were given intraperitoneal ghrelin 10 ng/kg/day for 7 days following induction of uveitis. On day 21 of the study, enucleated globes were subjected to histopathologic examination. Vitreous levels of IL-1, IL-6, and TNF-α were measured by enzyme-linked immunosorbent assay. Results Vitreous levels of IL-1, IL-6, and TNF-α were significantly increased in the sham group relative to the control group (P < 0.05), but showed a significant decrease in the group treated with infliximab (P < 0.05). Cytokine levels also decreased in the ghrelin-treated group, but the decrease was not statistically significant (P > 0.05). Conclusion Ghrelin failed to decrease the IL-1, IL-6, and TNF-α levels that play a critical role in the pathogenesis of uveitis. PMID:23341733

Endotoxins: The Critical Risk Factor in Reclaimed Water via Inhalation Exposure.

PubMed

Xue, Jinling; Zhang, Jinshan; Xu, Bi; Xie, Jiani; Wu, Wenzhao; Lu, Yun

2016-11-01

The use of reclaimed water for nonpotable uses requires consideration of potential adverse health effects. Considering that inhalation can be a significant route of transmission of microorganisms and inflammatory agents, this study used a mouse model to test the possible adverse effects of reclaimed water use during car washing where aerosols are generated. Intensive innate immune responses were found in the lungs after acute exposure, and the lavage polymorphonuclear cell proportion was the most sensitive end point. Four types of evidence are presented to demonstrate that the main risk factor that initiates innate inflammation is the free endotoxin. (1) Small molecules (<10 kDa) cannot induce inflammation. (2) The endotoxin levels of 11 water samples from five different plants showed positive correlations with inflammatory responses. (3) Actual water samples showed similar activities with free endotoxins other than bacterially bound endotoxins. (4) Specific removal of endotoxins with polymyxin B affinity chromatography further confirmed the role of free endotoxins. It is noteworthy that 62.9% of the investigated tertiary-treated water had endotoxin levels higher than the allowable acute threshold (120 endotoxin units/mL) under the hypothesized car wash condition, which strongly suggests the need to carefully consider the water treatment steps required to produce safe water for various reclaimed water end uses.

Characterization of rat model of acute anterior uveitis using optical coherence tomography angiography

NASA Astrophysics Data System (ADS)

Choi, Woo June; Pepple, Kathryn L.; Zhi, Zhongwei; Wang, Ruikang K.

2015-03-01

Uveitis, or ocular inflammation, is a cause of severe visual impairment. Rodent models of uveitis are powerful tools used to investigate the pathological mechanisms of ocular inflammation and to study the efficacy of new therapies prior to human testing. In this paper, we report the utility of spectral-domain optical coherence tomography (SD-OCT) angiography in characterizing the inflammatory changes induced in the anterior segment of a rat model of uveitis. Acute anterior uveitis (AAU) was induced in two rats by intravitreal injection of a killed mycobacterial extract. One of them received a concurrent periocular injection of steroids to model a treatment effect. OCT imaging was performed prior to inflammation induction on day 0 (baseline), and 2 days post-injection (peak inflammation). Baseline and inflamed images were compared. OCT angiography identified swelling of the cornea, inflammatory cells in the anterior and posterior chambers, a fibrinous papillary membrane, and dilation of iris vessels in the inflamed eyes when compared to baseline images. Steroid treatment was shown to prevent the changes associated with inflammation. This is a novel application of anterior OCT imaging in animal models of uveitis, and provides a high resolution, in vivo assay for detecting and quantifying ocular inflammation and the response to new therapies.

Rabbit hunter uveitis: case report of tularemia uveitis.

PubMed

Terrada, Céline; Azza, Said; Bodaghi, Bahram; Le Hoang, Phuc; Drancourt, Michel

2016-09-01

Literature reports on ophthalmological manifestations related to tularemia, a zoonose caused by the bacterium Francisella tularensis, largely refer to Parinaud's oculoglandular syndrome, which consists of the association of conjunctivitis with preauricular lymphadenitis. In this paper, we report a case of intraocular inflammation during tularemia infection. A 52-year-old Caucasian man was diagnosed with unilateral uveitis. The uveitis was posterior, with a 2+ vitritis and a large yellowish lesion involving the macula with an overlying sub-retinal detachment, extending inferiorly, and subretinal hemorrhages. Fluorescein angiography showed a late hyperfluorescence with focal vascular leakage. Ultrasound biomicroscopy confirmed the presence of a 3.8 mm parietal granuloma with a few calcifications in the left eye. While extensive work-up eliminated any other infectious and non-infectious etiology, tularemia was diagnosed by advanced serology consisting of two-dimensional Western-immunoblotting. The patient, a hunter, recalled having killed rabbits in the days before the symptoms appeared. Uveitis was rapidly controlled following treatment with doxycycline, yet three years after initiation of the treatment, the patient still complained of loss of vision in the left eye with a central scotoma. Posterior uveitis may be an infrequent manifestation of tularemia infection, and therefore this infection should be considered in the differential diagnosis of intraocular inflammation in areas where F. tularensis is endemic.

Duration of in vivo endotoxin tolerance in horses.

PubMed

Holcombe, Susan J; Jacobs, Carrie C; Cook, Vanessa L; Gandy, Jeffery C; Hauptman, Joseph G; Sordillo, Lorraine M

2016-05-01

Endotoxemia models are used to study mechanisms and treatments of early sepsis. Repeated endotoxin exposures induce periods of endotoxin tolerance, characterized by diminished proinflammatory responses to lipopolysaccharide (LPS) and modulated production of proinflammatory cytokines. Repeated measure designs using equine endotoxemia models are rarely performed, despite the advantages associated with reduced variability, because the altered responsiveness would confound study results and because the duration of equine endotoxin tolerance is unknown. We determined the interval of endotoxin tolerance, in vivo, in horses based on physical, clinicopathologic, and proinflammatory gene expression responses to repeated endotoxin exposures. Six horses received 30 ng/kg LPS in saline infused over 30 min. Behavior pain scores, physical examination parameters, and blood for complete blood count and proinflammatory gene expression were obtained at predetermined intervals for 24h. Horses received a total of 3 endotoxin exposures. The first exposure was LPS 1, followed 7 days later by LPS 7 or 14-21 days later by LPS 14-21. Lipopolysaccharide exposures were allocated in a randomized, crossover design. Lipopolysaccharide produced clinical and clinicopathologic signs of endotoxemia and increased expression of tumor necrosis factor alpha (TNFα), interleukin (IL)-6 and IL-8, P<0.001. Horses exhibited evidence of endotoxin tolerance following LPS 7 but not following LPS 14-21. Horses had significantly lower pain scores, heart rates, respiratory rates and duration of fever, after LPS 7 compared to LPS 1 and LPS 14-21, P<0.001, and expression of TNFα was lower in the whole blood of horses after LPS 7, P=0.05. Clinical parameters and TNFα gene expression were similar or slightly increased in horses following LPS 14-21 compared to measurements made in horses following LPS 1, suggesting that endotoxin tolerance had subsided. A minimum of 3 weeks between experiments is warranted if

No increase in endotoxin release during antibiotic killing of meningococci.

PubMed

Prins, J M; Speelman, P; Kuijper, E J; Dankert, J; van Deventer, S J

1997-01-01

Endotoxin is liberated following antibiotic killing of Gram-negative rods, and antibiotics may differ in this respect. Although the amount of filterable endotoxin has also been reported to increase following antibiotic killing of meningococci, it is unknown how this influences the host response. We investigated the influence of three antibiotics on levels of free endotoxin in culture medium and cytokine production in whole blood ex vivo during killing of four strains of meningococci. Bacterial killing was significantly more efficient with penicillin or ceftriaxone than with chloramphenicol, and free endotoxin levels were lower after exposure to antibiotics as compared with no treatment (ANOVA, P < 0.001). Endotoxin levels were lowest after exposure to chloramphenicol. In three of the four strains exposure to antibiotics resulted in considerably lower cytokine levels (ANOVA, P < 0.001), and TNF-alpha levels were significantly lower after exposure to penicillin or ceftriaxone than after chloramphenicol treatment. Only in the strain that induced the lowest levels of TNF-alpha were cytokine levels comparable for untreated and treated samples. We conclude that fear of excessive endotoxin release or cytokine production caused by effective antibiotics is not justified in the treatment of meningococcal infections.

Immunopathology of pineal glands from horses with uveitis.

PubMed

Kalsow, C M; Dubielzig, R R; Dwyer, A E

1999-06-01

Pinealitis accompanying uveitis is well established in laboratory models of experimental autoimmune uveoretinitis. In naturally occurring uveitis, pinealitis has been demonstrated in the pineal gland from a mare with active uveitis and is suspected in some human uveitides. We have evaluated pineal glands from horses with various stages of uveitis for signs of immunopathology accompanying spontaneous uveitis. Pineal glands from 10 horses with uveitis and from 13 horses without uveitis were evaluated for histochemical (H&E, collagen) and immunohistochemical (MHC class II antigen expression, infiltration of T and B lymphocytes, and glial fibrillary acidic protein (GFAP) and vimentin upregulation) evidence of inflammation. Septal areas of pineal glands from horses with uveitis had clusters of MHC class II antigen-expressing cells, T lymphocytes, and enhanced collagen deposition. These changes were not as readily observed in pineal glands from horses without uveitis. B lymphocytes were detected only in the pineal gland from the one mare with active uveitis in which T and B lymphocytes were organized into follicles. No differences in GFAP or vimentin immunoreactivity were noted in pineal glands from horses with or without uveitis. These pineal gland changes suggest that the pinealitis associated with equine uveitis is transient just as the uveitis of these horses is recurrent. Study of pineal glands from horses with clinically documented uveitis allows demonstration of subtle pineal changes associated with natural uveitis. Similar changes would be difficult to document in human patient populations.

Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Jiao; Shetty, Sreerama; Zhang, Ping

The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1 h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reductionmore » in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.« less

Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakamura, Yukiko K.; Metea, Christina; Karstens, Lisa

cell subset that is typically required to downregulate an immune response to prevent uncontrolled disease. Experimental autoimmune uveitis (EAU) is a very robust, widely use model of T lymphoocyte mediated uveitis that can be induced in a certain strains of mice (e.g. B10.RIII) by immunizing these animals with a specific retinal antigen, interphotoreceptor binding protein (IRBP), but requires co-administration of an adjuvant containing killed Mycobacterium antigen. Lastly, this model of inducible uveitis is analogous to the EAE model of demyelinating disease mentioned above. EAU is a thought to be predominantly Th1 and Th17 mediated.« less

Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis

DOE PAGES

Nakamura, Yukiko K.; Metea, Christina; Karstens, Lisa; ...

2016-07-01

cell subset that is typically required to downregulate an immune response to prevent uncontrolled disease. Experimental autoimmune uveitis (EAU) is a very robust, widely use model of T lymphoocyte mediated uveitis that can be induced in a certain strains of mice (e.g. B10.RIII) by immunizing these animals with a specific retinal antigen, interphotoreceptor binding protein (IRBP), but requires co-administration of an adjuvant containing killed Mycobacterium antigen. Lastly, this model of inducible uveitis is analogous to the EAE model of demyelinating disease mentioned above. EAU is a thought to be predominantly Th1 and Th17 mediated.« less

Serum and vitreous humor antibody titers in and isolation of Leptospira interrogans from horses with recurrent uveitis.

PubMed

Wollanke, B; Rohrbach, B W; Gerhards, H

2001-09-15

To measure antibody titers against Leptospira interrogans in serum and vitreous humor and determine the prevalence of L interrogans in vitreous humor of horses with recurrent uveitis. Cross-sectional study. 242 horses (270 eyes) with recurrent uveitis undergoing vitrectomy and 39 control horses (54 eyes) without any history or clinical signs of recurrent uveitis undergoing euthanasia or enucleation for unrelated reasons. Serum and vitreous humor were tested for antibodies against 13 serovars of L interrogans. Vitreous humor was submitted for leptospiral culture; isolates were typed to the serogroup level. Leptospira interrogans was isolated from vitreous humor from 120/229 (52%) horses (126/252 [50%] eyes) with recurrent uveitis but was not isolated from vitreous humor from 36 eyes of 21 control horses. Duration of recurrent uveitis was > or = 1 year for 45 of the 120 (38%) horses from which the organism was isolated. Geometric mean antibody titers against L interrogans in the vitreous humor and serum of horses with recurrent uveitis were 1:1,332 and 1:186, respectively. Only 91 of 120 (76%) horses from which the organism was isolated had a 4-fold or greater difference between serum and vitreous humor antibody titers. Results suggest that persistent ocular infection with L interrogans is common in horses with recurrent uveitis. A 4-fold increase in vitreous humor versus serum antibody titers may not be a sensitive test for the diagnosis of L interrogans-induced recurrent uveitis. We hypothesize that the immune component of recurrent uveitis can be directly induced and maintained by persistent infection of the eye with L interrogans.

Cytokines, chemokines and soluble adhesion molecules in aqueous humor of children with uveitis.

PubMed

Sijssens, Karen M; Rijkers, Ger T; Rothova, Aniki; Stilma, Jan S; Schellekens, Peter A W J F; de Boer, Joke H

2007-10-01

Uveitis in childhood is a visual threatening disease with a complication rate of more than 75%. Despite extensive research, the etiology of uveitis is still unclear although the general opinion is now that uveitis is a T-cell mediated disease. The purpose of this study was to investigate the profile of cytokines, chemotactic cytokines (chemokines) and soluble adhesion molecules in the aqueous humor (AqH) of children with uveitis in order to identify the factors that control the immune response in the eye. In this clinical laboratory investigation we analyzed, with a multiplex immunoassay, 16 immune mediators in the AqH of 25 children with uveitis and 6 children without uveitis. Increased levels of interleukin-2 (IL-2), IL-6, IL-10, IL-13, IL-18, interferon-gamma, tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1, RANTES, IL-8 and interferon-inducible 10-kDa protein were found in the AqH of children with uveitis compared with controls. No significant differences were found for IL-1 beta, IL-4, IL-12 p-70, soluble vascular cell adhesion molecule 1 and Eotaxin. Lower levels of IL-10 and IL-8 were found in quiet stage uveitis (surgical) samples compared with active uveitis (diagnostic) samples and in samples of patients treated with methotrexate (MTX) compared with samples of patients not treated with MTX. Lower levels of IL-10 were as well found in samples taken during the first 3 months after the diagnosis of uveitis than samples taken later during the disease process. No significant differences were found between patients treated with or without topical or systemic (perioperative and long term) corticosteroids. In conclusion, in children with uveitis, multiple intraocular cytokines, chemokines and soluble adhesion molecules are increased in the AqH regardless of active or inactive inflammation. Whether the IL-8 and IL-10 levels in AqH of children with uveitis are correlated with uveitis activity, early or late phase of the course of the disease

Management of pediatric uveitis

PubMed Central

Wentworth, Bailey A.; Freitas-Neto, Clovis A.

2014-01-01

Pediatric uveitis is a topic of special interest not only because of the unique diagnostic and therapeutic challenges but also because of the lifetime burden of vision loss if the problem is not adequately treated, as well as the economic and psychological toll on the family. Often, uveitis in children is discovered as part of a routine eye exam; this silent, insidious inflammation can be difficult to treat and can lead to further complications if not handled skillfully. Corticosteroids have long been the mainstay of therapy; however, the significant associated side effects mandate a corticosteroid-sparing therapeutic regimen in pursuit of remission. In this review, we cover the therapeutic options for pediatric uveitis, specifically focusing on the most common non-infectious varieties, juvenile idiopathic arthritis-associated uveitis and pars planitis. PMID:24991418

Juvenile idiopathic arthritis-associated uveitis.

PubMed

Clarke, Sarah L N; Sen, Ethan S; Ramanan, Athimalaipet V

2016-04-27

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management.

Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative.

PubMed

Dick, Andrew D; Rosenbaum, James T; Al-Dhibi, Hassan A; Belfort, Rubens; Brézin, Antoine P; Chee, Soon Phaik; Davis, Janet L; Ramanan, Athimalaipet V; Sonoda, Koh-Hei; Carreño, Ester; Nascimento, Heloisa; Salah, Sawsen; Salek, Sherveen; Siak, Jay; Steeples, Laura

2018-05-01

An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic review of the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE, CINAHL, SCOPUS, BIOSIS, and Web of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review. A total of 44 globally representative group members met in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations

Endotoxin, coliform, and dust levels in various types of rodent bedding.

PubMed

Whiteside, Tanya E; Thigpen, Julius E; Kissling, Grace E; Grant, Mary G; Forsythe, Diane

2010-03-01

Endotoxins in grain dust, household dust, and animal bedding may induce respiratory symptoms in rodents and humans. We assayed the endotoxin, coliform, and dust levels in 20 types of rodent bedding. Endotoxin concentrations were measured by using a commercial test kit, coliform counts were determined by using conventional microbiologic procedures, and dust content was evaluated by using a rotating-tapping shaker. Paper bedding types contained significantly less endotoxin than did other bedding types; the highest levels of endotoxin were detected in hardwood and corncob beddings. The range of endotoxin content for each bedding type was: corncob bedding, 1913 to 4504 endotoxin units per gram (EU/g); hardwood bedding, 3121 to 5401 EU/g; corncob-paper mixed bedding, 1586 to 2416 EU/g; and paper bedding, less than 5 to 105 EU/g. Coliform counts varied from less than 10 to 7591 cfu/g in corncob beddings, 90 to 4010 cfu/g in corncob-paper mixed beddings, less than 10 to 137 cfu/g in hardwood beddings, and less than 10 cfu/g in paper beddings. Average dust content was less than 0.15% in all commercial bedding types. We conclude that paper bedding is the optimal bedding type for conducting LPS inhalation studies and that rodent bedding containing high levels of endotoxin may alter the results of respiratory and immunologic studies in rodents.

Endotoxin, Coliform, and Dust Levels in Various Types of Rodent Bedding

PubMed Central

Whiteside, Tanya E; Thigpen, Julius E; Kissling, Grace E; Grant, Mary G; Forsythe, Diane B

2010-01-01

Endotoxins in grain dust, household dust, and animal bedding may induce respiratory symptoms in rodents and humans. We assayed the endotoxin, coliform, and dust levels in 20 types of rodent bedding. Endotoxin concentrations were measured by using a commercial test kit, coliform counts were determined by using conventional microbiologic procedures, and dust content was evaluated by using a rotating–tapping shaker. Paper bedding types contained significantly less endotoxin than did other bedding types; the highest levels of endotoxin were detected in hardwood and corncob beddings. The range of endotoxin content for each bedding type was: corncob bedding, 1913 to 4504 endotoxin units per gram (EU/g); hardwood bedding, 3121 to 5401 EU/g; corncob–paper mixed bedding, 1586 to 2416 EU/g; and paper bedding, less than 5 to 105 EU/g. Coliform counts varied from less than 10 to 7591 cfu/g in corncob beddings, 90 to 4010 cfu/g in corncob–paper mixed beddings, less than 10 to 137 cfu/g in hardwood beddings, and less than 10 cfu/g in paper beddings. Average dust content was less than 0.15% in all commercial bedding types. We conclude that paper bedding is the optimal bedding type for conducting LPS inhalation studies and that rodent bedding containing high levels of endotoxin may alter the results of respiratory and immunologic studies in rodents. PMID:20353693

Fucoidan extracted from Fucus evanescens prevents endotoxin-induced damage in a mouse model of endotoxemia.

PubMed

Kuznetsova, Tatyana A; Besednova, Natalya N; Somova, Larisa M; Plekhova, Natalya G

2014-01-31

An important problem of treating patients with endotoxemia is to find drugs to reduce the negative effects of endotoxin on the organism. We tested fucoidan (sulfated polysaccharide) from the brown alga Fucus evanescens as a potential drug in a mouse model of endotoxemia inducted by lipopolysaccharide (LPS). The survival time of mice injected with LPS increased under fucoidan treatment compared with the group of mice injected with LPS only. The preventive administration of fucoidan to mice with endotoxemia resulted in inhibition of increased levels of proinflammatory cytokines (TNFα and IL-6), as well as decreasing of the processes of hypercoagulability. The parenteral or per os administration of fucoidan resulted in decreasing the degree of microcirculatory disorders and secondary dystrophic-destructive changes in parenchymal organs of mice with endotoxemia. Taken together, these results demonstrate that fucoidan prevents endotoxin-induced damage in a mouse model of endotoxemia and increases the mice's resistance to LPS.

Pediatric uveitis: new and future treatments

PubMed Central

Mehta, Preema J.; Alexander, Janet L.; Sen, H. Nida

2017-01-01

Purpose of review Pediatric uveitis is relatively uncommon, accounting for only 5–10% of all patients with uveitis. However, owing to high prevalence of complications and devastating outcomes, its lifetime burden can be significant. Recent findings Immunomodulatory therapy has been associated with better outcomes in noninfectious pediatric uveitis. However, effective treatments are limited by medication-related complications, including multiorgan toxicities and systemic side effects. Summary We review the current therapies available to treat pediatric uveitis, discuss novel and future therapies, and provide clinical recommendations utilizing these new agents. The consideration for treatment regimens in noninfectious pediatric uveitis is multifactorial. Understanding past, present, and future technology will aid in treatment of a complex and refractory disease. PMID:23872814

The Dexamethasone Intravitreal Implant for Noninfectious Uveitis: Practice Patterns Among Uveitis Specialists.

PubMed

Burkholder, Bryn M; Moradi, Ahmadreza; Thorne, Jennifer E; Dunn, James P

2015-01-01

To describe the practice patterns and perceptions of uveitis specialists regarding the use of the intravitreal dexamethasone (DEX) implant for the treatment of noninfectious uveitis. We invited uveitis specialists to participate in an anonymous online survey. Among the 45 respondents, 76.5% identified uveitic macular edema as the most common clinical finding for which they use the DEX implant. The most common contraindications to DEX implantation were aphakia and glaucoma requiring >2 medications. Nearly two-thirds (64.3%) felt that the advent of the DEX implant did not change the frequency with which they used the fluocinolone acetonide (FA) implant, and about one-third (32.3%) preferred to use at least one DEX implant, before committing a patient to an FA implant. Uveitis physicians use the DEX implant for a wide range of clinical findings and uveitic diagnoses. There was no clear consensus on preferences regarding the use of DEX versus FA implants.

Endotoxin detection--from limulus amebocyte lysate to recombinant factor C.

PubMed

Ding, Jeak Ling; Ho, Bow

2010-01-01

Gram negative bacterial endotoxin is a biological pyrogen that causes fever when introduced intravenously. The endotoxin, also known as lipopolysaccharide (LPS), is found in the outer membrane of Gram-negative bacteria. During Gram-negative sepsis, endotoxin stimulates host macrophages to release inflammatory cytokines. However, excessive inflammation causes multiple organ failure and death. Endotoxins, which are ubiquitous pathogenic molecules, are a bane to the pharmaceutical industry and healthcare community. Thus early and sensitive detection of endotoxin is crucial to prevent endotoxaemia. The limulus amebocyte lysate (LAL) has been widely used for ~30 years for the detection of endotoxin in the quality assurance of injectable drugs and medical devices. The LAL constitutes a cascade of serine proteases which are triggered by trace levels of endotoxin, culminating in a gel clot at the end of the reaction. The Factor C, which normally exists as a zymogen, is the primer of this coagulation cascade. In vivo, Factor C is the perfect biosensor, which alerts the horseshoe crab of the presence of a Gram-negative invader. The hemostatic end-point entraps the invader, killing it and limiting further infection. However, as an in vitro endotoxin detection tool, variations in the sensitivity and specificity of LAL to endotoxin, and the dwindling supply of horseshoe crabs are posing increasing challenges to the biotechnology industry. This has necessitated the innovation of an alternative test for endotoxin. Thus, Factor C became the obvious, albeit tricky target for the recombinant technology effort. This chapter documents the backwater of mining the natural blood lysate of the endangered species to the monumental effort of genetic engineering, to produce recombinant Factor C (rFC). The rFC is a 132 kDa molecule, which was produced as a proenzyme inducible by the presence of trace levels of endotoxin. The rFC forms the basis of the "PyroGene" kit, which is a novel micro

Association of systemic lupus erythematosus with uveitis.

PubMed

Gallagher, Kevin; Viswanathan, Ananth; Okhravi, Narciss

2015-10-01

Systemic lupus erythematosus (SLE) can be associated with uveitis. The reported prevalence of SLE in patients with uveitis varies from 0.1% to 4.8%. Accordingly, the positive predictive value of antinuclear antibody testing in diagnosing SLE in a patient with uveitis varies enormously. An accurate estimate of SLE prevalence in uveitis is needed to establish the value of routine antinuclear antibody testing in patients with uveitis. A literature review using the Medline database was performed to find studies reporting data on uveitis etiology from January 1, 1984, to March 20, 2015. Studies were included where there were sufficient data to draw conclusions on the prevalence of SLE as an etiological factor in uveitis. Data for 53 315 patients were reviewed and 63 studies from 30 countries were included. The prevalence of SLE as a cause of uveitis was estimated to be 0.47% (95% CI, 0.41%-0.53%). The positive predictive value of routine antinuclear antibody testing was 2.9% (95% CI, 2.65%-3.19%). Systemic lupus erythematosus is a rare cause of uveitis. Routine antinuclear antibody testing has a low positive predictive value for SLE. These data suggest such testing should be reserved for patients where there is a higher pretest probability of SLE.

Clinical Trials in Noninfectious Uveitis

PubMed Central

Kim, Jane S.; Knickelbein, Jared E.; Nussenblatt, Robert B.; Sen, H. Nida

2015-01-01

The treatment of noninfectious uveitis continues to remain a challenge for many ophthalmologists. Historically, clinical trials in uveitis have been sparse, and thus, most treatment decisions have largely been based on clinical experience and consensus guidelines. The current treatment paradigm favors initiation then tapering of corticosteroids with addition of steroid-sparing immunosuppressive agents for persistence or recurrence of disease. Unfortunately, in spite of a multitude of highly unfavorable systemic effects, corticosteroids are still regarded as the mainstay of treatment for many patients with chronic and refractory noninfectious uveitis. However, with the success of other conventional and biologic immunomodulatory agents in treating systemic inflammatory and autoimmune conditions, interest in targeted treatment strategies for uveitis has been renewed. Multiple clinical trials on steroid-sparing immunosuppressive agents, biologic agents, intraocular corticosteroid implants, and topical ophthalmic solutions have already been completed, and many more are ongoing. This review discusses the results and implications of these clinical trials investigating both alternative and novel treatment options for noninfectious uveitis. PMID:26035763

Induction of endoplasmic reticulum stress under endotoxin tolerance increases inflammatory responses and decreases Pseudomonas aeruginosa pneumonia.

PubMed

Kim, Sena; Joe, Yeonsoo; Park, Se-Ung; Jeong, Sun Oh; Kim, Jin-Kyung; Park, Seong Hoon; Pae, Hyun-Ock; Surh, Young-Joon; Shin, Jaekyoon; Chung, Hun Taeg

2018-06-20

Endotoxin tolerance develops in the late phase of sepsis to protect cells from an early hyperinflammatory response. Nonetheless, because it induces an immunosuppressive environment, patients with sepsis in its late phase are affected by secondary infections, particularly bacterial pneumonia. Here, we showed that induction of endoplasmic reticulum (ER) stress leads to activation of glycogen synthase kinase 3β (GSK-3β) and X-box-binding protein 1 (XBP-1) in an inositol-requiring enzyme 1α (IRE1α)-mediated manner, which in turn restores the inflammatory response in endotoxin-tolerant macrophages. Animal and in vitro models of endotoxin tolerance were studied along with a model of LPS-induced endotoxin tolerance and a model of cecal ligation and puncture (CLP)-induced endotoxin tolerance. To detect the suppressed inflammatory response during endotoxin tolerance, inflammatory-cytokine expression levels were measured by quantitative real-time PCR and an ELISA. Our research revealed that induction of ER stress alleviated lung injury in a septic host infected with Pseudomonas aeruginosa via the activation of GSK-3β and XBP-1 in an IRE1α-mediated manner. Consequently, in the lungs of the septic host infected with P. aeruginosa, symptoms of pneumonia improved and the infecting bacteria were cleared. Thus, for septic patients, determination of immune status may guide the selection of appropriate immunomodulation, and ER stress can be a novel therapeutic strategy restoring the immune response in patients with endotoxin tolerance. ©2018 Society for Leukocyte Biology.

Removal of endotoxin from dairy wastewater

USDA-ARS?s Scientific Manuscript database

The efficacy of various treatments on removing endotoxin (ET) from wastewater was tested by using the treated water to induce a systemic reaction via intratracheal inoculation (20 ml/goat, 6 goats/group). Treatments (T1-T7) of wastewater were as follows: 1) autoclaved 15 min, centrifuged and contain...

Dopexamine reverses colonic but not gastric mucosal perfusion defects in lethal endotoxin shock.

PubMed

Tenhunen, J J; Martikainen, T J; Uusaro, A; Ruokonen, E

2003-12-01

Whilst dopexamine appears to increase overall splanchnic blood flow in postoperative and septic patients, the effects on gastric mucosal perfusion are controversial and based on concomitantly increasing mucosal to arterial PCO(2) gradients (PdCO(2)). We hypothesized that dopexamine alters splanchnic blood flow distribution and metabolism during experimental endotoxin shock and modifies the inflammatory response induced by endotoxin. In an experiment with anaesthetized normovolaemic, normoventilated pigs, 21 animals were randomized into: (i). subacute lethal endotoxin shock for 14 h (n=7 at baseline); (ii). endotoxin shock with dopexamine infusion (aiming to exceed baseline cardiac output, n=7); or (iii). controls (n=7). Regional blood flow and metabolism were monitored. Endotoxin produced a hypodynamic phase followed by a normo/hyperdynamic, hypotensive phase. Despite increasing systemic blood flow in response to dopexamine, proportional splanchnic blood flow decreased during the hypodynamic phase. Dopexamine gradually decreased fractional coeliac trunk flow, while fractional superior mesenteric arterial flow increased. Dopexamine induced early arterial hyperlactataemia and augmented the gastric PdCO(2) gradient while colonic luminal lactate release and colonic PdCO(2) gradient were reversed. Dopexamine did not modify the inflammatory response as evaluated by arterial IL-1beta and IL-6 concentrations. Dopexamine protects colonic, but not gastric mucosal epithelium in experimental endotoxin shock. This may be related to redistribution of blood flow within the splanchnic circulation.

Sarcoidosis and uveitis.

PubMed

Jamilloux, Yvan; Kodjikian, Laurent; Broussolle, Christiane; Sève, Pascal

2014-08-01

Uveitis is a frequent (20-50%) and early feature of sarcoidosis. Typical sarcoid uveitis presents with mutton-fat keratic precipitates, iris nodules, and anterior and posterior synechiae. Posterior involvement includes vitreitis, vasculitis, and choroidal lesions. Cystoid macular edema is the most important and sight-threatening consequence. Histologic proof from a biopsy is the gold standard for the diagnosis of ocular sarcoidosis. An international workshop has recently established diagnostic criteria for sarcoidosis uveitis when biopsy is unavailable or negative: these are based on a combination of ophthalmological findings and laboratory tests. The value of recent techniques, such as PET-scan and endoscopic ultrasound-guided, fine-needle aspiration of intrathoracic nodes needs to be assessed in future studies. Corticosteroids are the mainstay treatment for sarcoidosis. Systemic corticosteroids are indicated when uveitis does not respond to topical corticosteroids or when there is bilateral posterior involvement, especially macular edema and occlusive vasculitis. In up to 15% of cases, additional immunosuppression is used, including methotrexate, azathioprine, and mycophenolate mofetil. Infliximab and adalimumab have been recently proposed for the treatment of refractory or sight-threatening systemic sarcoidosis. Copyright © 2014 Elsevier B.V. All rights reserved.

[Effect of endotoxin pretreatment-induced glycogen synthase kinase-3 inhibition on glycogen metabolism in rat liver and the mechanism].

PubMed

Chen, Xiaole; Gong, Jianping; Xu, Faliang

2014-02-01

To investigate the changes in the functional activity of glycogen synthase kinase-3 (GSK-3) in the hepatic tissue after endotoxin (lipopolysaccharide, LPS) tolerance and explore the effects of LPS-induced GSK-3 inhibition on glycogen metabolism in the liver. Male SD rats were randomly divided into normal control, endotoxin pretreatment and GSK-3 inhibitor (lithium chloride) groups with corresponding pretreatments prior to a large dose of LPS challenge (10 mg/kg) to induce liver injury. Glycogen deposition and content in the hepatic tissue was detected using periodic acid-Schiff (PAS) staining and a glycogen quantification kit, respectively. Western blotting was performed for semi-quantitative analysis of protein level and inhibitory phosphorylation of GSK-3, and a Coomassie brilliant blue G-250-based colorimetric assay was used to detect calpain activity in the liver. Glycogen content in the liver decreased significantly after LPS challenge in all the 3 groups (P<0.05) but showed no significant difference among the groups (P>0.05). Both LPS and lithium chloride pretreatments caused a significant increase of liver glycogen content (P<0.05). LPS pretreatment induced inhibitory phosphorylation of GSK-3β (P<0.05) and partial cleavage of GSK-3α but did not affect the expression of GSK-3 protein (P>0.05). Large-dose LPS challenge significantly increased the activity of calpain in the liver tissue (P<0.05) to a comparable level in the 3 groups (P>0.05). Endotoxin pretreatment induces inhibitory phosphorylation of GSK-3β and partial cleavage of GSK-3α and promotes the deposition of liver glycogen but does not affect the activity of calpain, which may contribute to an increased glycogen reserve for energy supply in the event of large-dose LPS challenge.

Endotoxin and β-(1,3)-glucan levels in automobiles: a pilot study.

PubMed

Wu, Francis Fu-Sheng; Wu, Mei-Wen; Chang, Chin-Fu; Lai, Shu-Mei; Pierse, Nevil; Crane, Julian; Siebers, Rob

2010-01-01

Exposure to bacterial endotoxin and fungal β-(1,3)-glucan in the indoor environment can induce respiratory symptoms. Automobiles are an exposure source of allergens but it is not known if, and how much exposure there is to endotoxin and fungal β-(1,3)-glucan. The objective of the study was to determine whether automobiles are a potential source of exposure to these microbial products. Dust was sampled from the passenger seats of 40 automobiles. Specific Limulus amoebocyte kinetic assays were used to measure endotoxin and β-(1,3)-glucan, respectively. Endotoxin and β-(1,3)-glucan was detected in all samples ranging from 19.9-247.0 EU/mg and 1.6-59.8 μg/g, respectively. There were no significant differences in endotoxin levels between automobiles of smokers and non-smokers, but β-(1,3)-glucan levels were about two-fold higher in the automobiles of non-smokers. In conclusion, endotoxin and β-(1,3)-glucan exposure in automobiles at levels found in our study may be of importance for asthmatics.

Anti-inflammatory effect of cinnamaldehyde and linalool from the leaf essential oil of Cinnamomum osmophloeum Kanehira in endotoxin-induced mice.

PubMed

Lee, Shih-Chieh; Wang, Shih-Yun; Li, Chien-Chun; Liu, Cheng-Tzu

2018-01-01

Cinnamomum osmophloeum Kanehira is a Taiwan native plant that belongs to genus Cinnamomum and is also known as pseudocinnamomum or indigenous cinnamon. Its leaf is traditionally used by local people in cooking and as folk therapy. We previously demonstrated the chemical composition and anti-inflammatory effect of leaf essential oil of Cinnamomum osmophloeum Kanehira of linalool chemotype in streptozotocin-induced diabetic rats and on endotoxin-injected mice. The aim of the present study is to evaluate whether cinnamaldehyde and linalool the active anti-inflammatory compounds in leaf essential oil of Cinnamomum osmophloeum Kanehira. Before the injection of endotoxin, C57BL/6 mice of the experimental groups were administered cinnamaldehyde (0.45 or 0.9 mg/kg body weight) or linalool (2.6 or 5.2 mg/kg body weight), mice of the positive control group were administered the leaf essential oil (13 mg/kg body weight), and mice of the negative group were administered vehicle (corn oil, 4 mL/kg body weight) by gavage every other day for two weeks. All mice received endotoxin (i.p. 10 mg/mL/kg body weight) the next day after the final administration and were killed 12 h after the injection. Normal control mice were pretreated with vehicle followed by the injection with saline. None of the treatment found to affect body weight or food or water intake of mice before the injection of endotoxin. Cinnamaldehyde and linalool were found significantly reversed endotoxin-induced body weight loss and lymphoid organ enlargement compared with vehicle (P < 0.05). Both compounds also significantly lowered endotoxin-induced levels of peripheral nitrate/nitrite, interleukin (IL)-1β, IL-18, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and High-mobility group box 1 protein (HMGB-1), and levels of nitrate/nitrite, IL-1β, TNF-α, and IFN-γ in spleen and mesenteric lymph nodes (MLNs) (P < 0.05). Endotoxin-induced expression of toll-like receptor 4 (TLR4), Myeloid

[Ethanol changes sensitivity of Kupffer cells to endotoxin].

PubMed

Yamashina, Shunhei; Ikejima, Kenichi; Enomoto, Nobuyuki; Takei, Yoshiyuki; Sato, Nobuhiro

2003-10-01

Gut-derived endotoxin plays an important role in alcoholic liver injury. Intestinal sterilization with antibiotics (polymyxin B and neomycin) or inactivation of Kupffer cells with gadolinium chloride can prevent early alcohol-induced liver injury in the Tsukamoto-French model. Although short-term administration of alcohol enhances endotoxin hepatotoxicity, a majority of studies report that short-term ethanol inactivates Kupffer cells. It is therefore paradoxical that Kupffer cells are involved in alcoholic liver injury based on in vivo data with gadolinium chloride and antibiotics, yet ethanol blunts activation of isolated Kupffer cells. Accordingly, this review focuses on understanding this paradox by studying the temporal effect of ethanol in vivo on the response of subsequently isolated Kupffer cells. Mice were given ethanol intragastrically, and LPS was injected later. One hour after ethanol treatment, serum transaminases after LPS were 60% of control, while ethanol increased these parameters about 3-fold 21 hours after ethanol. Pretreatment with antibiotics blocked these effects of ethanol. Two hours after ethanol administration, the LPS-induced increases in intracellular calcium concentration and TNF alpha release by Kupffer cells was diminished by 50% of control, and these parameters were reciprocally enhanced two-fold at 24 hours. Sterilization of the gut with antibiotics blocked both effects of ethanol on intracellular calcium concentration and TNF alpha release. Twenty-four hours after ethanol, CD14 in Kupffer cells was elevated to about five-fold. In Kupffer cells from mice treated with ethanol 1 hour earlier, IRAK expression and activity and NF kappa B were decreased to 50-60% of control. In contrast, in Kupffer cells from mice treated with ethanol 21 hours earlier, LPS-induced TNF alpha production, expression and activity of IRAK were increased 1.5-fold over controls, while NF kappa B activation was elevated 3-fold. Kupffer cells isolated from rodents

Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences

PubMed Central

Purohit, Vishnudutt; Bode, J. Christian; Bode, Christiane; Brenner, David A.; Choudhry, Mashkoor A.; Hamilton, Frank; Kang, Y. James; Keshavarzian, Ali; Rao, Radhakrishna; Sartor, R. Balfour; Swanson, Christine; Turner, Jerrold R.

2008-01-01

This report is a summary of the symposium on Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, organized by National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, and National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health in Rockville, Maryland, October 11, 2006. Alcohol exposure can promote the growth of Gram negative bacteria in the intestine which may result in accumulation of endotoxin. In addition, alcohol metabolism by Gram negative bacteria and intestinal epithelial cells can result in accumulation of acetaldehyde, which in turn can increase intestinal permeability to endotoxin by increasing tyrosine phosphorylation of tight junction and adherens junction proteins. Alcohol-induced generation of nitric oxide may also contribute to increased permeability to endotoxin by reacting with tubulin, which may cause damage to microtubule cytoskeleton and subsequent disruption of intestinal barrier function. Increased intestinal permeability can lead to increased transfer of endotoxin from the intestine to the liver and general circulation where endotoxin may trigger inflammatory changes in the liver and other organs. Alcohol may also increase intestinal permeability to peptidoglycan which can initiate inflammatory response in liver and other organs. In addition, acute alcohol exposure may potentiate the effect of burn injury on intestinal bacterial growth and permeability. Decreasing the number of Gram negative bacteria in the intestine can result in decreased production of endotoxin as well as acetaldehyde which is expected to decrease intestinal permeability to endotoxin. In addition, intestinal permeability may be preserved by administering epidermal growth factor, L-glutamine, oats supplementation, or zinc thereby preventing the transfer of endotoxin to the general circulation. Thus reducing the number of intestinal Gram negative bacteria and

Endotoxin levels and contribution factors of endotoxins in resident, school, and office environments - A review

NASA Astrophysics Data System (ADS)

Salonen, Heidi; Duchaine, Caroline; Létourneau, Valérie; Mazaheri, Mandana; Laitinen, Sirpa; Clifford, Sam; Mikkola, Raimo; Lappalainen, Sanna; Reijula, Kari; Morawska, Lidia

2016-10-01

As endotoxin exposure has known effects on human health, it is important to know the generally existing levels of endotoxins as well as their contributing factors. This work reviews current knowledge on the endotoxin loads in settled floor dust, concentrations of endotoxins in indoor air, and different environmental factors potentially affecting endotoxin levels. The literature review consists of peer-reviewed manuscripts located using Google and PubMed, with search terms based on individual words and combinations. References from relevant articles have also been searched. Analysis of the data showed that in residential, school, and office environments, the mean endotoxin loads in settled floor dust varied between 660 and 107,000 EU/m2, 2180 and 48,000 EU/m2, and 2700 and 12,890 EU/m2, respectively. Correspondingly, the mean endotoxin concentrations in indoor air varied between 0.04 and 1610 EU/m3 in residences, and 0.07 and 9.30 EU/m3 in schools and offices. There is strong scientific evidence indicating that age of houses (or housing unit year category), cleaning, farm or rural living, flooring materials (the presence of carpets), number of occupants, the presence of dogs or cats indoors, and relative humidity affect endotoxin loads in settled floor dust. The presence of pets (especially dogs) was extremely strongly associated with endotoxin concentrations in indoor air. However, as reviewed articles show inconsistency, additional studies on these and other possible predicting factors are needed.

Isolation of Endotoxin Eliminating Lactic Acid Bacteria and a Property of Endotoxin Eliminating Protein.

PubMed

Kondo, Ayaka; Asami, Kyoko; Suda, Yoshihito; Shimoyamada, Makoto; Kanauchi, Makoto

2016-06-01

Recently, many scholars have reported lactic acid bacteria (LAB) functions, such as anticancer activity and anti-inflammatory activity for intestines. To decrease inflammatory substances such as endotoxins, LAB consumed safely with meals were isolated from food and food ingredients. First, LAB were isolated as 168 strains of bacillus LAB (49 strain) and coccus LAB (119 strains) from food ingredients and fermented foods such as rice, rice bran, malt, grains, miso soy paste, and some pickles. Their LAB (168 strains) were cultivated in medium containing endotoxin from Escherichia coli O18 LPS at 15 and 30 °C for 64 h to identify endotoxin-eliminating LAB. Consequently, the AK-23 strain was screened as an endotoxin-eliminating LAB strain. The strain decreased endotoxin in YP medium without sugar at 30 °C for 64 h until 9% of endotoxin. The strain was identified as Pediococcus pentosaceus according to morphological characteristics such as its cell shape, physiological characteristics related to its fermentation type, assimilation of sugars, pH tolerance, optimum growth temperature, and molecular biological characteristics as its homology to 16S rRNA. To investigate the location of the endotoxin-eliminating substance, 4 fractions were separated from AK-23 cells as extracellular, cell wall digestion, cytoplasm, and cell membrane fractions. The endotoxin-decreasing substance, located on a cell wall, was identified as a 217 kDa protein. © 2016 Institute of Food Technologists®

Endotoxin hitchhiking on polymer nanoparticles

NASA Astrophysics Data System (ADS)

Donnell, Mason L.; Lyon, Andrew J.; Mormile, Melanie R.; Barua, Sutapa

2016-07-01

The control of microbial infections is critical for the preparation of biological media including water to prevent lethal septic shock. Sepsis is one of the leading causes of death in the United States. More than half a million patients suffer from sepsis every year. Both gram-positive and gram-negative bacteria are responsible for septic infection by the most common organisms i.e., Escherichia coli and Pseuodomonas aeruginosa. The bacterial cell membrane releases negatively charged endotoxins upon death and enzymatic destruction, which stimulate antigenic response in humans to gram-negative infections. Several methods including distillation, ethylene oxide treatment, filtration and irradiation have been employed to remove endotoxins from contaminated samples, however, the reduction efficiency remains low, and presents a challenge. Polymer nanoparticles can be used to overcome the current inability to effectively sequester endotoxins from water. This process is termed endotoxin hitchhiking. The binding of endotoxin on polymer nanoparticles via electrostatic and hydrophobic interactions offers efficient removal from water. However, the effect of polymer nanoparticles and its surface areas has not been investigated for removal of endotoxins. Poly(ε-caprolactone) (PCL) polymer was tested for its ability to effectively bind and remove endotoxins from water. By employing a simple one-step phase separation technique, we were able to synthesize PCL nanoparticles of 398.3 ± 95.13 nm size and a polydispersity index of 0.2. PCL nanoparticles showed ∼78.8% endotoxin removal efficiency, the equivalent of 3.9 × 105 endotoxin units (EU) per ml. This is 8.34-fold more effective than that reported for commercially available membranes. Transmission electron microscopic images confirmed binding of multiple endotoxins to the nanoparticle surface. The concept of using nanoparticles may be applicable not only to eliminate gram-negative bacteria, but also for any gram

Use of Immunomodulatory Drugs at a Uveitis Clinic.

PubMed

Millán-Longo, Claudia; Peiteado, Diana; Schlincker, Armelle; Hidalgo, Ventura; Pieren, Amara; Balsa, Alejandro; de Miguel, Eugenio

2017-11-10

The treatment of noninfectious uveitis includes steroids and immunomodulatory drugs, the use of which has increased in the last few years, and the options have been enriched with the development of new treatments. However, clear therapeutic guidelines and protocols have not been developed. The purpose is to analyze the response to the drugs used and the characteristics of the patients treated at a multidisciplinary uveitis clinic. Observational and retrospective study of the patients attended to from January 2012 to December 2015. Infectious, posttraumatic and postoperative uveitis, as well as masquerade syndrome, were excluded. Two hundred six patients were included. Overall, 58.80% had uveitis without association of systemic disease, mostly idiopathic uveitis, and 35.65% had uveitis with systemic involvement, mainly related to spondyloarthritis. Uveitis without systemic association and anterior uveitis achieved disease control with local treatment more frequently than others (p=.002 and p <.001, respectively). In all, 49.76% of the patients required systemic treatment. Among those treated with immunomodulators, 53.26% needed a second drug and 31.52% needed a third drug. Women required immunomodulators more often than men (P=.042). Methotrexate was the most widely used immunomodulator. Posterior uveitis responded less favorably to the second immunomodulator than anterior uveitis (p=.006). Almost half of the patients needed an immunomodulatory drug and some of them required successive drug changes. Intermediate uveitis was the most treatment-refractory uveitis. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Role of interleukin 10 in norfloxacin prevention of luminal free endotoxin translocation in mice with cirrhosis.

PubMed

Gómez-Hurtado, Isabel; Moratalla, Alba; Moya-Pérez, Ángela; Peiró, Gloria; Zapater, Pedro; González-Navajas, José M; Giménez, Paula; Such, José; Sanz, Yolanda; Francés, Rubén

2014-10-01

Bacterial endotoxin is present in patients with advanced cirrhosis and can induce an immunogenic response without an overt infection. Norfloxacin is a gram-negative bactericidal drug able to maintain low endotoxin levels and stimulate IL-10 production. We aimed at investigating the role of IL-10 in decreasing endotoxin absorption in cirrhotic mice treated with norfloxacin. Cirrhosis was induced by carbon tetrachloride or bile duct ligation in wild type and IL10-deficient mice with or without norfloxacin prior to an intragastrical administration of E. coli, K. pneumonia or E. faecalis. Spontaneous and induced bacterial translocation, free endotoxin and cytokine levels were evaluated in mesenteric lymph nodes. Intestinal permeability was followed by fluorimetry and barrier integrity markers were measured in disrupted intestinal samples. The inflammatory-modulating mechanism was characterized in purified intestinal mononuclear cells. Norfloxacin reduced spontaneous and induced MLN positive-cultures in wild type and IL-10-deficient animals. However, reduction of free endotoxin levels was associated with norfloxacin in wild type but not in IL-10-deficient mice. Wild type but not IL-10-deficient mice treated with norfloxacin significantly normalized intestinal permeability and improved gut barrier integrity markers. The toll-like receptor 4-mediated pro-inflammatory milieu was modulated by norfloxacin in a concentration-dependent manner in cultured intestinal mononuclear cells of wild type mice but not of IL-10-deficient mice. The restoration of IL-10 levels in IL-10-deficient animals reactivated the norfloxacin effect on inflammatory-modulation, gut barrier permeability, and luminal endotoxin absorption. Norfloxacin not only reduces gram-negative intestinal flora but also participates in an IL-10-driven modulation of gut barrier permeability, thus reducing luminal free endotoxin absorption in experimental cirrhosis. Copyright © 2014 European Association for the Study

Acute bilateral uveitis and right macular edema induced by a single infusion of zoledronic acid for the treatment of postmenopausal osteoporosis as a substitution for oral alendronate: a case report.

PubMed

Tian, Yiming; Wang, Rui; Liu, Lianyuan; Ma, Chunming; Lu, Qiang; Yin, Fuzai

2016-02-11

Zoledronic acid-induced uveitis (ZAIU) is rare but severe, and has been recently considered part of an acute phase reaction. Only 15 cases have been reported since 2005. Here we describe a case with macular edema, which is the first reported case observed after long-term alendronate tolerance. A 63-year-old Asian woman received her first intravenous zoledronic acid treatment for the management of postmenopausal osteoporosis as a more convenient substitute for oral alendronate. Twenty-four hours later, bilateral eye irritations, periorbital swelling, blurred vision, and diplopia presented. The complete blood count and transaminase levels were normal, but the erythrocytic sedimentation, C-reactive protein, and serum C4 levels were elevated. On detailed ophthalmological examination, a diagnosis of bilateral acute uveitis and macular edema in the right eye was made. The ocular symptoms were not improved until administration of topical and oral steroids. Complete resolution was achieved. There was no rechallenge of bisphosphonates, and no recurrence at 6 months follow-up. Based on an extensive review, abnormal fundus is rarely reported, especially in cases of macular edema. Rechallenge with zoledronic acid in five cases induced no additional uveitis, and changing the medication to pamidronate in another patient was also tolerated. Interestingly, our patient suffered from uveitis soon after intravenous zoledronate exposure after a two-year tolerance to oral alendronate. This is the first report of zoledronic acid induced uveitis with macular edema after long-term alendronate tolerance. Prior oral alendronate may not entirely prevent ZAIU. Steroids are usually necessary in the treatment of ZAIU. Bisphosphonate rechallenge is not fully contraindicated, and prior steroid administration may be a more reasonable treatment choice according to the available evidence.

Comparative Proteomic Analysis of Two Uveitis Models in Lewis Rats.

PubMed

Pepple, Kathryn L; Rotkis, Lauren; Wilson, Leslie; Sandt, Angela; Van Gelder, Russell N

2015-12-01

Inflammation generates changes in the protein constituents of the aqueous humor. Proteins that change in multiple models of uveitis may be good biomarkers of disease or targets for therapeutic intervention. The present study was conducted to identify differentially-expressed proteins in the inflamed aqueous humor. Two models of uveitis were induced in Lewis rats: experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU). Differential gel electrophoresis was used to compare naïve and inflamed aqueous humor. Differentially-expressed proteins were separated by using 2-D gel electrophoresis and excised for identification with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF). Expression of select proteins was verified by Western blot analysis in both the aqueous and vitreous. The inflamed aqueous from both models demonstrated an increase in total protein concentration when compared to naïve aqueous. Calprotectin, a heterodimer of S100A8 and S100A9, was increased in the aqueous in both PMU and EAU. In the vitreous, S100A8 and S100A9 were preferentially elevated in PMU. Apolipoprotein E was elevated in the aqueous of both uveitis models but was preferentially elevated in EAU. Beta-B2-crystallin levels decreased in the aqueous and vitreous of EAU but not PMU. The proinflammatory molecules S100A8 and S100A9 were elevated in both models of uveitis but may play a more significant role in PMU than EAU. The neuroprotective protein β-B2-crystallin was found to decline in EAU. Therapies to modulate these proteins in vivo may be good targets in the treatment of ocular inflammation.

[Pathophysiology and new treatment of uveitis].

PubMed

Yanai, Ryoji; Takeda, Atsunobu; Yoshimura, Takeru; Sonoda, Koh-Hei

2014-01-01

Uveitis is narrow-defined inflammation of the uvea, also clinically include all inflammatory conditions in the eye. Uveitis may occur as a consequence of various causes and background, such as autoimmune diseases, infections, and hematopoietic malignancy. We have to treat uveitis not only controlling the inflammation but also maintaining up the visual function of the eye because the most uveitis is chronic and relapsing inflammatory disorder. Behçét's disease is a systemic disease and results in loss of vision without adequate treatment. Behçét's disease was a representative of vision loss uveitis because Behçét's patient usually had treatment resistance of conventional treatment, such as colchicine and cyclosporine. However, biological therapy with TNF-α, which started from 2007, has revolutionized the treatment strategy of Behçét's disease. It is not too much to say that Behçét's patient is free from fear of vision loss by the dramatic decrease of ocular attach. Biological therapy is not approved as a treatment of uveitis except Behçét's disease. Some protracted cases of Sarcoidosis and Vogt-Koyanagi-Harada disease are resistant to corticosteroid therapy and require new treatment. In this review, we discuss the pathophysiology of uveitis and report new treatment of Behçét's disease by biological therapy.

Nitrite/Nitrate responses to endotoxin in calves.

PubMed

Hüsler, B R; Blum, J W

2001-10-01

Plasma concentrations and urinary excretions of nitrite plus nitrate (NOx) increase in heifers after endotoxin-induced nitric oxide synthase activation. The rise can be enhanced by administration of arginine, the substrate for the production of nitric oxide, whose effects may be modified by the iron status. In 10-week-old veal calves (six Simmental x Red Holstein) arginine (0.5 g/kg body weight for 6 h) was intravenously infused. At 2 h after the start of the infusions Escherichia coli endotoxin O26:B6 (2 microg/kg body weight) was intravenously injected. This caused a rise of rectal temperature, heart rate, respiration rate, and of urinary NOx excretion, but not of plasma NOx concentrations, in contrast to the experience with older cattle to which the same amounts of arginine were infused before and during endotoxin administration. In 8-week-old veal calves (18 Simmental x Red Holstein) the question of whether oral supplementation with arginine and iron modifies NOx responses to endotoxin (2 microg/kg) was also investigated. The calves were divided between three groups (GrA-, GirA+, GrC) and before endotoxin injections GrA- was fed 0.5 g arginine/kg for 4 days, GrA+ was fed 0.5 g arginine/kg for 4 days plus 80 mg iron/kg milk for 2 weeks, whereas GrC was not supplemented with arginine or iron. Iron supplementation increased plasma iron concentrations and arginine supplementation increased plasma arginine and urea concentrations and urinary urea excretion. Ensuing administration of endotoxin enhanced plasma tumour necrosis factor-alpha concentrations, rectal temperature, heart rate, and respiration rate, but not plasma NOx concentrations in GrC and GrA- and only transiently and slightly increased plasma NOx concentrations in GrA+ but did not affect urinary NOx excretions. In conclusion, the expected stimulation of NOx responses to endotoxin by intravenous arginine infusion appears to be much weaker in young veal calves than in older cattle. The NOx responses in

Genetic variants in endotoxin signalling pathway, domestic endotoxin exposure and asthma exacerbations.

PubMed

Kljaic-Bukvic, Blazenka; Blekic, Mario; Aberle, Neda; Curtin, John A; Hankinson, Jenny; Semic-Jusufagic, Aida; Belgrave, Danielle; Simpson, Angela; Custovic, Adnan

2014-10-01

We investigated the interaction between genetic variants in endotoxin signalling pathway and domestic endotoxin exposure in relation to asthma presence, and amongst children with asthma, we explored the association of these genetic variants and endotoxin exposure with hospital admissions due to asthma exacerbations. In a case-control study, we analysed data from 824 children (417 asthmatics, 407 controls; age 5-18 yr). Amongst asthmatics, we extracted data on hospitalization for asthma exacerbation from medical records. Endotoxin exposure was measured in dust samples collected from homes. We included 26 single-nucleotide polymorphisms (SNPs) in the final analysis (5 CD14, 7LY96 and 14 TLR4). Two variants remained significantly associated with hospital admissions with asthma exacerbations after correction for multiple testing: for CD14 SNP rs5744455, carriers of T allele had decreased risk of repeated hospital admissions compared with homozygotes for C allele [OR (95% CI), 0.42 (0.25-0.88), p = 0.01, False Discovery Rate (FDR) p = 0.02]; for LY96 SNP rs17226566, C-allele carriers were at a lower risk of hospital admissions compared with T-allele homozygotes [0.59 (0.38-0.90), p = 0.01, FDR p = 0.04]. We observed two interactions between SNPs in CD14 and LY96 with environmental endotoxin exposure in relation to hospital admissions due to asthma exacerbation which remained significant after correction for multiple testing (CD14 SNPs rs2915863 and LY96 SNP rs17226566). Amongst children with asthma, genetic variants in CD14 and LY96 may increase the risk of hospital admissions with acute exacerbations. Polymorphisms in endotoxin pathway interact with domestic endotoxin exposure in further modification of the risk of hospitalization. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Uveitis

MedlinePlus

... the uveitis is caused by a body-wide (systemic) infection, you may be given antibiotics. You may ... vision Prevention If you have a body-wide (systemic) infection or disease, treating the condition will prevent ...

Anti-TNFα agents and methotrexate in spondyloarthritis related uveitis in a Chinese population.

PubMed

Lian, Fan; Zhou, Jun; Wei, Cui; Wang, Yu; Xu, Hanshi; Liang, Liuqin; Yang, Xiuyan

2015-11-01

This study seeks to evaluate the clinical characteristics of spondyloarthritis (SpA)-related uveitis in a cohort from South China and to assess the efficacy and safety of therapies based on TNF blockers. SpA patients with uveitis admitted to a south China hospital were enrolled. Demographic information, clinical characteristics, laboratory findings, intraocular inflammation, visual acuity, macular thickness, and treatments were documented. Of the 1,036 SpA patients reviewed, 182 had uveitis. Ankylosing spondylitis (AS) was the most common subtype. Unilateral uveitis was found in 51 cases (51/182, 28.0%), and unilateral alternating uveitis was found in 75 cases (75/182, 41.2%). Half of the cases were recurrent uveitis (52.2%), and acute onset was common (76.4%). The most serious complication was vision loss (0.5%). No significant difference in disease activity was found between the SpA patients with or without uveitis. Predominant improvements were found in cases treated with all three anti-TNFs (infliximab, adalimumab, and etanercept) and anti-TNFs plus methotrexate (MTX). Monotherapy of methotrexate was not adequate for inducing remission. Monotherapy of etanercept was not as effective as adalimumab and infliximab, mainly in the prevention of recurrence. No significant difference in effectiveness was found among the three anti-TNFs if MTX was added. Etanercept plus MTX were well tolerated. Infliximab and adalimumab were associated with more tuberculosis and/or hepatitis flares. Uveitis is common in SpA patients. Severe complications may develop in prolonged and intractable cases. Treatments based on anti-TNFs had good clinical response, and better safety documentation were observed in etanercept plus MTX compared to the other two anti-TNF monoclonal antibodies plus MTX.

Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis.

PubMed

Taylor, Simon R J; Banker, Alay; Schlaen, Ariel; Couto, Cristobal; Matthe, Egbert; Joshi, Lavnish; Menezo, Victor; Nguyen, Ethan; Tomkins-Netzer, Oren; Bar, Asaf; Morarji, Jiten; McCluskey, Peter; Lightman, Sue

2013-01-01

To assess the outcomes of the intravitreal administration of methotrexate in uveitis. Multicenter, retrospective interventional case series of patients with noninfectious uveitis. Thirty-eight eyes of 30 patients were enrolled, including a total of 54 intravitreal injections of methotrexate at a dose of 400 µg in 0.1 mL. The primary outcome measure was visual acuity. Secondary outcome measures included control of intraocular inflammation and cystoid macular edema, time to relapse, development of adverse events, and levels of systemic corticosteroid and immunosuppressive therapy. Methotrexate proved effective in controlling intraocular inflammation and improving vision in 30 of 38 eyes (79%). The side effect profile was good, with no reported serious ocular adverse events and only one patient having an intraocular pressure of >21 mmHg. Of the 30 eyes that responded to treatment, 8 relapsed, but 22 (73%) entered an extended period of remission, with the Kaplan-Meier estimate of median time to relapse for the whole group being 17 months. The eight eyes that relapsed were reinjected and all responded to treatment. One eye relapsed at 3 months, but 7 eyes again entered extended remission. Of the 14 patients on systemic therapy at the start of the study, 8 (57%) were able to significantly reduce this following intravitreal methotrexate injection. In patients with uveitis and uveitic cystoid macular edema, intravitreal MTX can effectively improve visual acuity and reduce cystoid macular edema and, in some patients, allows the reduction of immunosuppressive therapy. Some patients relapse at 3 to 4 months, but a large proportion (73%) enter an extended period of remission of up to 18 months. This larger study extends the results obtained from previous smaller studies suggesting the viability of intravitreal methotrexate as a treatment option in uveitis.

Tuberculous Posterior Sclero-Uveitis with Features of Vogt-Koyanagi-Harada Uveitis: An Unusual Case.

PubMed

Kalogeropoulos, Dimitrios; Kitsos, George; Konstantinidis, Athanasios; Gartzonika, Constantina; Svarna, Evgenia; Malamos, Konstantinos; Katsanevakis, Emmanouil; Kalogeropoulos, Chris

2017-04-08

BACKGROUND Ocular tuberculosis (TB) is a clinical entity that presents with a wide range of clinical manifestations. It is regarded as an extremely challenging condition from the point of view of diagnostic approach and calls for early diagnosis and prompt treatment, as it can potentially lead to blindness. CASE REPORT This is a case report of a 32-year-old male from southern India who has been living and working in Greece over the last 10 years and presented with 2-week history of pain and progressive visual impairment of his left eye. He underwent a thorough clinical ophthalmological examination and imaging of the fundus, and the findings were consistent with uveitis. However, the manifestations of the inflammation were complicated as they included features that could be attributed mainly to Vogt-Koyanagi-Harada (VKH) disease and tuberculous serpiginous-like uveitis. Therefore, a systemic evaluation, together with specific laboratory and paraclinical investigations, were carried out to define the etiology of the inflammation and develop an optimal therapeutic plan. Taking into account specific findings from the chest imaging, a positive purified protein derivative (PPD) skin test, and sputum cultures positive for Mycobacterium tuberculosis (MTB), we set a diagnosis of posterior sclero-uveitis and started our patient on anti-tuberculous treatment. CONCLUSIONS This case reveals an atypical manifestation of tuberculous sclero-uveitis imitating Vogt-Koyanagi-Harada disease together with a few characteristics of serpiginous-like tuberculous uveitis, emphasizing the fact that tuberculosis should always be included in the differential diagnosis of uveitis when there is no obvious underlying disease.

Movement of Endotoxin Through Soil Columns

PubMed Central

Goyal, Sagar M.; Gerba, Charles P.; Lance, J. Clarence

1980-01-01

Land treatment of wastewater is an attractive alternative to conventional sewage treatment systems and is gaining widespread acceptance. Although land application systems prevent surface water pollution and augment the available water supplies, the potential dangers to human health should be evaluated. Since sewage may contain high amounts of bacterial endotoxin, the removal of endotoxin from sewage by percolation through soil was investigated. It was found that 90 to 99% of the endotoxin was removed after travel of sewage through 100 to 250 cm of loamy sand soil. When distilled water was allowed to infiltrate into the soil to simulate rainfall, the endotoxin was mobilized and moved in a concentrated band through the soil column. On testing samples from actual land treatment sites, as much as 480 ng of endotoxin per milliliter was found in some groundwater samples. The presence of endotoxin in potable water is known to be a potential problem under some circumstances, but the importance of endotoxin in water supplies has not been fully assessed. Therefore, the design, operation, and management of land application systems should take into account the fate of endotoxin in groundwater beneath the sites. PMID:7387154

Short-chain inulin-like fructans reduce endotoxin and bacterial translocations and attenuate development of TNBS-induced colitis in rats.

PubMed

Ito, Hiroyuki; Tanabe, Hiroki; Kawagishi, Hirokazu; Tadashi, Wada; Yasuhiko, Tomono; Sugiyama, Kimio; Kiriyama, Shuhachi; Morita, Tatsuya

2009-10-01

Anti-inflammatory effects of short-chain inulin-like fructans (SCF) on trinitrobenzene sulfonic acid (TNBS)-induced colitis were investigated in rats, focusing specifically on endotoxin and bacterial translocations. SCF with degrees of polymerization (DP) of 4 and 8 were used. Rats were fed either control diet or diets including 60 g DP4 or DP8 per kilogram for 7 days, and then received intracolonic TNBS and were fed the respective diets for a further 10 days. DP4 and DP8 significantly reduced colonic injuries as assessed by damage score, but the reduction of colonic myeloperoxidase activity was manifest solely with DP8. At 3 days after colitis induction, bacterial translocation to the mesenteric lymph node was significantly lower in the DP4 and DP8 groups, but significant reduction in the portal endotoxin concentration was achieved solely in the DP8 group. Immediately prior to colitis induction, cecal immunoglobulin A and mucin concentrations were higher in the DP4 and DP8 groups, but these changes were abolished at 10 days post colitis induction. The data suggest that SCF exert prophylactic effects against TNBS colitis, presumably as a result of inhibitory effects on endotoxin and bacterial translocations.

Equine recurrent uveitis: treatment.

PubMed

Curling, Amanda

2011-06-01

Equine recurrent uveitis has traditionally been treated with medical management to reduce ocular inflammation and control pain during a single episode. Newer management methods include surgical options such as cyclosporine implantation and vitrectomy. These methods were developed not only to control inflammation but also to eliminate the underlying cause of uveitis in order to prevent recurrence.

Hormone and Cytokine Responses to Repeated Endotoxin Exposures-No Evidence of Endotoxin Tolerance After 5 Weeks in Humans.

PubMed

Rittig, Nikolaj; Thomsen, Henrik H; Bach, Ermina; Jørgensen, Jens Otto L; Møller, Niels

2015-07-01

Endotoxin administrations are used in experimental models of inflammatory disease. Short-term endotoxin tolerance in response to repeated endotoxin exposure is well known, but the duration of endotoxin tolerance in humans remains unknown. The main purpose of this study was to test whether endotoxin tolerance is present in vivo when separating endotoxin exposures with more than 5 weeks, a time span often used between individual investigations in clinical experimental studies. Seventeen healthy young men were exposed twice to Escherichia coli endotoxin. The inflammatory response was calculated as area under the curve between the first and second endotoxin exposures for heart rate, mean arterial blood pressure, temperature, cortisol, tumor necrosis factor α, and interleukin (IL)-1β, IL-6, and IL-10. The median interval between exposures was 90 days (range, 37-244). The ratio between the inflammatory responses during the second and the first endotoxin exposures was 0.89 ± 0.09 (P = 0.28) for tumor necrosis factor α, 0.96 ± 0.07 (P = 0.53) for IL-1β, 0.97 ± 0.11 (P = 0.78) for IL-6, 1.30 ± 0.18 (P = 0.12) for IL-10, and 0.92 ± 0.04 (P = 0.10) for cortisol. Our data do not show evidence of in vivo tolerance to repeated endotoxin exposure when administrations are separated with at least 5 weeks. This observation is important in the planning and interpretation of future experimental endotoxin studies.

Lymphocyte-dependent antibodies in uveitis.

PubMed

Pápai, I; Lehrner, J

1976-01-01

Lymphocyte-dependent antibodies were revealed in the serum of patients suffering from uveitis of various aetiologies. The serum was incubated with normal uveal tissue and the binding of non-immune human lymphocytes was investigated. In three cases of sympathetic ophthalmitis the lymphocytes accumulated around the melanine granules, while in another 17 patients with uveitis cases the lymphocytes accumulated around the capillaries. Uveal tissue incubated with control sera failed to bound lymphocytes. The lymphocytic infiltration in certain cases of chronic uveitis suggested the role of lymphocyte-mediating antibodies in the aetiology of these cases.

Comparative Proteomic Analysis of Two Uveitis Models in Lewis Rats

PubMed Central

Pepple, Kathryn L.; Rotkis, Lauren; Wilson, Leslie; Sandt, Angela; Van Gelder, Russell N.

2015-01-01

Purpose Inflammation generates changes in the protein constituents of the aqueous humor. Proteins that change in multiple models of uveitis may be good biomarkers of disease or targets for therapeutic intervention. The present study was conducted to identify differentially-expressed proteins in the inflamed aqueous humor. Methods Two models of uveitis were induced in Lewis rats: experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU). Differential gel electrophoresis was used to compare naïve and inflamed aqueous humor. Differentially-expressed proteins were separated by using 2-D gel electrophoresis and excised for identification with matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF). Expression of select proteins was verified by Western blot analysis in both the aqueous and vitreous. Results The inflamed aqueous from both models demonstrated an increase in total protein concentration when compared to naïve aqueous. Calprotectin, a heterodimer of S100A8 and S100A9, was increased in the aqueous in both PMU and EAU. In the vitreous, S100A8 and S100A9 were preferentially elevated in PMU. Apolipoprotein E was elevated in the aqueous of both uveitis models but was preferentially elevated in EAU. Beta-B2–crystallin levels decreased in the aqueous and vitreous of EAU but not PMU. Conclusions The proinflammatory molecules S100A8 and S100A9 were elevated in both models of uveitis but may play a more significant role in PMU than EAU. The neuroprotective protein β-B2–crystallin was found to decline in EAU. Therapies to modulate these proteins in vivo may be good targets in the treatment of ocular inflammation. PMID:26747776

Ocular immunology in equine recurrent uveitis.

PubMed

Deeg, Cornelia A

2008-09-01

Equine recurrent uveitis (ERU) is a disease with high prevalence and relevance for the equine population, since it results in blindness. Over the last decade, important advancements have been made in our understanding of the underlying immune responses in this disease. ERU is mediated by an autoaggressive Th1 response directed against several retinal proteins. Interphotoreceptor-retinoid binding protein (IRBP) and cellular retinaldehyde-binding protein (CRALBP) are capable to induce ERU-like disease in experimental horses, with the unique possibility to activate relapses in a well-defined manner. Further, proteomic evidence now suggests that retinal Mueller glial cells (RMG) may play a fatal role in uveitic disease progression by directly triggering inflammation processes through the expression and secretion of interferon-gamma. Ongoing relapses in blind eyes can be associated with stable expression of the major autoantigens in ERU retinas. This review briefly summarizes the most significant developments in uveitis immune response research.

Uveitis associated with juvenile idiopathic arthritis.

PubMed

Sen, Ethan S; Dick, Andrew D; Ramanan, Athimalaipet V

2015-06-01

Uveitis is a potentially sight-threatening complication of juvenile idiopathic arthritis (JIA). JIA-associated uveitis is recognized to have an autoimmune aetiology characterized by activation of CD4(+) T cells, but the underlying mechanisms might overlap with those of autoinflammatory conditions involving activation of innate immunity. As no animal model recapitulates all the features of JIA-associated uveitis, questions remain regarding its pathogenesis. The most common form of JIA-associated uveitis is chronic anterior uveitis, which is usually asymptomatic initially. Effective screening is, therefore, essential to detect early disease and commence treatment before the development of visually disabling complications, such as cataracts, glaucoma, band keratopathy and cystoid macular oedema. Complications can result from uncontrolled intraocular inflammation as well as from its treatment, particularly prolonged use of high-dose topical corticosteroids. Accumulating evidence supports the early introduction of systemic immunosuppressive drugs, such as methotrexate, as steroid-sparing agents. Prospective randomized controlled trials of TNF inhibitors and other biologic therapies are underway or planned. Future research should aim to identify biomarkers to predict which children are at high risk of developing JIA-associated uveitis or have a poor prognosis. Such biomarkers could help to ensure that patients receive earlier interventions and more-potent therapy, with the ultimate aim of reducing loss of vision and ocular morbidity.

New developments in uveitis associated with HLA B27.

PubMed

Rosenbaum, James T

2017-07-01

Uveitis is the most common, clinically apparent, extra-articular manifestation of axial spondyloarthritis. This review summarizes recent publications related to this form of uveitis. Studies published since the start of 2015 address the worldwide prevalence of human leukocyte antigen (HLA) B27-associated uveitis, the prevalence of axial spondyloarthritis among patients with B27-associated acute anterior uveitis (AAU), the genetics of AAU and some of the clinical implications of AAU. Progress has been made in the treatment of uveitis in general and in the treatment of uveitis in association with spondyloarthropathy in particular. The pathogenesis of AAU might derive clues from the above as well as from an understanding of the microbiome and possibly from knowledge derived from uveitis in association with Ebola. Although HLA B27-associated uveitis has been recognized since 1973, a variety of recent observations shed new light on this common clinical association with spondyloarthritis.

Long-term efficacy of abatacept in pediatric patients with idiopathic uveitis: a case series.

PubMed

Marrani, Edoardo; Paganelli, Valeria; de Libero, Cinzia; Cimaz, Rolando; Simonini, Gabriele

2015-10-01

Non-infectious uveitis represents one of the most common causes of blindness, even at pediatric age; in particular, idiopathic chronic uveitis can pose significant difficulties during treatment, due to a partial response to TNF-α antagonists. To date, very few case series exist describing the treatment of idiopathic uveitis not adequately controlled by TNF-α antagonists. The aim of our study is to describe the role of abatacept in achieving remission in patients with idiopathic uveitis previously treated with TNF-α antagonists, and to assess how long abatacept efficacy is maintained during follow-up. The treatment's safety profile and tolerability were also specifically investigated. Three patients affected with chronic idiopathic uveitis, who have been treated with abatacept due to loss of efficacy of TNF-α antagonists, were reviewed. Details of the demographic and clinical characteristics were recorded, and a summary of the medical history was obtained. Patients were regularly reviewed in the ophthalmology and rheumatology clinics. Assessment of their ocular condition was characterized according to the Standardization of Uveitis Nomenclature (SUN) group. In our patients, abatacept was able to induce remission and to discontinue systemic corticosteroids after a mean of 30 weeks; the drug maintained its efficacy through a long follow-up period (42, 33, and 18 months respectively), with an excellent safety profile. Our small case series seems to suggest abatacept to be a promising therapy in children affected with chronic idiopathic uveitis not adequately controlled by TNF-α antagonists.

The Association of Race with Childhood Uveitis

PubMed Central

Angeles-Han, Sheila T; McCracken, Courtney; Yeh, Steven; Jenkins, Kirsten; Stryker, Daneka; Travers, Curtis; Rouster-Stevens, Kelly; Vogler, Larry B.; Lambert, Scott R.; Drews-Botsch, Carolyn; Prahalad, Sampath

2015-01-01

Purpose To identify risk factors for a severe uveitis course among children with non-infectious uveitis. Design Retrospective cohort study Method This was a retrospective analysis of a prospectively collected database. Records of 94 children with uveitis were reviewed at enrollment and every 3-6 months (2011-2015). Severe uveitis was defined as a history of ocular complications or a visual acuity (VA) of ≤20/200. Children were compared by disease, VA, complications and race. Regression models were used to model risk factors for severe disease. When examining race, we focused on non-Hispanic African American and non-Hispanic White children only. Results Of 85 children with uveitis and complete ocular examinations, 27 (32%) had a history of a VA of ≤20/200. A subanalysis of non-Hispanic African American and White children showed an increased prevalence of VA ≤20/200 in non-Hispanic African Americans (18/25 (72%) vs. 4/43 (9%)). Non-Hispanic African Americans were more likely to be diagnosed at an older age (p=0.030), have intermediate uveitis (p=0.026), bilateral disease (p=0.032), a history of VA ≤20/50 (p=0.002), VA ≤20/200 (p<0.001), and a higher rate of complications (p<0.001). On multivariable analysis, non-Hispanic African American race was a significant predictor of blindness (OR=31.6, 95% CI (5.9– 168.5), p<0.001), after controlling for uveitis duration. Non-Hispanic African Americans also developed 2.2 times more unique complications per year of disease than non-Hispanic Whites when controlling for uveitis type and duration. Conclusions There appear to be racial differences in the outcomes of children with uveitis. Non-Hispanic African American children with non-juvenile idiopathic arthritis associated uveitis may have worse visual outcomes with increased vision loss and ocular complications. These findings highlight the need for future studies in minority populations. PMID:26255577

Endotoxin Studies And Biosolids Stabilization Research

EPA Science Inventory

This presentation has three parts; a review of bench-scale endotoxin research, a review of observations from a field scale endotoxin release study, and discussion of biosolids stabilization and characterization by PLFA/FAME microbial community analysis. Endotoxins are part of th...

A proteomic approach for studying the pathogenesis of spontaneous equine recurrent uveitis (ERU).

PubMed

Deeg, Cornelia A

2009-03-15

Equine recurrent uveitis (ERU) is a wide spread disease of the eye, which is the main cause for blindness in horses worldwide. Meanwhile, ERU is also accepted as the only reliable spontaneous model for human autoimmune uveitis. We identified and characterized novel autoantigens by analyzing the autoantibody-binding pattern from ERU cases to the retinal proteome. Cellular retinaldehyde-binding protein (CRALBP) and malate dehydrogenase (MDH) were detected as novel ERU autoantigens by this approach. B- and T-cell autoreactivity was detected to both autoantigens in ERU cases. The evaluation of the pathological relevance of CRALBP and MDH brought surprising results. While CRALBP-induced uveitis with high incidence in rats and horses, MDH was only uveitogenic in Lewis rats, but not in the horse itself.

Polysaccharide peptide from Coriolus versicolor induces interleukin 6-related extension of endotoxin fever in rats.

PubMed

Jedrzejewski, Tomasz; Piotrowski, Jakub; Kowalczewska, Malgorzata; Wrotek, Sylwia; Kozak, Wieslaw

2015-01-01

Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. In a previous study we showed that PSP induced a tumour necrosis factor-α (TNF-α)-dependent anapyrexia-like response in rats. Thus, PSP appears to be a factor which modifies a number of pathophysiological responses. Because of this, PSP is suggested as a potential adjuvant for cancer therapy during which cancer patients frequently contract microbial infections accompanied by fever. The aim of the present study was to investigate whether or not PSP can modulate the course of the fever in response to an antigen such as lipopolysaccharide (LPS). Body temperature (Tb) of male Wistar rats was measured by biotelemetry. PSP was injected intraperitoneally (i.p.) at a dose of 100 mg kg(-1), 2 h before LPS administration (50 µg kg(-1), i.p.). The levels of interleukin (IL)-6 and TNF-α in the plasma of rats were estimated 3 h and 14 h post-injection of PSP using a standard sandwich ELISA kit. We report that i.p. pre-injection of PSP 2 h before LPS administration expanded the duration of endotoxin fever in rats. This phenomenon was accompanied by a significant elevation of the blood IL-6 level of rats both 3 h and 14 h post-injection of PSP. Pre-treatment i.p. of the rats with anti-IL-6 antibody (30 µg/rat) prevented the PSP-induced prolongation of endotoxin fever. Based on these data, we conclude that PSP modifies the LPS-induced fever in IL-6-related fashion.

EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM

PubMed Central

Berry, L. Joe; Smythe, Dorothy S.

1961-01-01

In vitro secretion of glycocorticoids by adrenal glands pooled from several control mice was compared with that of glands removed from animals following injections of either ACTH or endotoxin. Both substances prevent glycocorticoid synthesis stimulated in vitro with ACTH. Cholesterol content of adrenal glands under these conditions was nearly depleted, indicating maximal response to ACTH or endotoxin prior to their removal for the in vitro tests. In an effort to account physiologically for the manner in which endotoxin suppresses or prevents the rise in urinary nitrogen excreted in response to ACTH, blood non-protein nitrogen levels (NPN) were determined. The following experimental conditions resulted in increased urinary nitrogen excretion but did not alter blood NPN: cortisone given alone or at the same time as endotoxin; ACTH alone; dichloroisoproterenol (DCI) given concurrently with endotoxin; and lactalbumin digest injected intraperitoneally. Increases (2- to 3-fold) in blood NPN were observed when endotoxin was given alone, concurrently with ACTH, or 3 hours prior to cortisone, DCI, or lactalbumin digest. Urinary nitrogen excretion showed no change under these conditions. The elevation in blood NPN in endotoxin-poisoned mice was found to be due almost entirely to urea nitrogen and not to amino acid nitrogen or to other nitrogenous wastes. Blood clearance of mulin, phenol red excretion, and urea elimination were each determined in control and in endotoxin-poisoned mice. The latter mice showed impaired renal function. Treatment with diuretics (diuril and aminophylline) failed to alter oliguria or elevated blood NPN. Hydergine treatment was also without effect. Total carcass NPN and urinary nitrogen excretion data were combined to give a picture of total protein catabolized by mice under different experimental conditions. Cortisone injected at the same time as endotoxin or 3 hours later resulted in the same increase in total NPN. However, in the former case all

Endotoxin predictors and associated respiratory outcomes differ with climate regions in the U.S.

PubMed

Mendy, Angelico; Wilkerson, Jesse; Salo, Pӓivi M; Cohn, Richard D; Zeldin, Darryl C; Thorne, Peter S

2018-03-01

Although endotoxin is a recognized cause of environmental lung disease, how its relationship with respiratory outcomes varies with climate is unknown. To examine the endotoxin predictors as well as endotoxin association with asthma, wheeze, and sensitization to inhalant allergens in various US climate regions. We analyzed data on 6963 participants in the National Health and Nutrition Examination Survey. Endotoxin measurements of house dust from bedroom floor and bedding were performed at the University of Iowa. Linear and logistic regression analyses were used to identify endotoxin predictors and assess endotoxin association with health outcomes. The overall median house dust endotoxin was 16.2 EU/mg; it was higher in mixed-dry/hot-dry regions (19.7 EU/mg) and lower in mixed-humid/marine areas (14.8 EU/mg). Endotoxin predictors and endotoxin association with health outcomes significantly differed across climate regions. In subarctic/very cold/cold regions, log 10 -endotoxin was significantly associated with higher prevalence of wheeze outcomes (OR:1.48, 95% CI:1.19-1.85 for any wheeze, OR:1.48, 95% CI:1.22-1.80 for exercise-induced wheeze, OR:1.50, 95% CI:1.13-1.98 for prescription medication for wheeze, and OR:1.95, 95% CI:1.50-2.54 for doctor/ER visit for wheeze). In hot-humid regions, log 10 -endotoxin was positively associated with any wheeze (OR:1.66, 95% CI:1.04-2.65) and current asthma (OR:1.56, 95% CI:1.11-2.18), but negatively with sensitization to any inhalant allergens (OR:0.83, 95% CI:0.74-0.92). Endotoxin predictors and endotoxin association with asthma and wheeze differ across U.S. climate regions. Endotoxin is associated positively with wheeze or asthma in cold and hot-humid regions, but negatively with sensitization to inhalant allergens in hot-humid climates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Endotoxin reduces specific pulmonary uptake of radiolabeled monoclonal antibody to angiotensin-converting enzyme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muzykantov, V.R.; Puchnina, E.A.; Atochina, E.N.

The biodistribution of radiolabeled monoclonal antibody (Mab) to angiotensin-converting enzyme (ACE) was examined in normal and endotoxin-treated rats. Endotoxin administration at a dose of 4 mg/kg induced mild or middle pulmonary edema. The ACE activity in lung homogenate remained virtually unchanged, while the activity of serum ACE increased 15 hr after endotoxin infusion. In normal rats, anti-ACE Mab accumulates specifically in the lung after i.v. injection. Endotoxin injection induces reduction of specific pulmonary uptake of this antibody. Even in non-edematous endotoxemia, the accumulation of anti-ACE Mab antibody (Mab 9B9) decreased from 19.02 to 11.91% of ID/g of tissue without anymore » change in accumulation of control nonspecific IgG. The antibody distribution in other organs and its blood level were almost the same as in the control. In a case of endotoxemia accompanied by increased microvascular permeability, the lung accumulation of Mab 9B9 was reduced to 9.17% of ID/g of tissue, while the accumulation of nonspecific IgG increased to 1.44% versus 0.89% in the control.« less

The contributions of adrenal hormones, hemodynamic factors, and the endotoxin-related stress reaction to stable prostaglandin analog-induced peripheral lymphopenia and neutrophilia.

PubMed

Ulich, T R; Keys, M; Ni, R X; del Castillo, J; Dakay, E B

1988-01-01

-independent, hemodynamic-independent mechanisms. The possibility that M-PGF2 alpha might be inducing neutrophilia via an endotoxin-like stress reaction was investigated by examining changes in circulating white blood cells in intact and adrenalectomized C3H/HeN (endotoxin-sensitive) and C3H/HeJ (endotoxin-resistant) mice after prostaglandin administration. No quantitative differences in the prostaglandin-induced neutrophilia were noted in C3H/HeJ mice as compared to the C3H/HeN mice.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of inducible nitric oxide synthase in vascular hyporeactivity of endotoxin-treated and portal hypertensive rats.

PubMed

Heinemann, A; Stauber, R E

1995-05-04

The involvement of the inducible nitric oxide (NO) synthase in the vascular hyporeactivity in portal vein-ligated rats was assessed in isolated perfused mesenteric arterial beds. Aminoguanidine, a selective inhibitor of the inducible NO synthase, restored the pressor responses to methoxamine in arteries of endotoxin-treated rats, but was ineffective in hyporeactive portal vein-ligated vessels. NG-Nitro-L-arginine methyl ester enhanced the responsiveness both in portal vein-ligated and sham-operated rats, without changing the difference between the two groups. These results not only indicate that the inducible NO synthase is not involved in the hyporeactivity to methoxamine in mesenteric arteries of portal hypertensive rats, but also suggest a role for factors other than NO.

Protective effect of cinnamic acid in endotoxin-poisoned mice.

PubMed

Xu, Feng; Wang, Feng; Wen, Taoqun; Sang, Wentao; He, Xinyu; Li, Ling; Zeng, Nan

2017-12-01

In this work, we aimed to evaluate the protective effect of cinnamic acid (CD) on lipopolysaccharide (LPS; Escherichia coli 055:B5)-induced endotoxin-poisoned mice and clarify the underlying mechanisms. The mice were administrated CD 5 d before 15 mg/kg LPS challenge. 12 hr later, thymus was separated for determination of thymus indexes. Lung and spleen tissues were collected for histologic examination and the wet/dry weight ratio of lung was calculated, and serum was acquired for tumor necrosis factor-α (TNF-α), interleukin (IL)-18, and IL-1β measurement. Moreover, the expression of NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome was determined in lung. CD increased the thymus indexes and decreased lung wet/dry weight ratio. In addition, CD improved the lung and spleen histopathological changes induced by LPS and decreased the number of neutrophils in lung tissues. CD also inhibited the pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) production in serum. Furthermore, CD suppressed the LPS-induced NLRP3, Caspase-1, and IL-1β mRNA expression in lung, as well as the expression of NLRP3 and Caspase-1 (p20) protein. CD may have protective effects in endotoxin-poisoned mice via inhibiting the activation of NLRP3 inflammasome, and can be considered as a potential therapeutic candidate for diseases involved in endotoxin poisoning such as sepsis. Copyright © 2017 John Wiley & Sons, Ltd.

The effect of low molecular weight dextran on haemodynamics and respiratory function during endotoxin-induced shock.

PubMed Central

Christenson, J T; al-Sarraf, A; Abu-Saleh, R

1992-01-01

The effects of low molecular weight dextran (LMWD) infusion, on gas exchange and haemodynamics were evaluated in sheep during endotoxin shock. The infusion of LMWD was started after signs of shock and lung injury were evident. After a stabilization period 10 micrograms kg-1 E. Coli endotoxin was infused i.v.. Endotoxin infusion resulted in an marked increase in pulmonary artery pressure (PAP) and decrease in mean arterial pressure (MAP), respiratory compliance, arterial oxygen tension (PaO2) and oxygen delivery index (DO2l). After 3 h MAP, PaO2, DO2l and compliance improved significantly in LMWD treated animals. The PAP had also decreased significantly in the LMWD-treated animals, but remained high in the controls (P less than 0.01). It was concluded that LMWD infusion improves haemodynamics and gas-exchange in sheep during endotoxin shock. PMID:1373624

The role of amoebocytes in endotoxin-mediated coagulation in the innate immunity of Achatina fulica snails.

PubMed

Biswas, C; Mandal, C

1999-02-01

Achatina amoebocyte lysate (AAL) derived from amoebocytes of Achatina fulica was activated by Gram-negative bacterial endotoxins in a time-dependent manner resulting in gel formation/coagulation. The activation and maximum proliferation of amoebocytes was observed 40 min after intramuscular injection (20 microg/snail) of endotoxin. Endotoxin-mediated proteolytic activity of AAL towards a serine-protease-specific chromogenic substrate was maximum at pH 8.0, 37 degrees C and within 15 min in a divalent-cation-dependent manner. The AAL activity induced by the endotoxin was directly dependent on the endotoxin concentration, showed a high specificity and saturated at higher endotoxin concentrations. An endotoxin-sensitive factor (ESF) was purified from AAL to apparent homogeneity by single-step affinity chromatography on a heparin-Sepharose 4B column. Native ESF of molecular weight 140 000 was composed of two identical subunits of molecular weight 70 000 attached through non-covalent association. A strong binding to endotoxin (Escherichia coli 055:B5) was exhibited by ESF with a 40-fold higher biological activity than AAL. The ESF was shown to have a unique Phe-Ile active site with regard to its alternate activation by alpha-chymotrypsin instead of endotoxin. The ESF was characterized as a serine protease type as evidenced by potent inhibition with specific inhibitors.

Anti-adalimumab antibodies in juvenile idiopathic arthritis-related uveitis.

PubMed

Leinonen, Sanna T; Aalto, Kristiina; Kotaniemi, Kaisu M; Kivelä, Tero T

2017-01-01

To evaluate the association of adalimumab trough levels and anti-adalimumab antibodies with activity of uveitis in juvenile idiopathic arthritis-related uveitis. This was a retrospective observational case series in a clinical setting at the Department of Ophthalmology, Helsinki University Hospital, Finland in 2014-2016. Thirty-one paediatric patients with chronic anterior juvenile idiopathic arthritis-related uveitis in 58 eyes and who had been on adalimumab ≥6 months were eligible for the study. Uveitis activity during adalimumab treatment, adalimumab trough levels and anti-adalimumab antibody levels were recorded. Anti-adalimumab antibody levels ≥12 AU /ml were detected in nine patients (29%). This level of anti-adalimumab antibodies was associated with a higher grade of uveitis (p<0.001), uveitis that was not in remission (p=0.001) and with lack of concomitant methotrexate therapy (p=0.043). In patients with anti-adalimumab antibody levels <12 AU/ml, higher serum trough levels did not associate with better control of uveitis (p=0.86). Adalimumab treatment might be better guided by monitoring anti-adalimumab antibody formation in treating JIA-related uveitis.

Clinical outcomes of intravenous immunoglobulin therapy in refractory uveitis.

PubMed

Garcia-Geremias, M; Carreño, E; Epps, S J; Lee, R W J; Dick, A D

2015-04-01

Intravenous immunoglobulin (IVIg) therapy has multiple mechanisms of immunomodulatory action. We wished therefore to assess its efficacy in a spectrum of patients with refractory uveitis. Retrospective review of clinical charts was conducted to document response to IVIg treatment in consecutive patients with treatment-refractory uveitis. Main outcome measures were control of intraocular inflammation, visual acuity, progression of the disease, and complications. Four (two male) patients, with a mean age at the beginning of the treatment of 47 years (range: 39-64), were included in the study. Indication for treatment was patients with active non-infectious uveitis refractory to steroids and immunomodulatory therapy. All patients received a course of 0.5 g/kg per day of IVIg for three consecutive days, repeating this course at a mean of 11 week (range: 2-39 weeks) intervals when indicated clinically. The median duration of the IVIg therapy was 7 months (range: 3-14 months). In three patients treatment resulted in stabilisation and prevention of progression of the disease, and additionally in two patients it facilitated a decrease in prednisolone dose. Treatment failed to induce long-term remission in one patient with recurrence of macular oedema. IVIg was well tolerated with neither immediate nor longer-term adverse events observed. In three out of four cases IVIg was an effective adjunctive therapy and well tolerated for the management of treatment-refractory uveitis.

Ultrafiltration and endotoxin removal from dialysis fluids.

PubMed

Di Felice, A; Cappelli, G; Facchini, F; Tetta, C; Cornia, F; Aimo, G; Lusvarghi, E

1993-06-01

Biocompatibility in hemodialysis is now regarded as a multifactorial problem and dialysate represents a main risk. Pyrogenic fractions mostly coming from gram-negative bacteria easily pass through dialysis membrane, either by backdiffusion or by backfiltration, and induce blood cell activation. To demonstrate the long-term efficiency of a 2 m2 polyamide ultrafilter in producing a pyrogen free solution, we used an experimental circuit ultrafiltering for 240 hours (500 ml/min) a bicarbonate dialysate contaminated (5 to 48 EU/ml) by a Pseudomonas aeruginosa filtrate. The efficiency was monitored by LAL-test and IL-1 PBMC so to detect not only lipid A containing endotoxins but also other cytokines inducing bacterial fractions. At the post-ultrafilter sampling port the LAL-test was < 0.005 to 0.034 EU/ml; IL-1 PBMC was below the detection limit (20 pg/ml) being 27 to 63 pg/ml at the pre-ultrafilter level. Polyamide ultrafiltration represents an efficient system to obtain an endotoxin-free dialysate and a single filter works up to 240 hours.

Endotoxin Exposure: Predictors and Prevalence of Associated Asthma Outcomes in the United States

PubMed Central

Mendy, Angelico; Metwali, Nervana; Salo, Päivi; Co, Caroll; Jaramillo, Renee; Rose, Kathryn M.; Zeldin, Darryl C.

2015-01-01

Rationale: Inhaled endotoxin induces airway inflammation and is an established risk factor for asthma. The 2005–2006 National Health and Nutrition Examination Survey included measures of endotoxin and allergens in homes as well as specific IgE to inhalant allergens. Objectives: To understand the relationships between endotoxin exposure, asthma outcomes, and sensitization status for 15 aeroallergens in a nationally representative sample. Methods: Participants were administered questionnaires in their homes. Reservoir dust was vacuum sampled to generate composite bedding and bedroom floor samples. We analyzed 7,450 National Health and Nutrition Examination Survey dust and quality assurance samples for their endotoxin content using extreme quality assurance measures. Data for 6,963 subjects were available, making this the largest study of endotoxin exposure to date. Log-transformed endotoxin concentrations were analyzed using logistic models and forward stepwise linear regression. Analyses were weighted to provide national prevalence estimates and unbiased variances. Measurements and Main Results: Endotoxin exposure was significantly associated with wheeze in the past 12 months, wheeze during exercise, doctor and/or emergency room visits for wheeze, and use of prescription medications for wheeze. Models adjusted for age, sex, race and/or ethnicity, and poverty-to-income ratio and stratified by allergy status showed that these relationships were not dependent upon sensitization status but were worsened among those living in poverty. Significant predictors of higher endotoxin exposures were lower family income; Hispanic ethnicity; participant age; dog(s), cat(s), cockroaches, and/or smoker(s) in the home; and carpeted floors. Conclusions: In this U.S. nationwide representative sample, higher endotoxin exposure was significantly associated with measures of wheeze, with no observed protective effect regardless of sensitization status. PMID:26258643

CRALBP is a highly prevalent autoantigen for human autoimmune uveitis.

PubMed

Deeg, Cornelia A; Raith, Albert J; Amann, Barbara; Crabb, John W; Thurau, Stephan R; Hauck, Stefanie M; Ueffing, Marius; Wildner, Gerhild; Stangassinger, Manfred

2007-01-01

Cellular retinaldehyde binding protein (CRALBP) is an autoantigen in spontaneous equine recurrent uveitis. In order to test whether CRALBP contributes to human autoimmune uveitis, the specificity of antibodies from human uveitis patient's sera was first evaluated in two-dimensional (2D) Western blot analysis. Subsequent identification of the immunoreactive proteins by mass spectrometry resulted in the identification of CRALBP as a putative autoantigen. Additionally, sera from human uveitis and control patients were by Western blot using purified human recombinant CRALBP. Anti-CRALBP autoantibodies occur more frequently (P<.01) in human uveitis patients than in normal controls. Thirty out of 56 tested uveitis patient's sera contained autoantibodies reactive against CRALBP, compared to only four out of 23 normal control subjects. The presence of CRALBP autoantibodies in 54% of tested uveitis patients supports CRALBP as a possible autoantigen in human autoimmune uveitis.

Viral posterior uveitis

PubMed Central

Lee, Joanne H.; Agarwal, Aniruddha; Mahendradas, Padmamalini; Lee, Cecilia S.; Gupta, Vishali; Pavesio, Carlos E.; Agrawal, Rupesh

2017-01-01

The causes of posterior uveitis can be divided into infectious, autoimmune, or masquerade syndromes. Viral infections, a significant cause of sight-threatening ocular diseases in the posterior segment, include human herpesviruses, measles, rubella, and arboviruses such as dengue, West Nile, and chikungunya virus. Viral posterior uveitis may occur as an isolated ocular disease in congenital or acquired infections or as part of a systemic viral illness. Many viruses remain latent in the infected host with a risk of reactivation that depends on various factors, including virulence and host immunity, age, and comorbidities. Although some viral illnesses are self-limiting and have a good visual prognosis, others, such as cytomegalovirus retinitis or acute retinal necrosis, may result in serious complications and profound vision loss. Since some of these infections may respond well to antiviral therapy, it is important to work up all cases of posterior uveitis to rule out an infectious etiology. We review the clinical features, diagnostic tools, treatment regimens, and long-term outcomes for each of these viral posterior uveitides. PMID:28012878

Pattern differences in experimental fevers induced by endotoxin, endogenous pyrogen, and prostaglandins.

PubMed

Morimoto, A; Nakamori, T; Watanabe, T; Ono, T; Murakami, N

1988-04-01

To distinguish pattern differences in experimentally induced fevers, we investigated febrile responses induced by intravenous (IV), intracerebroventricular (ICV), and intra-preoptic/anterior hypothalamic (POA) administration of bacterial endotoxin (lipopolysaccharide, LPS), endogenous pyrogen (EP), human recombinant interleukin-1 alpha (IL-1), and prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha). Intravenous LPS, EP, or IL-1 in high concentrations caused biphasic fever. In low concentrations, they induced only the first phase of fever. Latency to onset and time to first peak of fever induced by IV injection of LPS or EP were almost the same as those after ICV or POA injection of PGE2. Fever induced by ICV or POA administration of LPS, EP, IL-1, or PGF2 alpha had a long latency to onset and a prolonged time course. There were significant differences among the latencies to fever onset exhibited by groups that received ICV or POA injections of LPS, EP, or PGF2 alpha and by groups given IV injections of LPS or EP and ICV or POA injections of PGE2. Present observations indicate different patterns of fever produced by several kinds of pyrogens when given by various routes. These results permit us to consider the possibility that there are several mediators or multiprocesses underlying the pathogenesis of fever.

Endotoxins in cotton: washing effects and size distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olenchock, S.A.; Mull, J.C.; Jones, W.G.

1983-01-01

Endotoxin contamination was measured in washed and unwashed cottons from three distinct growing areas, California, Mississippi, and Texas. The data show differences in endotoxin contamination based upon the geographic source of the cotton. It is also shown that washing bulk cotton before the carding process results in lower endotoxin in the cotton dust. Washing conditions can affect the endotoxin levels, and all size fractions of the airborne dust contain quantifiable endotoxin contamination. Endotoxin analyses provide a simple and reliable method for monitoring the cleanliness of cotton or airborne cotton dusts.

Clinical characteristics, treatment and ocular complications of HLA-B27-related anterior uveitis and HLA-B27-non related anterior uveitis.

PubMed

Valls Pascual, Elia; Fontanilla Ortega, Pablo; Vicens Bernabeu, Elvira; Martínez-Costa, Lucía; Blanco Alonso, Ricardo

2016-01-01

Anterior uveitis is the most common type of intraocular inflammation. Those associated to HLA-B27 represent 18 to 32% of all anterior uveitis cases. To describe clinical characteristics, systemic treatment need, and frequency and type of ocular complications in a cohort of patients diagnosed with HLAB27-related anterior uveitis and in a cohort of patients diagnosed with HLA-B27 non-related anterior uveitis. To establish if statistically significant differences between both cohorts exist. We performed a retrospective cohort study including patients with non infectious anterior uveitis related and not related to the antigen HLA-B27. 162 patients were included, 58 diagnosed with HLA-B27-related anterior uveitis (cohort HLA-B27+1) and 104 diagnosed with HLA-B27- non related anterior uveitis (cohort HLA-B27-). No statistically significant differences were found regarding clinical characteristics between both cohorts with the exception of a higher frequency of recurrences in cohort HLA-B27+ and a higher frequency of chronic uveitis in cohort HLA-B27-. No differences were found regarding systemic treatment use nor development of ocular complications. In contrast to previous studies, we neither found higher male gender predominance in the cohort of patients with HLA-B27-related anterior uveitis, Nor did we find differences regarding average age, laterality, development of complications nor use of systemic corticosteroids. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Diet-induced obesity attenuates endotoxin-induced cognitive deficits.

PubMed

Setti, Sharay E; Littlefield, Alyssa M; Johnson, Samantha W; Kohman, Rachel A

2015-03-15

Activation of the immune system can impair cognitive function, particularly on hippocampus dependent tasks. Several factors such as normal aging and prenatal experiences can modify the severity of these cognitive deficits. One additional factor that may modulate the behavioral response to immune activation is obesity. Prior work has shown that obesity alters the activity of the immune system. Whether diet-induced obesity (DIO) influences the cognitive deficits associated with inflammation is currently unknown. The present study explored whether DIO alters the behavioral response to the bacterial endotoxin, lipopolysaccharide (LPS). Female C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for a total of five months. After consuming their respective diets for four months, mice received an LPS or saline injection and were assessed for alterations in spatial learning. One month later, mice received a second injection of LPS or saline and tissue samples were collected to assess the inflammatory response within the periphery and central nervous system. Results showed that LPS administration impaired spatial learning in the control diet mice, but had no effect in DIO mice. This lack of a cognitive deficit in the DIO female mice is likely due to a blunted inflammatory response within the brain. While cytokine production within the periphery (i.e., plasma, adipose, and spleen) was similar between the DIO and control mice, the DIO mice failed to show an increase in IL-6 and CD74 in the brain following LPS administration. Collectively, these data indicate that DIO can reduce aspects of the neuroinflammatory response as well as blunt the behavioral reaction to an immune challenge. Copyright © 2014 Elsevier Inc. All rights reserved.

Measurement of endotoxin.

PubMed

Phillips, J; Harrison, P; Hale, G

2000-01-01

Bacterial endotoxin is probably the most common significant contaminant that might be found in antibody preparations. It is found ubiquitously in normal environments but its pyrogenic effects in vivo can be lethal. It is absolutely vital to control the level of endotoxin in therapeutic products, but its significance for experimental work must not be underestimated since it can have numerous confounding effects both in vivo and in vitro. Methods for removing endotoxin from products have been described (1-4), but in our experience, it is much better to avoid it from the beginning by scrupulous control of raw materials and use of good aseptic technique. To grow, bacteria need water; therefore, the most likely sources of endotoxin are water and any process equipment that has been wet. Water must be obtained from a controlled source that is low in endotoxin. If you do not have a suitable dedicated water purification system, then it is best to purchase purified water. Water for irrigation (from a pharmaceutical supplier) is possibly the most economic. Equipment in contact with cells or products should preferably be sterile disposable plastic. Standard tissue culture ware is usually very reliable. Plastic bags for media and process intermediates are now widely available in all sizes (e.g., Stedim, Aubagne, France) and should be used in preference to glass bottles. Silicone tubing (food or medical grade) is suitable for all fluid transfers and should not be reused. If reusable equipment is essential, it can be soaked in 0.5 M NaOH and/or baked in an oven at high temperature (steam sterilization is not sufficient) (1).

Choline or CDP-choline alters serum lipid responses to endotoxin in dogs and rats: involvement of the peripheral nicotinic acetylcholine receptors.

PubMed

Ilcol, Yesim Ozarda; Yilmaz, Zeki; Cansev, Mehmet; Ulus, Ismail H

2009-09-01

We showed previously that choline administration protects dogs from endotoxin-induced multiple organ injury and platelet dysfunctions. Because sepsis/endotoxemia is associated with alterations in lipid metabolism, we have investigated whether choline or cytidine-5'-diphosphate choline, a choline donor, alters serum lipid responses to endotoxin in dogs and rats. In response to endotoxin, serum concentrations of triglycerides, choline-containing phospholipids, total cholesterol, and high-density lipoprotein cholesterol increased in a dose- and time-related manner. Administration of choline (20 mg/kg i.v. in dogs or 90 mg/kg i.p. in rats) or cytidine-5'-diphosphate choline (70 mg/kg i.v. in dogs) 5 min before and 4 and 8 h after endotoxin blocked or attenuated the increases in serum triglycerides, total cholesterol, and nonesterified fatty acids. Endotoxin-induced elevations in serum phospholipid levels did not change in rats and were enhanced in dogs by choline. In rats, serum lipid response to endotoxin was accompanied by severalfold elevations in serum levels of hepatorenal injury markers; their elevations were also blocked by choline. Pretreatment with hexamethonium blocked choline's effects on serum lipids and hepatorenal injury markers. Pretreatment with atropine blocked endotoxin-induced elevations in serum lipid and hepatorenal injury markers, but failed to alter choline's actions on these parameters. Choline treatment improved survival rate of rats in lethal endotoxin shock. In conclusion, these data show that choline treatment alters serum lipid responses to endotoxin and prevents hepatorenal injury during endotoxemia through a nicotinic acetylcholine receptor-mediated mechanism. Hence, choline and choline-containing compounds may have a therapeutic potential in the treatment of endotoxemia/sepsis.

The Manchester Uveitis Clinic: the first 3000 patients--epidemiology and casemix.

PubMed

Jones, Nicholas P

2015-04-01

To demonstrate the demography, anatomical, and diagnostic classification of patients with uveitis attending the Manchester Uveitis Clinic (MUC), a specialist uveitis clinic in the northwest of England, UK. Retrospective retrieval of data on a computerized database incorporating all new referrals to MUC from 1991 to 2013. A total of 3000 new patients with uveitis were seen during a 22-year period. The anatomical types seen were anterior 46%; intermediate 11.1%; posterior 21.8%; and panuveitis 21.1%. The most common diagnoses were Fuchs heterochromic uveitis (11.5% of total), sarcoidosis-related uveitis (9.7%), idiopathic intermediate uveitis (7.9%), idiopathic acute anterior uveitis (7.0%), and toxoplasmosis (6.9%). Syphilis and tuberculosis-associated uveitis increased markedly in frequency during the study period. The uveitis casemix in this region reflects a predominantly white Caucasian population in a temperate country, but with changing characteristics owing to increasing immigration, enhanced diagnostic techniques, changes in referral pattern, and some real changes in disease incidence.

Equine recurrent uveitis: classification, etiology, and pathogenesis.

PubMed

Curling, Amanda

2011-06-01

Equine recurrent uveitis is a cyclical disease that affects the eye and often leads to high management costs and unfavorable results, such as blindness. Research has improved understanding of the roles of various etiologies, especially leptospirosis, in initiating and perpetuating the pathogenesis of equine recurrent uveitis. Research has also led to the discovery that specific breeds and horses with specific coat color patterns may be predisposed to developing recurrent uveitis.

Polymorphisms of endotoxin pathway and endotoxin exposure: in vitro IgE synthesis and replication in a birth cohort.

PubMed

Sahiner, U M; Semic-Jusufagic, A; Curtin, J A; Birben, E; Belgrave, D; Sackesen, C; Simpson, A; Yavuz, T S; Akdis, C A; Custovic, A; Kalayci, O

2014-12-01

Genetic variants in endotoxin signaling pathway are important in modulating the effect of environmental endotoxin on asthma and atopic phenotypes. Our objective was to determine the single nucleotide polymorphisms (SNPs) in the endotoxin signaling pathway that may influence in vitro IgE synthesis and to investigate the relationship between these variants and endotoxin exposure in relation to the development of asthma and atopy in a birth cohort. Peripheral blood mononuclear cells from 45 children with asthma were stimulated with 2 and 200 ng/ml lipopolysaccharide in vitro and IgE was measured in the culture supernatants. Children were genotyped for 121 SNPs from 30 genes in the endotoxin signaling pathway. Variants with a dose-response IgE production in relation to lipopolysaccharide (LPS) were selected for replication in a population-based birth cohort, in which we investigated the interaction between these SNPs and endotoxin exposure in relation to airway hyper-responsiveness, wheeze, and atopic sensitization. Twenty-one SNPs in nine genes (CD14, TLR4, IRF3, TRAF-6, TIRAP, TRIF, IKK-1, ST-2, SOCS1) were found to modulate the effect of endotoxin on in vitro IgE synthesis, with six displaying high linkage disequilibrium. Of the remaining 15 SNPs, for seven we found significant relationships between genotype and endotoxin exposure in the genetic association study in relation to symptomatic airway hyper-responsiveness (CD14-rs2915863 and rs2569191, TRIF-rs4807000), current wheeze (ST-2-rs17639215, IKK-1-rs2230804, and TRIF-rs4807000), and atopy (CD14-rs2915863 and rs2569192, TRAF-6-rs5030411, and IKK-1-rs2230804). Variants in the endotoxin signaling pathway are important determinants of asthma and atopy. The genotype effect is a function of the environmental endotoxin exposure. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The role of methotrexate in resolving ocular inflammation after specific therapy for presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis.

PubMed

Sahin, Ozlem; Ziaei, Alireza

2014-07-01

This study was designed to investigate whether the antiinflammatory and antiproliferative activity of oral and intravitreal methotrexate (MTX) suppresses intraocular inflammation in patients with presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis. Interventional prospective study including three cases with presumed latent syphilitic uveitis treated with intravenous penicillin and oral MTX, and two cases with presumed tuberculosis-related uveitis treated with standard antituberculosis therapy and intravitreal MTX injections. Treatment efficacy of all cases was assessed by best-corrected visual acuity, fundus fluorescein angiography, and optical coherence tomography. Four eyes of 3 patients with presumed latent syphilitic uveitis had improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema in 6 months with oral MTX therapy. No recurrence of intraocular inflammation was observed in 6 months to 18 months of follow-up period after cessation of MTX. Two eyes of two patients with presumed tuberculosis-related uveitis showed improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema after intravitreal injections of MTX. No recurrence of intraocular inflammation was observed in 6 months to 8 months of follow-up period after cessation of antituberculous therapy. For the first time in the treatment of presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis, we believe that MTX might have an adjunctive role to suppress intraocular inflammation, reduce uveitic macular edema, and prevent the recurrences of the diseases.

SUBCHRONIC ENDOTOXIN INHALATION CAUSES PERSISTENT AIRWAY DISEASE

EPA Science Inventory

ABSTRACT

The endotoxin component of organic dusts causes acute reversible airflow obstruction and airway inflammation. To test the hypothesis that endotoxin alone causes airway remodeling, we have compared the response of two inbred mouse strains to subchronic endotoxin ...

In vitro effects of calcium hydroxide and polymyxin B on endotoxins in root canals.

PubMed

Oliveira, L D; Leão, M V P; Carvalho, C A T; Camargo, C H R; Valera, M C; Jorge, A O C; Unterkircher, C S

2005-02-01

To evaluate the effects of intracanal medicaments on endotoxins in root canals. Seventy-five freshly extracted maxillary incisors were used in this study. The crowns of teeth were sectioned near the CEJ in order to standardize the root length to 14 mm. The root canals were instrumented to an apical size #50 file and irrigated with 1% sodium hypochlorite solution and sterilized with 60Co gamma irradiation. Standardized suspension containing Escherichia coli endotoxin was inoculated into the 60 root canals. The specimens were randomly assigned to 5 groups (n=15), according to the intracanal medicament used: (G1) calcium hydroxide; (G2) polymyxin B; (G3) combination neomycin-polymyxin B-hydrocortisone; (G4) positive control (no intracanal medicament); (G5) negative control (no endotoxin and no intracanal medicament). After 7 days, the detoxification of endotoxin was evaluated by Limulus lysate assay and antibody production in B-lymphocytes culture. Groups 1, 2 and 5 presented the best results by Limulus lysate and were significantly different to groups 3 and 4 (p<0.05). Stimulation of antibodies production in cell culture by groups 1 and 6 was smaller and statistically different than groups 2, 3, 4 and 5 (p<0.05). Groups 2 and 5 induced a small increase in the antibodies production in relation to the groups 1 and 6. Groups 3 and 4 induced a significant increase of antibodies production (p<0.05). The calcium hydroxide and polymyxin B intracanal medicaments detoxified endotoxin in root canals and altered the properties of LPS to stimulate the antibody production by B-lymphocytes. The combination neomycin-polymyxin B-hydrocortisone did not detoxified endotoxin.

Remission of Intermediate Uveitis: Incidence and Predictive Factors.

PubMed

Kempen, John H; Gewaily, Dina Y; Newcomb, Craig W; Liesegang, Teresa L; Kaçmaz, R Oktay; Levy-Clarke, Grace A; Nussenblatt, Robert B; Rosenbaum, James T; Sen, H Nida; Suhler, Eric B; Thorne, Jennifer E; Foster, C Stephen; Jabs, Douglas A; Payal, Abhishek; Fitzgerald, Tonetta D

2016-04-01

To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. Retrospective cohort study. Involved eyes of patients with primary noninfectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at ≥2 visits spanning ≥90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval [CI], 7.4-10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (hazard ratio [HR] [vs no PPV] = 2.39; 95% CI, 1.42-4.00), diagnosis of intermediate uveitis within the last year (HR [vs diagnosis >5 years ago] =3.82; 95% CI, 1.91-7.63), age ≥45 years (HR [vs age <45 years] = 1.79; 95% CI, 1.03-3.11), female sex (HR = 1.61; 95% CI, 1.04-2.49), and Hispanic race/ethnicity (HR [vs white race] = 2.81; 95% CI, 1.23-6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status were not associated with differential incidence. Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed patients and older, female, and Hispanic patients were more likely to remit. With regard to management, pars plana vitrectomy was associated with increased probability of remission. Copyright © 2016 Elsevier Inc. All rights reserved.

Remission of Intermediate Uveitis: Incidence and Predictive Factors

PubMed Central

Kempen, John H.; Gewaily, Dina Y.; Newcomb, Craig W.; Liesegang, Teresa L.; Kaçmaz, R. Oktay; Levy-Clarke, Grace A.; Nussenblatt, Robert B.; Rosenbaum, James T.; Sen, H. Nida; Suhler, Eric B.; Thorne, Jennifer E.; Foster, C. Stephen; Jabs, Douglas A.; Payal, Abhishek; Fitzgerald, Tonetta D.

2016-01-01

Purpose To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. Design Retrospective cohort study. Methods Involved eyes of patients with primary non-infectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at ≥2 visits spanning ≥90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. Results Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1,934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval (CI), 7.4–10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (HR (vs. no PPV)=2.39; 95% CI, 1.42–4.00), diagnosis of intermediate uveitis within the last year (vs. diagnosis >5 years ago)=3.82; 95% CI, 1.91–7.63), age ≥45 years (HR (vs. age <45 years)=1.79; 95% CI, 1.03–3.11), female sex (HR=1.61; 95% CI, 1.04–2.49), and Hispanic race/ethnicity (HR (vs. white race)=2.81; 95% CI, 1.23–6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status were not associated with differential incidence. Conclusions Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed cases, and older, female and Hispanic cases were more likely to remit. With regards to management, pars plana vitrectomy was associated with increased probability of remission. PMID:26772874

Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats

PubMed Central

Shih, Chih-Chin; Hii, Hiong-Ping; Tsao, Cheng-Ming; Chen, Shiu-Jen; Ka, Shuk-Man; Liao, Mei-Hui; Wu, Chin-Chen

2016-01-01

Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis. PMID:26918767

Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats.

PubMed

Shih, Chih-Chin; Hii, Hiong-Ping; Tsao, Cheng-Ming; Chen, Shiu-Jen; Ka, Shuk-Man; Liao, Mei-Hui; Wu, Chin-Chen

2016-01-01

Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.

Adalimumab for the treatment of refractory noninfectious paediatric uveitis.

PubMed

Muñoz-Gallego, Alicia; Barral, Estefanía; Enríquez, Eugenia; Tejada, Pilar; Barceló, Ana; de Inocencio, Jaime

2017-06-01

To report the experience of our center with the use of adalimumab (ADA) for the treatment of severe refractory noninfectious paediatric uveitis. The study is a retrospective case series of all paediatric patients with refractory uveitis who were treated with ADA at the Paediatric Uveitis Unit of our center from 2008 to 2015. We present 12 patients (6 Juvenile idiopathic arthritis-associated uveitis, 4 idiopathic panuveitis, 1 early-onset sarcoidosis-associated panuveitis, and 1 intermediate uveitis), with uveitis in 19/24 eyes. Once ADA therapy was started, all the patients presented improved activity according to Standardization of Uveitis Nomenclature (SUN) criteria. Nine out of the 12 patients had structural damage before ADA could be started: cataract (n = 4), glaucoma (n = 2), cystic macular edema (n = 1), exudative retinal detachment (n = 1), and optic disk edema (n = 5). Visual acuity improved or maintained stable in 17/19 affected eyes, and only 2 eyes decreased its visual acuity because of structural damage, which was already present before ADA therapy. In our experience, ADA presents a good safety profile and is efficacious in the treatment of paediatric patients with different forms of refractory noninfectious uveitis.

Retinal imaging in uveitis

PubMed Central

Gupta, Vishali; Al-Dhibi, Hassan A.; Arevalo, J. Fernando

2014-01-01

Ancillary investigations are the backbone of uveitis workup for posterior segment inflammations. They help in establishing the differential diagnosis and making certain diagnosis by ruling out certain pathologies and are a useful aid in monitoring response to therapy during follow-up. These investigations include fundus photography including ultra wide field angiography, fundus autofluorescence imaging, fluorescein angiography, optical coherence tomography and multimodal imaging. This review aims to be an overview describing the role of these retinal investigations for posterior uveitis. PMID:24843301

Profile of adalimumab and its potential in the treatment of uveitis

PubMed Central

Balevic, Stephen J; Rabinovich, C Egla

2016-01-01

Uveitis refers to the presence of intraocular inflammation, and as a strict definition compromises the iris and ciliary body anteriorly and the choroid posteriorly (the uvea). Untreated, uveitis can lead to visual loss or blindness. The etiology of uveitis can include both infectious and noninfectious (usually immune-mediated) causes, the latter of which are often mediated predominantly by Th1 CD4+ T-cells that secrete proinflammatory cytokines. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine involved in the pathogenesis of uveitis, which at high concentrations can cause excess inflammation and tissue damage. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF-α. Historically, corticosteroids and methotrexate were used to treat uveitis; however, newer biologic agents such as adalimumab have revolutionized therapy for noninfectious uveitis. Adalimumab has shown efficacy in treating refractory uveitis in multiple settings, including idiopathic disease, juvenile idiopathic arthritis, sarcoidosis, Behçets disease, and uveitis secondary to spondyloarthropathies, among several other noninfectious uveitis conditions. In this paper, we will review the profile of adalimumab, the role of TNF-α in uveitis, discuss safety data, and summarize key articles evaluating the efficacy of adalimumab in treating uveitis secondary to the most commonly associated autoimmune diseases. PMID:27698552

Profile of adalimumab and its potential in the treatment of uveitis.

PubMed

Balevic, Stephen J; Rabinovich, C Egla

2016-01-01

Uveitis refers to the presence of intraocular inflammation, and as a strict definition compromises the iris and ciliary body anteriorly and the choroid posteriorly (the uvea). Untreated, uveitis can lead to visual loss or blindness. The etiology of uveitis can include both infectious and noninfectious (usually immune-mediated) causes, the latter of which are often mediated predominantly by Th1 CD4 + T-cells that secrete proinflammatory cytokines. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine involved in the pathogenesis of uveitis, which at high concentrations can cause excess inflammation and tissue damage. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF-α. Historically, corticosteroids and methotrexate were used to treat uveitis; however, newer biologic agents such as adalimumab have revolutionized therapy for noninfectious uveitis. Adalimumab has shown efficacy in treating refractory uveitis in multiple settings, including idiopathic disease, juvenile idiopathic arthritis, sarcoidosis, Behçets disease, and uveitis secondary to spondyloarthropathies, among several other noninfectious uveitis conditions. In this paper, we will review the profile of adalimumab, the role of TNF-α in uveitis, discuss safety data, and summarize key articles evaluating the efficacy of adalimumab in treating uveitis secondary to the most commonly associated autoimmune diseases.

Endotoxin content in endodontically involved teeth. 1975.

PubMed

Schein, Benjamin; Schilder, Herbert

2006-04-01

Fluid was aspirated from the root canals of 40 endodontically involved teeth. This fluid was assayed for endotoxin with the limulus lysate test. Pulpless teeth contained greater concentrations of endotoxin than those with vital pulps. Symptomatic teeth also contained more endotoxin than asymptomatic teeth.

Obesity Increases Sensitivity to Endotoxin Liver Injury: Implications for the Pathogenesis of Steatohepatitis

NASA Astrophysics Data System (ADS)

Yang, Shi Qi; Zhi Lin, Hui; Lane, M. Daniel; Clemens, Mark; Diehl, Anna Mae

1997-03-01

Genetically obese fatty/fatty rats and obese/obese mice exhibit increased sensitivity to endotoxin hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS). Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of tumor necrosis factor α (TNFα ), the proven affecter of endotoxin liver injury, is no greater in the livers, white adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury. Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese animals. After exposure to LPS, mRNA of interferon γ , which sensitizes hepatocytes to TNF toxicity, is overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by sensitizing hepatocytes to endotoxin.

Impact of Juvenile Idiopathic Arthritis Associated Uveitis in Early Adulthood

PubMed Central

Vernie, Lenneke A.; Rothova, Aniki; v. d. Doe, Patricia; Los, Leonoor I.; Schalij-Delfos, Nicoline E.; de Boer, Joke H.

2016-01-01

Background Typically juvenile idiopathic arthritis (JIA)-associated uveitis (further referred as ‘JIA-uveitis’) has its onset in childhood, but some patients suffer its, sometimes visual threatening, complications or ongoing disease activity in adulthood. The objective of this study was to analyze uveitis activity, complications and visual prognosis in adulthood. Methods In this multicenter study, 67 adult patients (129 affected eyes) with JIA-uveitis were retrospectively studied for best corrected visual acuity, visual fields, uveitis activity, topical/systemic treatments, ocular complications, and ocular surgeries during their 18th, 22nd and 30th year of life. Because treatment strategies changed after the year 1990, outcomes were stratified for onset of uveitis before and after 1990. Results Sixty-two of all 67 included patients (93%) had bilateral uveitis. During their 18th life year, 4/52 patients (8%) had complete remission, 28/52 (54%) had uveitis activity and 37/51 patients (73%) were on systemic immunomodulatory treatment. Bilateral visual impairment or legal blindness occurred in 2/51 patients (4%); unilateral visual impairment or legal blindness occurred in 17/51 patients (33%) aged 18 years. The visual prognosis appeared to be slightly better for patients with uveitis onset after the year 1990 (for uveitis onset before 1990 (n = 7) four patients (58%) and for uveitis onset after 1990 (n = 44) 13 patients (30%) were either visual impaired or blind). At least one ocular surgery was performed in 10/24 patients (42%) between their 18th and 22nd year of life. Conclusions Bilateral visual outcome in early adulthood in patients with JIA-uveitis appears to be fairly good, although one third of the patients developed one visually impaired or blind eye. However, a fair amount of the patients suffered from ongoing uveitis activity and needed ongoing treatment as well as surgical interventions. Awareness of these findings is important for ophthalmologists and

Are Cockroaches an Important Source of Indoor Endotoxins?

PubMed

Lai, Ka Man

2017-01-18

Endotoxins are common indoor biocontaminants. Their levels have been shown to link to many sources and factors. One of them is cockroach infestation but the role of cockroaches and contamination mechanisms are unclear. We hypothesized that not only is cockroach infestation a sign of poor hygiene, but it also contributes to indoor endotoxins via fecal contamination. In this study, different cockroach species were caught in homes. The endotoxin and allergen levels and their ratios in cockroach feces were determined. To estimate the amount of indoor endotoxins that originated from cockroaches, a new approach of using these new cockroach endotoxin and allergen ratios to compare with environmental data was employed. We found that Supella (S.) longipalpa , Periplaneta (P.) australasiae , and Blattella (B.) germanica were dominant in homes. On average, P. australasiae feces had a higher level but greater variation of endotoxins. B. germanica feces had the highest levels of allergens measured. Depending on environmental bacterial load and the type of cockroaches present, cockroach endotoxins in the environment may vary greatly. Cockroaches directly contribute to indoor endotoxins rather than just being a sign of poor hygiene. The type and extent of cockroach infestation should be taken into consideration when assessing and remediating indoor endotoxin contamination.

Are Cockroaches an Important Source of Indoor Endotoxins?

PubMed Central

Lai, Ka Man

2017-01-01

Endotoxins are common indoor biocontaminants. Their levels have been shown to link to many sources and factors. One of them is cockroach infestation but the role of cockroaches and contamination mechanisms are unclear. We hypothesized that not only is cockroach infestation a sign of poor hygiene, but it also contributes to indoor endotoxins via fecal contamination. In this study, different cockroach species were caught in homes. The endotoxin and allergen levels and their ratios in cockroach feces were determined. To estimate the amount of indoor endotoxins that originated from cockroaches, a new approach of using these new cockroach endotoxin and allergen ratios to compare with environmental data was employed. We found that Supella (S.) longipalpa, Periplaneta (P.) australasiae, and Blattella (B.) germanica were dominant in homes. On average, P. australasiae feces had a higher level but greater variation of endotoxins. B. germanica feces had the highest levels of allergens measured. Depending on environmental bacterial load and the type of cockroaches present, cockroach endotoxins in the environment may vary greatly. Cockroaches directly contribute to indoor endotoxins rather than just being a sign of poor hygiene. The type and extent of cockroach infestation should be taken into consideration when assessing and remediating indoor endotoxin contamination. PMID:28106812

Incidence and risk factors for chronic uveitis following cataract surgery.

PubMed

Patel, Chirag; Kim, Stephen Jae; Chomsky, Amy; Saboori, Mazeyar

2013-04-01

To determine the incidence of and associated risk factors for uveitis after cataract surgery. A total of 17,757 eyes were identified and records of 42 eyes that developed uveitis and 2320 eyes that did not were reviewed. Postsurgical uveitis was defined as persistent inflammation for ≥ 6 months after surgery. Forty-two eyes of 35 patients developed uveitis (0.24%). Eleven patients underwent consecutive cataract surgery but developed unilateral uveitis, and intraoperative complications occurred in 55% of uveitic eyes compared to 0% in fellow eyes (p < 0.05). Median duration of inflammation was 8 and 11.5 months in eyes with and without vitrectomy (p < 0.05). Intraocular complications occurred in 44 and 8.3% of eyes that did and did not develop uveitis, respectively (p = 0.01). Postsurgical uveitis developed after approximately 1 in 400 cataract surgeries and occurred more frequently in eyes experiencing intraoperative complications.

The Use of Biologic Therapies in Uveitis.

PubMed

Schwartzman, Sergio; Schwartzman, Monica

2015-12-01

Therapy for autoimmune ophthalmic disease is currently evolving. The improved understanding of the abnormal immune response in the various forms of uveitis has resulted in targeted therapy. The aberrations of the immune system have been characterized by atypical cell populations, cytokine expression, and cell-cell interactions. Different patterns of cytokine expression have now been delineated in the abnormal uveal tract with exaggerated and/or abnormal expression of TNF, IL-1, IL-2, IL-6, and IL-17. The development of therapies for other conditions in which these cytokines play an important role has resulted in the availability of biological agents that have been adopted for use in the therapy for uveitis. Adalimumab and infliximab have been the best studied anti-TNF agents and indeed have now been recommended by an expert panel as first-line treatment of ocular manifestations of Behçet's disease and second-line treatment for other forms of uveitis (Levy-Clarke et al. (Ophthalmology, 2013). Other anti-TNF agents have been studied as well. Daclizumab, a monoclonal antibody directed against the IL-2 receptor, has also demonstrated utility in treating uveitis as have some of the anti-IL1 agents. Gevokizumab has been granted orphan drug designation for the treatment of resistant forms of uveitis. Therapies affecting IL-6, including tocilizumab are being studied, and available medications that block antigen presenting cell and T cell interaction such as abatacept have been reported to be effective in uveitis. Interferons as well as rituximab have also been evaluated in small studies. Although these biologic therapies have provided a larger armamentarium to treat uveitis, challenges remain. Uveitis is not a single illness; rather, it is a manifestation of many potential systemic diseases that may have very specific individual therapeutic targets. Identifying and characterizing these underlying diseases is not always achieved, and more importantly, the most effective

Endotoxins in urban air in Stockholm, Sweden

NASA Astrophysics Data System (ADS)

Nilsson, S.; Merritt, A. S.; Bellander, T.

2011-01-01

Endotoxins, i.e. components originating from the outer membrane in the cell wall of Gram-negative bacteria, activate the human immune system, which may result in airway symptoms such as shortness of breath and airway inflammation. Endotoxins are present in the environment, both outdoors and indoors, and stay airborne for a long time. In order to investigate the levels of endotoxins in urban air and the influence of traffic and meteorological factors, particles (PM 10 and PM 2.5) were collected at five sites in Stockholm, Sweden on four occasions per site between May and September 2009. Endotoxins were extracted from the filters and analysis was conducted with the Limulus Amebocyte Lysate (LAL)-assay. Endotoxins were present in urban air in Stockholm, albeit in low levels, and were similar to levels found in urban areas outside Sweden. To our knowledge, this is the northernmost location where endotoxins have been measured. The endotoxin levels found in PM 10 ranged from 0.020 to 0.107 EU m -3 with a geometric mean of 0.050 EU m -3 and the levels found in PM 2.5 ranged from 0.005 to 0.064 EU m -3 with a geometric mean of 0.015 EU m -3. No obvious effects of traffic or meteorological factors on endotoxin levels were observed, although a moderate correlation could be seen with soot. The small number of sampling sites is however a shortcoming of the present study. In future studies, more sites and sampling during all seasons would be preferable in order to get a better picture of the influence of different sources on endotoxin levels.

Detecting endotoxin with a flow cytometry-based magnetic aptasensor.

PubMed

Zuo, Ming-Yan; Chen, Li-Juan; Jiang, Hao; Tan, Lin; Luo, Zhao-Feng; Wang, Yan-Mei

2014-12-01

Endotoxin, which is also known as lipopolysaccharide (LPS), is a marker for intruding gram-negative pathogens. It is essential to detect endotoxin quickly and sensitively in a complex milieu. A new flow cytometry (FCM)-based magnetic aptasensor assay that employs two endotoxin-binding aptamers and magnetic beads has been developed to detect endotoxin. The endotoxin-conjugated sandwich complex on magnetic beads was observed by scanning confocal laser microscopy. The resulting magnetic aptasensor rapidly detected (<1 min) endotoxin within a broad dynamic detection range of 10(-8) to 10(0)mg/ml in the presence of bovine serum albumin (BSA), RNA, sucrose, and glucose, which are most likely to coexist with endotoxin in the majority of biological liquids. Only 2 μl of magnetic aptasensor was required to quantify the endotoxin solution. Furthermore, the magnetic aptasensor could be regenerated seven times and still presented an outstanding response to the endotoxin solution. Therefore, the magnetic aptasensor exhibited high sensitivity, selectivity, and reproducibility, thereby serving as a powerful tool for the quality control and high-throughput detection of endotoxin in the food and pharmaceutical industries. Copyright © 2014 Elsevier Inc. All rights reserved.

HLA-B27 Anterior Uveitis: Immunology and Immunopathology.

PubMed

Wakefield, Denis; Yates, William; Amjadi, Shahriar; McCluskey, Peter

2016-08-01

Acute anterior uveitis (AAU) is the commonest type of uveitis and HLA-B27 AAU is the most frequently recognized type of acute anterior uveitis and anterior uveitis overall. Recent evidence indicates that acute anterior uveitis is a heterogenous disease, is polygenic and is frequently associated with the spondyloarthropathies (SpA). Studies of patients with AAU and animal models of disease indicate a role for innate immunity, the IL-23 cytokine pathway and exogenous factors, in the pathogenesis of both SpA and acute anterior uveitis. Recently described genetic associations cluster around immunologic pathways, including the IL-17 and IL-23 pathways, antigen processing and presentation, and lymphocyte development and activation. Patients with ankylosing spondylitis (AS) and AAU share other genetic markers, such as ERAP-1, which show strong evidence of gene-gene interaction and point to new mechanisms of disease pathogenesis. These observations have major implications for understanding the pathogenesis of HLA-B27 diseases, such as AAU, and may lead to the development of more specific therapy for AAU. Received 6 January 2016; revised 6 February 2016; accepted 18 February 2016; published online 31 May 2016.

Pigment dispersion syndrome masquerading as acute anterior uveitis.

PubMed

Gonzalez-Gonzalez, Luis Alonso; Rodríguez-García, Alejandro; Foster, C Stephen

2011-06-01

Signs and symptoms of pigment dispersion may be confused with those of acute anterior uveitis. This case series is intended to aid the ophthalmologist in the clinical differentiation between these two disorders. The authors present a series of 6 patients with pigment dispersion who were initially diagnosed as having acute anterior uveitis and treated with anti-inflammatory medication, including corticosteroids. The patients were referred for a second opinion due to poor or no response to therapy and were found to have pigment dispersion instead of uveitis. Symptoms of pigment dispersion may consist of blurred vision, redness, ocular pain, and photophobia, all of which are also symptoms of acute anterior uveitis. These symptoms, plus the fact that pigment floating in the aqueous humor can be mistaken for inflammation, make diagnosis challenging. Moreover, the possible co-existence of true anterior uveitis and pigment dispersion makes the diagnosis and treatment more difficult.

Esculin attenuates endotoxin shock induced by lipopolysaccharide in mouse and NO production in vitro through inhibition of NF-κB activation.

PubMed

Li, Weifeng; Wang, Yu; Wang, Xiumei; He, Zehong; Liu, Fang; Zhi, Wenbing; Zhang, Hailin; Niu, Xiaofeng

2016-11-15

Esculin, a coumarin compound derived from the traditional Chinese herbs such as Cortex Fraxini, has long been used for treating inflammatory and vascular diseases. In present study, we analyzed the role of esculin against macrophages and endotoxin shock induced by lipopolysaccharide (LPS) in mice. Here, we demonstrated that esculin suppressed inflammatory reactions in macrophages and protected mice from LPS-induced endotoxin shock. We found that esculin significantly inhibited the production of nitric oxide (NO) production via the inhibition of nuclear factor-κB (NF-κB) activation in macrophages. In animal model, esculin pretreatment significantly improved the survival rate of mice. LPS-induced increase of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in serum, lung, liver and kidney were markedly inhibited by esculin. IL-10, an anti-inflammatory cytokine, was up-regulated by esculin. Moreover, the histopathological analyses showed that esculin significantly attenuated the tissues injury of lung, liver, kidney in endotoxic mice. In addition, esculin significantly diminished the protein expression of NF-κB p65 in lung, liver, kidney, which resulted in lower levels of inflammatory mediators. These results suggest that esculin may be a potential drug for treatment of various inflammatory diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-TNF therapy for juvenile idiopathic arthritis-related uveitis

PubMed Central

Semeraro, Francesco; Arcidiacono, Barbara; Nascimbeni, Giuseppe; Angi, Martina; Parolini, Barbara; Costagliola, Ciro

2014-01-01

Juvenile idiopathic arthritis-related uveitis is the most common type of uveitis in childhood and one of the main causes of visual impairment in children. The introduction of biological treatment has widened the range of therapeutic options for children with uveitis refractory to standard nonbiologic immunosuppressants. Data from clinical trials suggest that both adalimumab and infliximab have demonstrated effectiveness and safety in open-label studies, although no large, randomized, controlled trials have been reported so far. The role of etanercept in treating juvenile idiopathic arthritis-related uveitis is not yet well defined. In our experience, anti-tumor necrosis factor therapy has been shown to be more effective than steroids and/or methotrexate in treating uveitis. Up to now, tumor necrosis factor blocking compounds have been reserved for the treatment of the most severe cases of refractory uveitis, and larger prospective clinical trials are required in order to better assess the safety of these new compounds. PMID:24711694

Anti-TNF therapy for juvenile idiopathic arthritis-related uveitis.

PubMed

Semeraro, Francesco; Arcidiacono, Barbara; Nascimbeni, Giuseppe; Angi, Martina; Parolini, Barbara; Costagliola, Ciro

2014-01-01

Juvenile idiopathic arthritis-related uveitis is the most common type of uveitis in childhood and one of the main causes of visual impairment in children. The introduction of biological treatment has widened the range of therapeutic options for children with uveitis refractory to standard nonbiologic immunosuppressants. Data from clinical trials suggest that both adalimumab and infliximab have demonstrated effectiveness and safety in open-label studies, although no large, randomized, controlled trials have been reported so far. The role of etanercept in treating juvenile idiopathic arthritis-related uveitis is not yet well defined. In our experience, anti-tumor necrosis factor therapy has been shown to be more effective than steroids and/or methotrexate in treating uveitis. Up to now, tumor necrosis factor blocking compounds have been reserved for the treatment of the most severe cases of refractory uveitis, and larger prospective clinical trials are required in order to better assess the safety of these new compounds.

Platelet-Activating Factor (PAF) Receptor Antagonism Modulates Inflammatory Signaling in Experimental Uveitis.

PubMed

Elison, Jasmine R; Weinstein, Jessica E; Sheets, Kristopher G; Regan, Cornelius E; Lentz, Jennifer J; Reinoso, Maria; Gordon, William C; Bazan, Nicolas G

2018-04-11

The phospholipid mediator platelet-activating factor (PAF) activates an inflammatory response that includes arachidonic acid release and prostaglandin production in the eye, increasing vascular permeability and inflammation. The purpose of this study is to investigate the action of LAU-0901, a novel PAF receptor antagonist, on experimental uveitis. Uveitis was induced in Lewis rats by lipopolysaccharide treatment. LAU-0901 was then delivered systemically in different concentrations at plus 4 and 16 hours, or vehicle injected as controls. Additional animals were used for histological analyses of untreated, uveitis, and uveitis-plus-LAU-0901 retinas. Conventional histological and immunohistochemical methods were employed. A slit lamp and Spectral Domain-Ocular Coherence Tomography (SD-OCT) retinal imager was used for anterior segment photography and posterior pole OCT. Rats were euthanized 4 hours after the second LAU-0901 injection in this 24-hour model. Aqueous humor was collected and quantified, and also analyzed for tumor necrosis factor alpha (TNF-α). Uveitic eyes demonstrated hypopyon formation, leukocyte infiltration, and an increase in aqueous protein and TNF-α levels. LAU-0901 treatment resulted in a dose-dependent reduction in inflammation, reflected by reduced total protein levels (up to a 64% reduction). Moreover, hypopyon was prevented, leukocytes were absent in vitreous and aqueous humor, and TNF-α levels were reduced by 91%. The PAF receptor antagonist LAU-0901 decreases ocular inflammation in a rat model of anterior uveitis in a dose-dependent manner, suggesting that use of this molecule may provide a means to attenuate inflammation onset and offer a future alternative or adjunctive treatment for ocular inflammation.

Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects.

PubMed

Lira, Fabio S; Rosa, Jose C; Pimentel, Gustavo D; Souza, Hélio A; Caperuto, Erico C; Carnevali, Luiz C; Seelaender, Marília; Damaso, Ana R; Oyama, Lila M; de Mello, Marco T; Santos, Ronaldo V

2010-08-04

A sedentary lifestyle increases the risk of developing cardiovascular disease, obesity, and diabetes. This phenomenon is supported by recent studies suggesting a chronic, low-grade inflammation status. Endotoxin derived from gut flora may be key to the development of inflammation by stimulating the secretion of inflammatory factors. This study aimed to examine plasma inflammatory markers and endotoxin levels in individuals with a sedentary lifestyle and/or in highly trained subjects at rest. Fourteen male subjects (sedentary lifestyle n = 7; highly trained subjects n = 7) were recruited. Blood samples were collected after an overnight fast (approximately 12 h). The plasmatic endotoxin, plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 (MCP1), ICAM/CD54, VCAM/CD106 and lipid profile levels were determined. Endotoxinemia was lower in the highly trained subject group relative to the sedentary subjects (p < 0.002). In addition, we observed a positive correlation between endotoxin and PAI-1 (r = 0.85, p < 0.0001), endotoxin and total cholesterol (r = 0.65; p < 0.01), endotoxin and LDL-c (r = 0.55; p < 0.049) and endotoxin and TG levels (r = 0.90; p < 0.0001). The plasma levels of MCP-1, ICAM/CD54 and VCAM/CD106 did not differ. These results indicate that a lifestyle associated with high-intensity and high-volume exercise induces favorable changes in chronic low-grade inflammation markers and may reduce the risk for diseases such as obesity, diabetes and cardiovascular diseases.

IL-6 blockade in the management of non-infectious uveitis.

PubMed

Lopalco, Giuseppe; Fabiani, Claudia; Sota, Jurgen; Lucherini, Orso Maria; Tosi, Gian Marco; Frediani, Bruno; Iannone, Florenzo; Galeazzi, Mauro; Franceschini, Rossella; Rigante, Donato; Cantarini, Luca

2017-07-01

Several pathogenetic studies have paved the way for a newer more rational therapeutic approach to non-infectious uveitis, and treatment of different forms of immune-driven uveitis has drastically evolved in recent years after the advent of biotechnological drugs. Tumor necrosis factor-α targeted therapies, the first-line recommended biologics in uveitis, have certainly led to remarkable results in patients with non-infectious uveitis. Nevertheless, the decision-making process turns out to be extremely difficult in anti-tumor necrosis factor or multidrug-resistant cases. Interleukin (IL)-6 holds a critical role in the pathogenic pathways of uveitis, due to its extended and protean range of effects. On this background, manipulation of IL-6 inflammatory cascade has unraveled encouraging outcomes. For instance, rising evidence has been achieved regarding the successful use of tocilizumab, the humanized monoclonal antibody targeted against the IL-6 receptor, in treating uveitis related to juvenile idiopathic arthritis or Behçet's disease. Similar findings have also been reported for uveitis associated with systemic disorders, such as rheumatoid arthritis or multicentric Castleman disease, but also for idiopathic uveitis, the rare birdshot chorioretinopathy, and even in cases complicated by macular edema. This work provides a digest of all current experiences and evidences concerning IL-6 blockade, as suggested by the medical literature, proving its potential role in the management of non-infectious uveitis.

The Eyes Have It: A Rheumatologist's View of Uveitis.

PubMed

Rosenbaum, James T; Dick, Andrew D

2018-05-23

Uveitis is defined as intraocular inflammation. It is an extra-articular manifestation of many forms of joint disease which include spondyloarthritis, juvenile idiopathic arthritis, and Behcet's disease. Rheumatologists may be asked to consult on patients with uveitis in order to identify an associated systemic illness. Diagnoses such as spndyloarthritis, sarcoidosis, and interstitial nephritis with uveitis are frequently overlooked by referring ophthalmologists. Alternatively rheumatologists may be asked to help manage the immunosuppression including biologics which can be required to treat a subset of patients with uveitis. This review is written to provide rheumatologists with the necessary information to facilitate collaboration in co-managing patients with uveitis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Prevalence of Toxoplasma gondii and Toxocara canis among patients with uveitis.

PubMed

Lim, Su Jin; Lee, Sang Eun; Kim, Sun Hyun; Hong, Sung-Hee; You, Yong Sung; Kwon, Oh Woong; Kim, Hyeun Seung

2014-10-01

To investigate the prevalence of Toxoplasma gondii and Toxocara canis in patients with uveitis. Patients with uveitis were examined. Serum antibodies to T. gondii and T. canis were tested by using enzyme-linked immunosorbent assay (ELISA). Polymerase chain reaction (PCR) was done using blood and aqueous humor (AH). 98 patients were enrolled. Mean age was 43.5 ± 13.2 years. Six patients were seropositive for T. gondii with the following pattern-anterior uveitis: 1; posterior uveitis with retinitis: 2; pan uveitis: 2. One patient had a positive result of PCR for T.gondii in AH, who showed pan uveitis. 23 patients were positive to serum IgG for T. canis with the following clinical manifestation-granuloma: 6; pigmented scar: 3; virtrits: 6-but none were PCR positive. T.gondii and T.canis are still one of the important causes of uveitis. Ocular toxocariasis is not an uncommon cause of uveitis even in adult.

Airborne endotoxin in woodworking (joinery) shops.

PubMed

Harper, Martin; Andrew, Michael E

2006-01-01

Symptoms such as shortness of breath and cough have been noted in woodworking facilities even where wood dust itself is well-controlled. Suspicion has fallen on other possible contaminants in the workplace atmosphere, including bacterial endotoxin. A few studies have indicated potentially high endotoxin exposure with exposure to fresh wood in sawmills and in the production of fiberboard and chipboard, but fewer studies have been carried out on exposure to endotoxin in dry wood work, for example in joineries. A study of the endotoxin content of airborne wood dust samples from US woodworking facilities is presented, from the re-analysis of samples which previously had been taken to establish mass collection relationships between the IOM sampler, the closed-face 37 mm plastic cassette (CFC) sampler and the Button sampler. Endotoxin was strongly correlated with total dust, but the endotoxin content of a few fresh wood samples was found to be up to ten times higher per unit of wood dust than for dried-wood samples, and this difference was significant. No long-term time-weighted average sample exceeded the recommended limit value of 50 EU m(-3) (EU, endotoxin units)used in the Netherlands, although a number of the IOM samples came close (seven samples or 44% exceeded 20 EU m(-3)) and one short-term (48 minute) sample registered a high value of 73 EU m(-3). The geometric mean concentration from the IOM samples (11 EU m(-3)) is within the range of geometric means found from Australian joineries (3.7-60, combined: 24 EU m(-3)). In contrast, the corresponding values from the CFC (3.6 EU m(-3)), and the Button sampler (2.1 EU m(-3)) were much lower and no samples exceeded 20 EU m(-3). Endotoxin is likely only to be a significant problem in working with dried woods when associated with very high dust levels, where the wood dust itself is likely to be a cause for concern. The results from the few samples in this study where fresh wood was being worked were similar to results

[Diagnosis of herpetic uveitis and keratouveitis].

PubMed

Schacher, S; Garweg, J G; Russ, C; Böhnke, M

1998-05-01

In epithelial viral keratitis as in viral retinitis, the diagnosis is made on the basis of typical clinical findings. A laboratory confirmation is achieved in over 80% using routine laboratory methods. In contrast, it is almost impossible to confirm the diagnosis of stromal herpetic keratitis in vivo using the currently available laboratory methods. Nothing is known about the situation in cases of viral anterior uveitis. Of 52 patients with granulomatous anterior uveitis, 31 were diagnosed on the basis of clinical findings as active herpetic uveitis (group 1), 14 as active granulomatous uveitis of unknown origin (group 2), and 7 had inactive disease after quietening down of herpetic uveitis (group 3). From all patients, aqueous humor was collected at the time of diagnosis and processed for viral culture, Herpes antigen ELISA, and amplification of viral DNA of HSV-1 and VZV. Viral growth in culture was found in only one case in group 3. In this group, viral antigen or viral DNA were detected in no case. Herpes antigen was found in 5/31 cases (16%) in group 1 and in 1/11 cases (9%) in group 2, and viral DNA was found in 8/31 cases from group 1 (5x HSV-1 and 3x VZV) and in 5/14 cases (31%) from group 2. After combination of antigen detection and DNA amplification, the presence of virus was confirmed in 14/45 cases (29%). Virus culture has not proven useful in the diagnosis of viral anterior segment disease. Despite their high overall sensitivity, neither antigen ELISA nor the amplification of viral DNA proved sensitive enough to establish a viral etiology. Nevertheless, a laboratory confirmation should be attempted in granulomatous uveitis of unknown origin after preclusion of an underlying systemic disease because of the consequences of a diagnosis of viral anterior segment disease for treatment and prognosis.

Effects of Endotoxin and Psychological Stress on Redox Physiology, Immunity and Feather Corticosterone in Greenfinches

PubMed Central

Meitern, Richard; Sild, Elin; Lind, Mari-Ann; Männiste, Marju; Sepp, Tuul; Karu, Ulvi; Hõrak, Peeter

2013-01-01

Assessment of costs accompanying activation of immune system and related neuroendocrine pathways is essential for understanding the selective forces operating on these systems. Here we attempted to detect such costs in terms of disruption to redox balance and interference between different immune system components in captive wild-caught greenfinches (Carduelis chloris). Study birds were subjected to an endotoxin-induced inflammatory challenge and temporary exposure to a psychological stressor (an image of a predator) in a 2*2 factorial experiment. Injection of bacterial endotoxin resulted in up-regulation of two markers of antioxidant protection – erythrocyte glutathione, and plasma oxygen radical absorbance (OXY). These findings suggest that inflammatory responses alter redox homeostasis. However, no effect on markers of oxidative damage to proteins or DNA in erythrocytes could be detected. We found no evidence that the endotoxin injection interfered with antibody production against Brucella abortus antigen or the intensity of chronic coccidiosis. The hypothesis of within-immune system trade-offs as a cost of immunity was thus not supported in our model system. We showed for the first time that administration of endotoxin can reduce the level of corticosterone deposited into feathers. This finding suggests a down-regulation of the corticosterone secretion cascade due to an endotoxin-induced immune response, a phenomenon that has not been reported previously. Exposure to the predator image did not affect any of the measured physiological parameters. PMID:23805316

Pharmacotherapy for uveitis: current management and emerging therapy

PubMed Central

Barry, Robert J; Nguyen, Quan Dong; Lee, Richard W; Murray, Philip I; Denniston, Alastair K

2014-01-01

Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects. PMID:25284976

Pattern of uveitis in a university-based referral center in southern Thailand.

PubMed

Sittivarakul, Wantanee; Bhurayanontachai, Patama; Ratanasukon, Mansing

2013-01-01

To identify the characteristics (demographics, anatomical classification, diagnoses, and treatment) of all uveitis patients who were seen at our newly started Uveitis and Ocular Inflammatory Disease Clinic over a two-year period. The computerized uveitis database files and medical records for all new consecutive patients seen at our Uveitis and Ocular Inflammatory Disease Clinic from January 2010 through December 2011 were included. A total of 254 patients were seen during the study period. Anterior uveitis and panuveitis were most frequently found, each accounting for around 35% of cases. Specific diagnoses were established in 70.9% of patients and the top five most common specific diagnoses were VKH (11%), HLA-B27-associated anterior uveitis (7.9%), Behçet disease (7.1%), toxoplasmosis (7.1%), and herpetic anterior uveitis (4.7%). In this setting, the authors found VKH to be the most common diagnosis in the noninfectious uveitis group. Regarding infectious uveitis, toxoplasmosis ranked the most common diagnosis.

Burden and direct costs of non infectious uveitis in Spain.

PubMed

Adán-Civera, Alfredo Manuel; Benítez-Del-Castillo, José Manuel; Blanco-Alonso, Ricardo; Pato-Cour, Esperanza; Sellas-Fernández, Agustí; Bañares-Cañizares, Antonio

2016-01-01

There is no updated information on epidemiology and cost of management of non infectious uveitis (NIU) in Spain. This study assessed the frequency of various types of uveítis as well as associated costs of resources used in their management. NIU epidemiological data and direct costs were collected from a literature search. This was complemented with consensus information from 2 expert panel meetings and data from questionnaires to ophthalmologists and rheumatologists, experts on these conditions. Healthcare resources costs were obtained from the Oblikue database, from a medical society and from approved drug prices in Spain. During 2011 the estimate number of NIU was 9,398 (45% male, 70% aged 16-65 years). Incidence per type of uveitis was: acute anterior uveitis (AAU) 55%; posterior uveitis (PU) and pan-uveitis (PanU) 15% each; adult chronic anterior uveitis, paediatric chronic anterior uveitis and intermediate uveitis 5% each. Among total costs (77,834,282.10€), initial drug therapy was the highest (43,602,359.29€), followed by surgical treatment of complications (8,367,420.43€). With respect to types of uveitis, PanU (26,692,948.29€), PU (22,283,330.50€) and AAU (14,336,755.38€) showed the highest associated costs. Non infectious uveitis is associated to high costs in Spain, both in its diagnosis and in its treatment. Early diagnosis and treatment should allow for substantial savings for the National Health System. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Uveitis profile and treatment response in Iranian patients with sarcoidosis.

PubMed

Mahmoudzadeh, Pouya; Tousi, Adib; Ramezani, Alireza; Soheilian, Roham; Soheilian, Masoud

2015-06-01

The aim of the study was to assess the clinical features and treatment responses in Iranian patients with sarcoid uveitis. A retrospective review of patients diagnosed with sarcoid uveitis from 1996 to 2010 was performed in a referral clinic in Tehran, Iran. Demographic and clinical features of patients, treatment modalities and therapeutic responses, and outcomes were recorded. Sixty-six eyes from 36 patients were studied. Twenty cases had biopsy-proven sarcoidosis. Mean duration of follow-up was 44.7 ± 45 months (range 3-175). Thirty-six eyes (54.5 %) had intermediate uveitis, 25 (37.9 %) panuveitis, and 5 (7.6 %) anterior uveitis. Twenty patients (55.5 %) responded to both systemic and/or topical corticosteroids, and 16 (44.4 %) required immunomodulatory drugs for control of uveitis. All of the patients finally responded to treatment in the form of inflammation reduction and/or vision improvement. The average time interval before initial clinical response following treatment was 3.2 ± 3 months (range 1-72). This study disclosed a higher predominance of females and intermediate form of uveitis in Iranian patients with sarcoid uveitis. Use of immunomodulatory drugs combined with corticosteroids resulted in good visual outcome and control of uveitis with a possible fewer corticosteroid side effects.

Treatment strategies for childhood noninfectious chronic uveitis: an update.

PubMed

Cantarini, Luca; Simonini, Gabriele; Frediani, Bruno; Pagnini, Ilaria; Galeazzi, Mauro; Cimaz, Rolando

2012-01-01

Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, noninfectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, for example, juvenile idiopathic arthritis, a significant number of cases in children show no associated signs or symptoms and are labeled as idiopathic. We reviewed the available literature. Taking into account this evidence, an anti-inflammatory therapy based on an immunomodulatory approach seems a reasonable strategy for noninfectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive strategy is supported only at evidence level III. Our aim is to review the currently available medical strategies for the treatment of childhood sight-threatening chronic uveitis. Uveitis in children can be severe. Methotrexate is the drug of choice for recalcitrant cases, and biologic therapies can be useful in selected situations.

Field Studies Measuring the aerosolization of Endotoxin ...

EPA Pesticide Factsheets

Endotoxin is a component of the cell walls of Gram-negative bacteria and is known to be present in biosolids. Endotoxins have been shown to be a potent stimulator of the innate immune response causing airway irritation and shortness of breath. Class B biosolids are routinely applied to agricultural lands in the US to enhance soil properties and can be used as an alternative to chemical fertilizers. This study investigated the aerosolized endotoxin produced during the land application of Class B biosolids from various wastewater treatment plants on agricultural land and a concrete surface at two sites in Colorado, USA. Aerosolized endotoxin was captured using HiVol sampler fitted with glass fiber filter, polycarbonate filter cassette (both open and closed), and BioSampler impinger air samplers. Endotoxins were also measured in the bulk biosolids to allow for correlating bulk biosolids concentrations with aerosol emission rates. Endotoxin concentrations in biosolids, impinger solutions, and filter extracts were determined using the kinetic Limulus amebocyte lysate assay. Aerosolized endotoxin concentration was detected from all sites with levels ranging from 0.5 to 642 EU/m3. The four types of sampling apparatus were compared and the HiVol and open-faced cassette samplers used produced higher TWA measurements (EU/m3) than the impinger and closed cassette samplers. Ambient wind speed at the sites was found to be the variable best describing the results wit

Intestinal radiation syndrome: sepsis and endotoxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geraci, J.P.; Jackson, K.L.; Mariano, M.S.

Rats were whole-body irradiated with 8-MeV cyclotron-produced neutrons and /sup 137/Cs ..gamma.. rays to study the role of enteric bacteria and endotoxin in the intestinal radiation syndrome. Decrease in intestinal weight was used as an index of radiation-induced breakdown of the mucosa. Neutron and ..gamma..-ray doses that were sublethal for intestinal death resulted in a dose-dependent decrease in intestinal weight, reaching minimal values 2 to 3 days after exposure, followed by recovery within 5 days after irradiation. Neutron and photon doses that caused intestinal death resulted in greater mucosal breakdown with little or no evidence of mucosal recovery. The presencemore » of fluid in the intestine and diarrhea, but not bacteremia or endotoxemia, were related to mucosal breakdown and recovery. Neither sepsis nor endotoxin could be detected in liver samples taken at autopsy from animals which died a short time earlier from intestinal injury. These results suggest that overt sepsis and endotoxemia do not play a significant role in the intestinal radiation syndrome.« less

Presumed tuberculous uveitis in non-endemic country for tuberculosis: case series from a New Zealand tertiary uveitis clinic.

PubMed

Ng, Ken K; Nisbet, Mitzi; Damato, Erika M; Sims, Joanne L

2017-05-01

To describe the clinical spectrum of presumed tuberculous (TB) uveitis in a developed, non-endemic country of high immigrant population. Retrospective review of a consecutive case series. All 39 patients diagnosed with presumed TB uveitis at the tertiary uveitis service in Auckland from 2007 to 2014. Clinical chart review. Patient demographics, risk factors, ophthalmic manifestations, management and outcome. The median age was 37 years (interquartile range [IQR] 31-52) and 56% were female. The majority (97%) were born outside of New Zealand, and 77% had no TB-related history. Radiological abnormalities consistent with TB were evident in seven patients, including three who had culture positive pulmonary disease. Anterior uveitis was diagnosed in ten patients (26%), anterior and intermediate uveitis in eight (21%), posterior uveitis in 13 (33%) and panuveitis in eight (21%). Sixteen (41%) had retinal vasculitis, and five (13%) had multifocal serpiginoid choroiditis. Common complications included cataract (51%), ocular hypertension (36%), broad posterior synechiae (33%) and cystoid macular oedema (28%). Anti-TB treatment was initiated in 30 patients (76%). All but three patients completed the intended course of six to 12 months. Following anti-TB treatment, 67% remained in remission for at least 12 months, and all but two patients successfully stopped systemic steroids. The median initial and final visual acuity was 6/9 (IQR 6/6-6/18) and 6/6 (IQR 6/6-6/9), respectively. Despite a wide range of ocular presentations and complications, our cohort demonstrated good remission rate and visual prognosis following anti-TB treatment in carefully selected patients. © 2016 Royal Australian and New Zealand College of Ophthalmologists.

Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects

PubMed Central

2010-01-01

Introduction A sedentary lifestyle increases the risk of developing cardiovascular disease, obesity, and diabetes. This phenomenon is supported by recent studies suggesting a chronic, low-grade inflammation status. Endotoxin derived from gut flora may be key to the development of inflammation by stimulating the secretion of inflammatory factors. This study aimed to examine plasma inflammatory markers and endotoxin levels in individuals with a sedentary lifestyle and/or in highly trained subjects at rest. Methods: Fourteen male subjects (sedentary lifestyle n = 7; highly trained subjects n = 7) were recruited. Blood samples were collected after an overnight fast (~12 h). The plasmatic endotoxin, plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 (MCP1), ICAM/CD54, VCAM/CD106 and lipid profile levels were determined. Results Endotoxinemia was lower in the highly trained subject group relative to the sedentary subjects (p < 0.002). In addition, we observed a positive correlation between endotoxin and PAI-1 (r = 0.85, p < 0.0001), endotoxin and total cholesterol (r = 0.65; p < 0.01), endotoxin and LDL-c (r = 0.55; p < 0.049) and endotoxin and TG levels (r = 0.90; p < 0.0001). The plasma levels of MCP-1, ICAM/CD54 and VCAM/CD106 did not differ. Conclusion These results indicate that a lifestyle associated with high-intensity and high-volume exercise induces favorable changes in chronic low-grade inflammation markers and may reduce the risk for diseases such as obesity, diabetes and cardiovascular diseases. PMID:20684772

Bilateral Herpes Simplex Uveitis: Review of the Literature and Own Reports‏.

PubMed

de-la-Torre, Alejandra; Valdes-Camacho, Juanita; Foster, C Stephen

2017-08-01

Herpes simplex-associated uveitis is usually considered a unilateral eye disease, and rarely included in the differential diagnosis whenever there is bilateral involvement. We report three cases of bilateral herpetic anterior uveitis. We evaluated three patients who presented with clinical manifestations of bilateral uveitis suggestive of viral origin. We found intraocular hypertension, cells in the anterior chamber, paralytic mydriasis, iris atrophy with transillumination defects, and variable anterior vitreous cellularity. According to the clinical findings, supported with herpes-specific antibody titers and aqueous humor PCR results in two of them, they were diagnosed with bilateral anterior herpetic uveitis. Our patients were initially misdiagnosed as having non-infectious uveitis and were treated with immunomodulatory medications, which could have favored the extension of infection bilaterally. Although uncommon, bilateral herpetic uveitis should always be considered in the differential diagnoses, when patients present with hypertensive uveitis in both eyes.

Clinical and investigative profile of biopsy-proven sarcoid uveitis in India.

PubMed

Ganesh, Sudha K; Agarwal, Manisha

2008-01-01

Retrospective analysis of the clinical features, investigative profile, response to treatment, and final visual outcome in histopathologically confirmed cases of sarcoid uveitis. Retrospective case series analysis was done of 15 eyes of 9 patients seen between July 1999 and August 2003 with biopsy-proven sarcoid uveitis. There were 3 were males and 6 females. The mean age at presentation was 44.1 years (range 11-62 years), The mean follow-up was 28.4 months. Six patients had bilateral ocular involvement and 3 had unilateral involvement. Five out of 9 patients had primarily ocular involvement. The most common presentation was intermediate uveitis and granulomatous anterior uveitis in 7 patients. Eight of 9 patients responded well to the medical treatment with systemic and periocular steroids. Ocular lesions can be the primary manifestation of systemic sarcoidosis. Sarcoid uveitis in the Asian Indian population often presents an intermediate uveitis with granulomatous anterior uveitis.

Uveitis in Children: Diagnosis and Management.

PubMed

Gupta, Anju; Ramanan, A V

2016-01-01

Uveitis is a term used to describe inflammation of uvea, which is the middle layer of eye. It is an important cause of blindness in children in both developed and developing countries. Delayed diagnosis, inadequate treatment and risk of amblyopia are some of the factors that are unique to childhood uveitis and are responsible for significant morbidity seen with this disease.

Surface sampling for endotoxin assessment using electrostatic wiping cloths.

PubMed

Thorne, Peter S; Metwali, Nervana; Avol, Ed; McConnell, Rob S

2005-07-01

Much of the cost of exposure assessment for studies of residential cohorts is in scheduling and travel time for field staff. One way to reduce costs is to simplify methods such that subjects can sample their own residence. Analysis of settled dust is being widely used for assessment of exposures to allergens, lead and pesticides and can also be used for endotoxins. While vacuum sampling is the most common surface sampling method, wipe sampling has the advantage that it can be readily performed by the resident when convenient and samples can then be mailed to researchers. Thus, we evaluated the feasibility of wipe sampling for endotoxin environmental assessment using electrostatic wipes with or without the use of disposable examination gloves. Multiple lots of six types of commercial wipes and eight types of gloves were extracted and analyzed for endotoxin content using the kinetic chromogenic Limulus amebocyte lysate assay. Wipes were compared across brands, between lots, within lots, between pairs depending on proximity to cardboard packaging, and in wipe tests with or without gloves. Collected dust samples of known concentration were also tested in spiking assays for endotoxin recovery. The most striking finding was the high variability of endotoxin contamination of both wipes and gloves across brands and between various lots. The content of endotoxin in unused gloves ranged from <1.5 to 5810 endotoxin units (EU). The range for unused wipes was 3.6-87.8 EU. Surfaces of equal loading and area were sampled using three types of cloths that had low initial endotoxin contamination. The cloths were very good at collecting dust and endotoxin could be assayed from aqueous extracts of the wipes. Samples collected using cloths with bare washed hands yielded higher endotoxin loading per mass of collected dust versus samples collected wearing endotoxin-free gloves. This demonstrated additional endotoxin loading from the subject's hand. This study shows that wipe sampling

Adalimumab for the treatment of uveitis.

PubMed

LaMattina, Kara C; Goldstein, Debra A

2017-03-01

Adalimumab, an inhibitor of tumor necrosis factor-alpha (TNFα), is the only systemic non-corticosteroid agent which has been approved by the US Food and Drug Administration (FDA) for the treatment of non-infectious uveitis. Areas covered: The aim of this review is to summarize the research which demonstrated the effectiveness of adalimumab in the treatment of intraocular inflammation and helped to establish its side effect profile, ultimately leading to its FDA approval. Expert commentary: Adalimumab is a useful second-line agent in the treatment of non-infectious uveitis. While it is only approved in the United States for use in intermediate, posterior, and panuveitis in adults, I find it to be effective in off-label treatment of pediatric uveitis and scleritis as well.

A biological study establishing the endotoxin limit of biomaterials for bone regeneration in cranial and femoral implantation of rats.

PubMed

Haishima, Yuji; Hasegawa, Chie; Todoki, Kazuo; Sasaki, Kazuo; Niimi, Shingo; Ozono, Satoru

2017-08-01

The purpose of this study was to accurately quantify the risk of endotoxin contamination in biomaterials for bone regeneration in order to establish the acceptable endotoxin limit. Collagen sheets containing varying amounts of purified endotoxin from Escherichia coli and dried, heat-killed E. coli or Staphylococcus aureus cells were implanted into cranial or femoral defects in rats. These defects were artificially prepared to a size of 5 × 5 mm or a diameter of 1 mm, respectively. The degree of osteoanagenesis was assessed by soft X-ray radiography and histopathology at 1 and 4 weeks after implantation. The collagen sheet containing the dried E. coli cells showed a dose-dependent delay in cranial and/or femoral osteoanagenesis at endotoxin activities of more than 33.6 EU/mg, at which no inflammatory response was observed. In contrast, no such observation occurred with the collagen sheet containing S. aureus cells. These results suggest that endotoxins may affect the process of osteoanagenesis. Additionally, the no-observed-adverse-effect level was 9.6 EU/mg, corresponding to 255 EU/kg body weight in rats. Interestingly, no delay in osteoanagenesis was induced by the implantation of collagen sheets containing purified endotoxin at any dose tested. This suggested that pure endotoxin implanted into tissues having poor circulation of bodily fluids without bleeding may not be recognized as a foreign substance and may not induce a significant biological response. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1514-1524, 2017. © 2016 Wiley Periodicals, Inc.

Allantoin as a solid phase adsorbent for removing endotoxins.

PubMed

Vagenende, Vincent; Ching, Tim-Jang; Chua, Rui-Jing; Gagnon, Pete

2013-10-04

In this study we present a simple and robust method for removing endotoxins from protein solutions by using crystals of the small-molecule compound 2,5-dioxo-4-imidazolidinyl urea (allantoin) as a solid phase adsorbent. Allantoin crystalline powder is added to a protein solution at supersaturated concentrations, endotoxins bind and undissolved allantoin crystals with bound endotoxins are removed by filtration or centrifugation. This method removes an average of 99.98% endotoxin for 20 test proteins. The average protein recovery is ∼80%. Endotoxin binding is largely independent of pH, conductivity, reducing agent and various organic solvents. This is consistent with a hydrogen-bond based binding mechanism. Allantoin does not affect protein activity and stability, and the use of allantoin as a solid phase adsorbent provides better endotoxin removal than anion exchange, polymixin affinity and biological affinity methods for endotoxin clearance. Copyright © 2013 Elsevier B.V. All rights reserved.

Influence of droplet size, pH and ionic strength on endotoxin-triggered ordering transitions in liquid crystalline droplets

PubMed Central

Miller, Daniel S.; Abbott, Nicholas L.

2012-01-01

We report an investigation of ordering transitions that are induced in water-dispersed, micrometer-sized droplets of a thermotropic liquid crystal (LC) by the bacterial lipopolysaccharide endotoxin. We reveal that the ordering transitions induced by endotoxin – from a bipolar state of the droplets to a radial state – are strongly dependent on the size of the LC droplets. Specifically, as the diameters of the LC droplets increase from 2 μm to above 10 μm (in phosphate buffered saline with an ionic strength of 90 mM and a pH of 7.2), we measured the percentage of droplets exhibiting a radial configuration in the presence of 100 pg/mL endotoxin to decrease from 98 ± 1 % to 3 ± 2 %. In addition, we measured a decrease in either the ionic strength or pH of the aqueous phase to reduce the percentage of droplets exhibiting a radial configuration in the presence of endotoxin. These results, when interpreted within the context of a simple thermodynamic model that incorporates the contributions of elasticity and surface anchoring to the free energies of the LC droplets, lead us to conclude that (i) the elastic constant K24 plays a central role in determining the size-dependent response of the LC droplets to endotoxin, and (ii) endotoxin-triggered ordering transitions occur only under solution conditions (pH, ionic strength) where the combined contributions of elasticity and surface anchoring to the free energies of the bipolar and radial configurations of the LC droplets are similar in magnitude. Our analysis also suggests that the presence of endotoxin perturbs the free energies of the LC droplets by ~10−17 J/droplet, which is comparable to the standard free energy of self-association of ~103 endotoxin molecules. These results, when combined with prior reports of localization of endotoxin at the center of LC droplets, are consistent with the hypothesis that self-assembly of endotoxin within micrometer-sized LC droplets provides the driving force for the ordering

Management of Uveitis in Spondyloarthropathy: Current Trends

PubMed Central

Gupta, Nikhil; Agarwal, Aditi

2018-01-01

Spondyloarthritis is a chronic inflammatory disease predominantly affecting joints of the axial skeleton. However, as many as 50% of patients with this disease may have extra-articular manifestations, which include uveitis; psoriasis; inflammatory bowel disease such as Crohn disease or ulcerative colitis; cardiovascular manifestations in the form of conduction abnormalities, atherosclerosis, or valvular heart disease; pulmonary involvement; and rarely renal involvement. Uveitis occurs in 25% to 40% of patients with spondyloarthritis. Management of uveitis is crucial to prevent morbidity caused by vision loss and secondary complications. Treatment ranges from local therapies to systemic drugs and varies depending on the severity and response to treatment. Categories of medical treatment include nonsteroidal anti-inflammatory agents, corticosteroids, and steroid-sparing agents. Biologic therapies such as antitumor necrosis factor agents act early in the disease process and have revolutionized the field of rheumatology, including management of uveitis. This review will focus on the management of ophthalmic manifestations in spondyloarthropathies. PMID:29272246

Prevalence of Toxoplasma gondii and Toxocara canis among Patients with Uveitis.

PubMed

Lim, Su Jin; Lee, Sang Eun; Kim, Sun Hyun; Hong, Sung-Hee; You, Yong Sung; Kwon, Oh Woong; Kim, Hyeun Seung

2015-04-01

To investigate the prevalence of Toxoplasma gondii and Toxocara canis in patients with uveitis. Patients with uveitis were examined. Serum antibodies to T. gondii and T. canis were tested by using the enzyme-linked immunosorbent assay. Polymerase chain reaction (PCR) was done using blood and aqueous humor (AH). Ninety-eight patients were enrolled. Mean age was 43.5 ± 13.2 years. Six patients were seropositive for T. gondii with the following pattern: anterior uveitis, 1; posterior uveitis with retinitis, 2; pan uveitis, 2. One patient had a positive PCR result for T. gondii in AH, who showed panuveitis. Twenty-three patients were positive to serum IgG for T. canis with the following clinical manifestation: granuloma, 6; pigmented scar, 3; vitritis, 6--but none were PCR positive. T. gondii and T. canis are still important causes of uveitis. Ocular toxocariasis is not an uncommon cause of uveitis, even in adults.

Incidence and prevalence of uveitis in South Korea: a nationwide cohort study.

PubMed

Rim, Tyler Hyungtaek; Kim, Sung Soo; Ham, Don-Il; Yu, Seung-Young; Chung, Eun Jee; Lee, Sung Chul

2018-01-01

To evaluate the incidence and prevalence of uveitis and associated risk factors in South Korea. For this retrospective national cohort study, approximately 1 000 000 Korean residents were randomly selected from the Korean National Health Insurance Service database. Uveitis was defined according to the Korean Classification of Diseases. The uveitis incidence and prevalence were calculated. Sociodemographic factors and comorbidities associated with uveitis were evaluated via Cox proportional regression models. A total of 1 094 440 subjects were evaluated over 7 051 346 person-years (mean follow-up: 6.44 years). Overall, 7447 newly developed uveitis cases were identified during the period of 2007-2013; the average incidence of uveitis was 10.6 per 10 000 person-years (95% CI 10.3 to 10.8). The average incidences of anterior and non-anterior uveitis were 9.0 and 1.5 per 10 000 person-years, respectively. The prevalence rates of uveitis, anterior uveitis and non-anterior uveitis were 17.3, 15.0 and 2.3 per 10 000 persons, respectively, during the period of 2007-2013. Increasing age, male sex, residing in a relatively rural area and high income were associated with uveitis, along with Behçet's disease, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematous, ulcerative colitis and tuberculosis. The overall incidence of uveitis in Korea was similar to those reported in Taiwan and the USA. Despite a potentially inaccurate disease definition, claims data may be useful for monitoring the substantial uveitis burden in South Korea. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Endotoxins and other sepsis triggers.

PubMed

Opal, Steven M

2010-01-01

Endotoxin, or more accurately termed bacterial lipopolysaccharide (LPS), is recognized as the most potent microbial mediator implicated in the pathogenesis of sepsis and septic shock. Yet despite its discovery well over a century ago, the fundamental role of circulating endotoxin in the blood of most patients with septic shock remains enigmatic and a subject of considerable controversy. LPS is the most prominent 'alarm molecule' sensed by the host's early warning system of innate immunity presaging the threat of invasion of the internal milieu by Gram-negative bacterial pathogens. In small doses within a localized tissue space, LPS signaling is advantageous to the host in orchestrating an appropriate antimicrobial defense and bacterial clearance mechanisms. Conversely, the sudden release of large quantities of LPS into the bloodstream is clearly deleterious to the host, initiating the release of a dysregulated and potentially lethal array of inflammatory mediators and procoagulant factors in the systemic circulation. The massive host response to this single bacterial pattern recognition molecule is sufficient to generate diffuse endothelial injury, tissue hypoperfusion, disseminated intravascular coagulation and refractory shock. Numerous attempts to block endotoxin activity in clinical trials with septic patients have met with inconsistent and largely negative results. Yet the groundbreaking discoveries within the past decade into the precise molecular basis for LPS-mediated cellular activation and tissue injury has rekindled optimism that a new generation of therapies that specifically disrupt LPS signaling might succeed. Other microbial mediators found in Gram-positive bacterial and viral and fungal pathogens are now appreciated to activate many of the same host defense networks induced by LPS. This information is providing novel interventions in the continuing effots to improve the care of septic patients. Copyright 2010 S. Karger AG, Basel.

Assessing endotoxins in equine-derived snake antivenoms: Comparison of the USP pyrogen test and the Limulus Amoebocyte Lysate assay (LAL).

PubMed

Solano, Gabriela; Gómez, Aarón; León, Guillermo

2015-10-01

Snake antivenoms are parenterally administered; therefore, endotoxin content must be strictly controlled. Following international indications to calculate endotoxin limits, it was determined that antivenom doses between 20 mL and 120 mL should not exceed 17.5 Endotoxin Units per milliliter (EU/mL) and 2.9 EU/mL, respectively. The rabbit pyrogen test (RPT) has been used to evaluate endotoxin contamination in antivenoms, but some laboratories have recently implemented the LAL assay. We compared the capability of both tests to evaluate endotoxin contamination in antivenoms, and we found that both methods can detect all endotoxin concentrations in the range of the antivenom specifications. The acceptance criteria of RPT and LAL must be harmonized by calculating the endotoxin limit as the quotient of the threshold pyrogenic dose and the therapeutic dose and the dose administered to rabbits as the quotient of the threshold pyrogenic dose and the endotoxin limit. Since endotoxins from Gram-negative bacteria exert different pyrogenicity, if contamination occurred, antivenom batches that induce pyrogenic reactions may be found in spite of passing LAL specifications. Although LAL assay can be used to assess endotoxin content throughout the antivenom manufacturing process, we recommend that the release of final products be based on the results of both methods. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of garlic oil and two of its major organosulfur compounds, diallyl disulfide and diallyl trisulfide, on intestinal damage in rats injected with endotoxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiang, Y.-H.; Jen, L.-N.; Su, H.-Y.

Garlic and its active components are known to possess antioxidant and antiinflammatory effects. The present study investigated the effects of garlic oil and its organosulfur compounds on endotoxin-induced intestinal mucosal damage. Wistar rats received by gavage 50 or 200 mg/kg body weight garlic oil (GO), 0.5 mmol/kg body weight diallyl disulfide or diallyl trisulfide, or the vehicle (corn oil; 2 ml/kg body weight) every other day for 2 weeks before being injected with endotoxin (i.p., 5 mg/kg body weight). Control rats were administered with corn oil and were injected with sterile saline. Samples for the measurement of proinflammatory cytokines weremore » collected 3 h after injection, and all other samples were collected 18 h after injection. The low dose of GO suppressed endotoxin-induced inducible nitric oxide synthase (iNOS) activity, ulceration, and apoptosis in the intestinal mucosa (P < 0.05). The high dose of GO significantly lowered the peripheral level of nitrate/nitrite and endotoxin-induced iNOS activity in the intestinal mucosa (P < 0.05) but worsened intestinal mucosal damage accompanied by elevated peripheral proinflammatory cytokines. Diallyl trisulfide but not diallyl disulfide showed similar toxic effect as that of high-dose GO. These results suggest the preventive effect and possible toxicity of garlic oil and its organosulfur compounds in endotoxin-induced systemic inflammation and intestinal damage.« less

Comparative Analysis of Hepatic CD14 Expression between Two Different Endotoxin Shock Model Mice: Relation between Hepatic Injury and CD14 Expression

PubMed Central

Hozumi, Hiroyasu; Tada, Rui; Murakami, Taisuke; Adachi, Yoshiyuki; Ohno, Naohito

2013-01-01

CD14 is a glycoprotein that recognizes gram-negative bacterial lipopolysaccharide (LPS) and exists in both membrane-bound and soluble forms. Infectious and/or inflammatory diseases induce CD14 expression, which may be involved in the pathology of endotoxin shock. We previously found that the expression of CD14 protein differs among the endotoxin shock models used, although the reasons for these differences are unclear. We hypothesized that the differences in CD14 expression might be due to liver injury, because the hepatic tissue produces CD14 protein. We investigated CD14 expression in the plasma and liver in the carrageenan (CAR)-primed and D-galN-primed mouse models of endotoxin shock. Our results showed that severe liver injury was not induced in CAR-primed endotoxin shock model mice. In this CAR-primed model, the higher mRNA and protein expression of CD14 was observed in the liver, especially in the interlobular bile duct in contrast to D-galN-primed-endotoxin shock model mice. Our findings indicated that the molecular mechanism(s) underlying septic shock in CAR-primed and D-galN-primed endotoxin shock models are quite different. Because CD14 expression is correlated with clinical observations, the CAR-primed endotoxin shock model might be useful for studying the functions of CD14 during septic shock in vivo. PMID:23308276

Mediated effect of endotoxin and lead upon hepatic metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuttner, R.E.; Ebata, T.; Schumer, W.

A test was made of the possibility that gram-negative bacterial cell wall lipopolysaccharides acted directly on key glucoregulatory enzymes in rat liver cytosol to cause the characteristic hypoglycemia of severe endotoxemia. Fasted male rats were sensitized to endotoxin by the simultaneous intravenous injection of lead acetate. The minimum systemic dosage of endotoxin necessary to perturb the normal pattern of hepatic glycolytic intermediates was determined by serial testing with diminishing dosages of endotoxin. The hepatocyte concentration of endotoxin was then calculated from this minimum dosage by use of literature data on the fraction of endotoxin delivered to liver cells after amore » systemic intravenous injection of radiochromium labeled lipopolysaccharides. Accepting a molecular weight of 118,000 daltons for the smallest endotoxin monomer capable of evoking a physiologic response, the molar amount of endotoxin present in 1 gram of hepatocytes was readily calculated. The concentration of glucoregulatory enzymes in parenchymal cells was then estimated from other literature sources. It was found that the amount of endotoxin in the hepatocytes was insufficient to combine directly with even 1 per cent of the quantity of a single key glucoregulatory enzyme in liver parenchyma. Since a one to one stoichiometric reaction between endotoxin and enzyme could not occur in the liver cytosol, a direct interaction mechanism between agonist and biocatalyst can be ruled out. It is concluded that bacterial endotoxin must act on hepatic glucoregulation by an indirect mechanism presumably based upon the release and operation of mediators.« less

Characteristics of childhood uveitis leading to visual impairment and blindness in the Netherlands.

PubMed

Hettinga, Ymkje M; Verhagen, Fleurieke H; van Genderen, Maria; de Boer, Joke H

2014-12-01

To investigate the clinical characteristics of childhood uveitis leading to visual impairment or blindness. In this descriptive study, we reviewed data from the medical records of 58 children with visual impairment or blindness due to childhood uveitis, which were seen at an institute for visually impaired patients (Bartiméus) between January 1981 and December 2012, in a retrospective, cross-sectional manner. Thirty-two of the 58 children (55%) were visually impaired and 26 (45%) were legally blind. Uveitis was posterior in 76% of all cases. Infectious uveitis represented 74% of all cases, of which 86% was congenital. Five patients (9%) had uveitis related to a systemic disease, and ten patients (17%) had idiopathic uveitis. There was a decrease in infectious causes over the last decades (p = 0.04) and an increase in idiopathic uveitis (p < 0.01), but the rate of children with posterior uveitis remained constant. There was an overall decrease in the number of children with uveitis referred to Bartiméus. The number of ocular complications at the time of intake was higher in children with acquired disease compared with congenital diseases (p < 0.01), as it was in children with non-infectious uveitis compared with infectious uveitis (p = 0.04). Most comorbidities that were noted were seen in children with infectious uveitis. Most patients suffering from visual impairment or blindness due to childhood uveitis had posterior and/or infectious uveitis, mostly congenital. There is a shift in causes which shows a decrease in infectious causes and an increase in idiopathic causes. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Blockade of the interaction of leukotriene b4 with its receptor prevents development of autoimmune uveitis.

PubMed

Liao, Tianjiang; Ke, Yan; Shao, Wen-Hai; Haribabu, Bodduluri; Kaplan, Henry J; Sun, Deming; Shao, Hui

2006-04-01

To investigate the role of leukotriene B4 (LTB4) and its receptor BLT1 in the pathogenesis of mouse uveitis. Experimental autoimmune uveitis (EAU) was induced in B10RIII mice by immunization of interphotoreceptor retinoid binding protein (IRBP; peptide sequence 161-180) or in C57BL/6 (B6) mice by transfer of activated T cells specific for IRBP1-20. The animals were then treated with and without the BLT1 receptor antagonist, CP105696, at the disease onset after immunization or at day 0 or day 6 after T-cell transfer. EAU was also induced in wild-type B6 (WT) and BLT1-deficient (BLT1-/-) mice by reciprocal transfer of the T cells from B6 to BLT1-deficient mice and vise versa. Clinical signs of inflammation and ocular histology were compared. The chemotactic activity of LTB4 on naïve and IRBP-specific autoreactive T cells as well as effector leukocytes was examined. The treatment of CP105696, greatly reduced the intensity of ongoing disease. IRBP1-20-specific T cells derived from wild-type B6 mice induced only mild uveitis in syngeneic BLT1-deficient mice and that IRBP1-20-specific T cells derived from BLT1-/- mice induced milder disease in wild-type B6 mice than those derived from wild-type B6 mice, suggesting that expression of the LTB4 receptor on both activated autoreactive T cells and effector leukocytes was necessary for ocular inflammation to occur. Consistent with these data, transfer of autoreactive T cells from B6 mice to 5-lipoxygenase-deficient (5-LO-/-) mice, which have a functional defect in LTB4 expression, also failed to induce uveitis in the recipient mice. The results demonstrate a critical role for LTB4 in ocular inflammation and in the development and progression of EAU and suggest a new potential target for therapeutic intervention in this disease.

New Immunosuppressive Therapies in Uveitis Treatment

PubMed Central

Mérida, Salvador; Palacios, Elena; Navea, Amparo; Bosch-Morell, Francisco

2015-01-01

Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines. PMID:26270662

Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

PubMed

Oray, Merih; Tuğal-Tutkun, İlknur

2016-04-01

Pediatric uveitis may be a serious health problem because of the lifetime burden of vision loss due to severe complications if the problem is not adequately treated. Juvenile idiopathic arthritis (JIA)-associated uveitis is characterized by insidious onset and potentially blinding chronic anterior uveitis. Periodic ophthalmologic screening is of utmost importance for early diagnosis of uveitis. Early diagnosis and proper immunomodulatory treatment are essential for good visual prognosis. The goal of treatment is to achieve enduring drug-free remission. The choice of therapeutic regimen needs to be tailored to each individual case. One must keep in mind that patients under immunomodulatory treatment should be monitored closely due to possible side effects. Local and systemic corticosteroids have long been the mainstay of therapy; however, long-term corticosteroid therapy should be avoided due to serious side effects. Steroid-sparing agents in the treatment of JIA-associated uveitis include antimetabolites and biologic agents in refractory cases. Among the various immunomodulatory agents, methotrexate is generally the first choice, as it has a well-established safety and efficacy profile in pediatric cases and does not appear to increase the risk of cancer. Other classic immunomodulators that may also be used in combination with methotrexate include azathioprine, mycophenolate mofetil, and cyclosporin A. Biologic agents, primarily tumor necrosis factor alpha inhibitors including infliximab or adalimumab, should be considered in cases of treatment failure with classic immunomodulatory agents.

The Potential Role of an Endotoxin Tolerance-Like Mechanism for the Anti-Inflammatory Effect of Spirulina platensis Organic Extract in Macrophages.

PubMed

Pham, Tho X; Park, Young-Ki; Bae, Minkyung; Lee, Ji-Young

2017-03-01

Endotoxin tolerance is a phenomenon where exposure of innate immune cells to lipopolysaccharide (LPS) induces a refractory state to subsequent endotoxin exposures. The goal of this study was to investigate if Spirulina platensis organic extract (SPE) induces an endotoxin tolerance-like state. We used splenocytes and peritoneal macrophages from C57BL/6J mice fed a high-fat/high-sucrose (HF/HS) control or a HF/HS diet containing 0.25% (w/w) SPE for 16 weeks for ex vivo LPS stimulation and endotoxin-tolerant (ET) macrophages to evaluate the effects of SPE on endotoxin tolerance. Cells from SPE-fed mice displayed significantly less expression of proinflammatory genes than those from control mice. ET macrophages were produced in vitro by incubating RAW 264.7 macrophages with low-dose LPS to determine the energy phenotype of naive, SPE-treated, and ET macrophages. Compared to naive macrophages exposed to a high-dose LPS (100 ng/mL) for the first time, ET macrophages showed significantly less proinflammatory gene expression after LPS stimulation, which was also observed with SPE treatment. Consistently, nuclear translocation of p65 was markedly reduced in both ET- and SPE-treated macrophages on LPS stimulation with increase in nuclear protein levels of p50 and B cell lymphoma 3-encoded protein. In conclusion, the anti-inflammatory effect of SPE is at least partly attributable to the induction of an endotoxin tolerance-like state in macrophages, which shares common characteristics of macrophage endotoxin tolerance.

[Tubulointerstitial nephritis with uveitis (TINU) syndrome. A relatively rare rheumatological differential diagnosis with unexplained uveitis].

PubMed

Häusler, U; Guminski, B; Helmchen, U; Kisters, K; Heinz, C; Braun, J

2013-05-01

The tubulo-interstitial nephritis and uveitis (TINU) syndrome, first described in 1975, is a rare disease most probably of autoimmune origin that is characterized by unilateral or bilateral uveitis and tubulointerstitial nephritis. Most patients are adolescents and it is sometimes associated with other autoimmune diseases, such as spondyloarthritis, rheumatoid arthritis and hyperthyroidosis. This article reports the case of a 43-year-old female patient who presented with refractory recurrent bilateral uveitis despite therapy with high doses of corticosteroids in combination with cyclosporin. When the patient was referred to this hospital for rheumatological examination after almost 1 year of therapy, mild renal insufficiency and proteinuria were found. The kidney biopsy revealed interstitial nephritis, partly crescent-shaped and partly chronic. A diagnosis of TINU syndrome was made and treatment with adalimumab in combination with methotrexate was started. The favorable clinical outcome indicated that tumor necrosis factor (TNF) alpha may play an important role in the pathogenesis of TINU syndrome.

Epidemiology of uveitis among the Chinese population in Taiwan: a population-based study.

PubMed

Hwang, De-Kuang; Chou, Yiing-Jeng; Pu, Cheng-Yun; Chou, Pesus

2012-11-01

This study aimed to investigate the incidence and prevalence of uveitis in Taiwan, and then analyzed the risk factors related to uveitis using multivariate regression. Population-based cohort study using medical claims data. We randomly selected 1 000 000 residents from the Taiwan National Health Insurance Research Database. All participants with correct registry data (96%) were included in the study. The study period was from 2000 to 2008. All types of uveitis were identified using the International Classification of Diseases, 9th revision, Clinical Modification diagnostic codes. The annual incidence and cumulative prevalence of uveitis were calculated. A univariate and a multivariate Poisson regression were used to determine the risk factors associated with uveitis. The first diagnosis of uveitis noted during the study period. The annual cumulative incidence rate of uveitis ranged from 102.2 to 122.0 cases per 100 000 persons over the study period, and the average incidence density was 111.3 cases per 100 000 person-years (95% confidence interval, 108.4-114.1). The cumulative prevalence was found to have increased from 318.8 cases per 100 000 persons in 2003 to 622.7 cases per 100 000 persons in 2008. Anterior uveitis was the most common location and accounted for 77.7% of all incident cases, which was followed by panuveitis, posterior uveitis, and intermediate uveitis. Multivariate regression analysis showed that males, the elderly, and individuals who lived in an urban area had higher incidence rates for uveitis. The epidemiology of uveitis in Taiwan differs from most previous studies in other countries. The incidence of uveitis in Taiwan has increased significantly recently. The elderly and individuals living in urban areas are the populations that are most commonly affected by uveitis. These findings are consistent with suggestions found in several recent studies. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights

Immunosuppressive Treatment of Non-infectious Uveitis: History and Current Choices.

PubMed

Zhao, Chan; Zhang, Meifen

2017-04-10

Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveitis. Although systemic corticosteroids have been the gold standard of immunosup- pressive treatment for uveitis since first introduced in 1950s, its side effects of long-term use often warrant an adjuvant treatment to reduce the dosage/duration of corticosteroids needed to maintain disease control. Conventional immunosuppressive drugs, classified into alkylating agent, antimetabolites and T cell inhibitors, have been widely used as corticosteroid-sparing agents, each with characteristic safety/tolerance profiles on different uveitis entities. Recently, biologic agents, which target specific molecules in immunopathogenesis of uveitis, have gained great interest as alternative treatments for refractory uveitis based on their favorable safety and effectiveness in a variety of uveitis entities. However, lack of large randomized controlled clinical trials, concerns about efficacy and safety of long-term usage, and economic burden are limiting the use of biologics in non-infectious uveitis. Local administration of immunosuppressive drugs (from corticosteroids to biologics) through intraocular drug delivery systems represent another direction for drug development and is now under intense investigation, but more evidences are needed to support their use as regular alternative treatments for uveitis. With the numerous choices belonging to different treatment modalities (conventional immunosuppressive agents, biologics and local drug delivery systems) on hand, the practice patterns have been reported to vary greatly from center to center. Factors influence uveitis specialists' choices of immunosuppressive agents may be complex and may include personal familiarity, treatment availability, safety/tolerability, effectiveness, patient compliance, cost concerns and

Capillary Electrophoresis Chips for Fingerprinting Endotoxin Chemotypes and Subclasses.

PubMed

Kocsis, Béla; Makszin, Lilla; Kilár, Anikó; Péterfi, Zoltán; Kilár, Ferenc

2017-01-01

Endotoxins (lipopolysaccharides, LPS; lipooligosaccharides, LOS) are components of the envelope of Gram-negative bacteria. These molecules, responsible for both advantageous and harmful biological activity of these microorganisms, are highly immunogenic and directly involved in numerous bacterial diseases in humans, such as Gram-negative sepsis. The characterization of endotoxins is of importance, since their physiological and pathophysiological effects depend on their chemical structure. The differences among the LPS from different bacterial serotypes and their mutants include variations mainly within the composition and length or missing of their O-polysaccharide chains. Microchip electrophoretic methodology enables the structural characterization of LPS molecules from several bacteria and the quantitative evaluation of components of endotoxin extracts. The improved microchip electrophoretic method is based on the direct labeling of endotoxins by covalent binding of a fluorescent dye. The classification of the S-type LPSs can be done according to their electrophoretic profiles, which are characteristics of the respective bacterial strains. According to the number, distribution, and the relative amounts of components in an endotoxin extract, it is possible to differentiate between the S-type endotoxins from different Gram-negative bacterial strains. The microchip electrophoresis affords high-resolution separation of pure and partially purified (e.g., obtained from whole-cell lysate) S and R endotoxins. This microchip technique provides a new, standardizable, fast, and sensitive method for the detection of endotoxins and for the quantitative evaluation of components of an endotoxin extract.

Pediatric uveitis.

PubMed

Patel, Hemang; Goldstein, Debra

2003-02-01

Uveitis in children is an entity most pediatricians and ophthalmologists seldom encounter. It is prevalent in society, however, and the high incidence of sight-threatening complications in untreated children warrants a baseline knowl-edge of the diseases and disorders involved as well as a sense of when to refer to a specialist.

21 CFR 866.3210 - Endotoxin assay.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Endotoxin assay. 866.3210 Section 866.3210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3210 Endotoxin assay. (a...

21 CFR 866.3210 - Endotoxin assay.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Endotoxin assay. 866.3210 Section 866.3210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3210 Endotoxin assay. (a...

21 CFR 866.3210 - Endotoxin assay.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Endotoxin assay. 866.3210 Section 866.3210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3210 Endotoxin assay. (a...

21 CFR 866.3210 - Endotoxin assay.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Endotoxin assay. 866.3210 Section 866.3210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3210 Endotoxin assay. (a...

21 CFR 866.3210 - Endotoxin assay.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Endotoxin assay. 866.3210 Section 866.3210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3210 Endotoxin assay. (a...

Human leukocyte antigen B27 and B51 double-positive Behçet uveitis.

PubMed

Ahn, Jae Kyoun; Park, Yeoung Geol

2007-10-01

To describe the clinical characteristics of human leukocyte antigen (HLA) B27 and B51 double-positive Behçet uveitis and to determine whether the coexistence of HLA-B27 can affect Behçet uveitis. We retrospectively reviewed the medical records of patients with Behçet uveitis and patients with HLA-B27-associated non-Behçet uveitis who underwent HLA-B27 and HLA-B51 typing and were followed up for more than 3 years. We divided the patients into 3 groups according to HLA-B27/B51 status and compared the clinical outcomes. Main outcome measures were demographic features, uveitis characteristics, complications, treatments, and visual prognosis. Fourteen patients with HLA-B27(+)B51(+) Behçet uveitis, 43 patients with HLA-B27(-)B51(+) Behçet uveitis, and 41 patients with HLA-B27(+)B51(-) non-Behçet uveitis were identified. HLA-B27(+)B51(+) Behçet uveitis showed the demographic features similar to HLA-B27(-) counterparts. However, HLA-B27(+)B51(+) Behçet uveitis showed less involvement of posterior segments, a less chronic course, fewer complications in posterior segments, and less use of systemic medication or surgical intervention for inflammatory control, similar to HLA-B27(+)B51(-) non-Behçet uveitis. The long-term vision prognosis of HLA-B27(+)B51(+) Behçet uveitis was more favorable than that of HLA-B27(-)B51(+) Behçet uveitis. Our results indicate that HLA-B27(+)B51(+) Behçet uveitis is a benign subgroup of Behçet uveitis. The positivity of HLA-B27 may be a good prognostic factor in Behçet uveitis.

Zinc metallothionein (MT) induction by parenteral iron and endotoxin: A temporal analysis of hepatic MT mRNA changes

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCormick, C.C.

The present study was undertaken to compare the temporal characteristics of iron-induced hepatic MT mRNA accumulation to that effected by endotoxin. Young chicks were given (ip) either endotoxin, ferrous gluconate or an equivalent volume of saline. At various times following injections, liver was obtained from 5 chicks per treatment for total RNA extraction. Equal amounts of total hepatic RNA from each chick were pooled and 10 {mu}g separated by denaturing agarose gel electrophoresis. Hepatic MT mRNA and albumin mRNA were analyzed by Northern blot analysis using synthetic oligonucleotides. The results indicated little temporal difference in the accumulation of hepatic MTmore » mRNA as affected by either endotoxin or iron. In both treatments, MT mRNA was minimally affected at 3 hours post-injection. Maximum accumulation was achieved during a 6 h period from 6 to 12 hours post-injection. At 24 hours, MT mRNA was considerably higher in liver of endotoxin-injected chicks when compared to that of iron-injection chicks. Albumin expression appeared not to be substantially affected by either treatment. The results suggest that the induction of hepatic MT by iron injection is not substantially different than that observed following endotoxin administration. It would be speculative to suggest that the processes by which MT is induced under these conditions are also similar.« less

A MECHANISM OF THE GLYCOGENOLYTIC ACTION OF BACTERIAL ENDOTOXIN

PubMed Central

Sanford, Jay P.; Barnett, Jack A.; Gott, Cora

1960-01-01

These experiments have demonstrated that liver glycogen may rise or fall after endotoxin administration, depending upon the antecedent diet and that total adrenalectomy followed by corticosteroid replacement abolishes the glycogenolytic effect of sublethal doses of endotoxin. It is concluded that the derangements of carbohydrate metabolism observed following the administration of sublethal quantities of bacterial endotoxin represent, not a direct hepatotoxic effect of endotoxin, but rather the passive consequence of epinephrine release. PMID:13746229

Phospholipid imprinted polymers as selective endotoxin scavengers

NASA Astrophysics Data System (ADS)

Sulc, Robert; Szekely, Gyorgy; Shinde, Sudhirkumar; Wierzbicka, Celina; Vilela, Filipe; Bauer, David; Sellergren, Börje

2017-03-01

Herein we explore phospholipid imprinting as a means to design receptors for complex glycolipids comprising the toxic lipopolysaccharide endotoxin. A series of polymerizable bis-imidazolium and urea hosts were evaluated as cationic and neutral hosts for phosphates and phosphonates, the latter used as mimics of the phospholipid head groups. The bis-imidazolium hosts interacted with the guests in a cooperative manner leading to the presence of tight and well defined 1:2 ternary complexes. Optimized monomer combinations were subsequently used for imprinting of phosphatidic acid as an endotoxin dummy template. Presence of the aforementioned ternary complexes during polymerization resulted in imprinting of lipid dimers - the latter believed to crudely mimic the endotoxin Lipid A motif. The polymers were characterized with respect to template rebinding, binding affinity, capacity and common structural properties, leading to the identification of polymers which were thereafter subjected to an industrially validated endotoxin removal test. Two of the polymers were capable of removing endotoxin down to levels well below the accepted threshold (0.005 EU/mg API) in pharmaceutical production.

Modification of sample processing for the Limulus amebocyte lysate assay enhances detection of inflammogenic endotoxin in intact bacteria and organic dust.

PubMed

Hoppe Parr, Kimberly A; Hađina, Suzana; Kilburg-Basnyat, Brita; Wang, Yifang; Chavez, Dulce; Thorne, Peter S; Weiss, Jerrold P

2017-04-01

The pro-inflammatory potency and causal relationship with asthma of inhaled endotoxins have underscored the importance of accurately assessing the endotoxin content of organic dusts. The Limulus amebocyte lysate (LAL) assay has emerged as the preferred assay, but its ability to measure endotoxin in intact bacteria and organic dusts with similar sensitivity as purified endotoxin is unknown. We used metabolically radiolabeled Neisseria meningitidis and both rough and smooth Escherichia coli to compare dose-dependent activation in the LAL with purified endotoxin from these bacteria and shed outer membrane (OM) blebs. Labeled [ 14 C]-3-OH-fatty acids were used to quantify the endotoxin content of the samples. Purified meningococcal and E. coli endotoxins and OM blebs displayed similar specific activity in the LAL assay to the purified LPS standard. In contrast, intact bacteria exhibited fivefold lower specific activity in the LAL assay but showed similar MD-2-dependent potency as purified endotoxin in inducing acute airway inflammation in mice. Pre-treatment of intact bacteria and organic dusts with 0.1 M Tris-HCl/10 mM EDTA increased by fivefold the release of endotoxin. These findings demonstrate that house dust and other organic dusts should be extracted with Tris/EDTA to more accurately assess the endotoxin content and pro-inflammatory potential of these environmental samples.

Modification of Sample Processing for the Limulus Amebocyte Lysate Assay Enhances Detection of Inflammogenic Endotoxin in Intact Bacteria and Organic Dust

PubMed Central

Hoppe Parr, Kimberly A.; Hađina, Suzana; Kilburg-Basnyat, Brita; Wang, Yifang; Chavez, Dulce; Thorne, Peter S.; Weiss, Jerrold P.

2018-01-01

The pro-inflammatory potency and causal relationship with asthma of inhaled endotoxins have underscored the importance of accurately assessing the endotoxin content of organic dusts. The Limulus Amebocyte Lysate (LAL) assay has emerged as the preferred assay but its ability to measure endotoxin in intact bacteria and organic dusts with similar sensitivity as purified endotoxin is unknown. We used metabolically radiolabeled Neisseria meningitidis and both rough and smooth Escherichia coli to compare dose-dependent activation in the LAL with purified endotoxin from these bacteria and shed outer membrane (OM) blebs. Bacteria labeled with [14C]-3-OH-fatty acids were used to quantify the endotoxin content of the samples. Purified meningococcal and E. coli endotoxins and OM blebs displayed similar specific activity in the LAL assay to the purified LPS standard. In contrast, intact bacteria exhibited 5-fold lower specific activity in the LAL assay but showed similar MD-2-dependent potency as purified endotoxin in inducing acute airway inflammation in mice. Pretreatment of intact bacteria and organic dusts with 0.1M Tris-HCl/10mM EDTA increased by 5-fold the release of endotoxin. These findings demonstrate that house dust and other organic dusts should be extracted with Tris/EDTA to more accurately assess the endotoxin content and pro-inflammatory potential of these environmental samples. PMID:28359219

Detection of endotoxins and other pyrogens using human whole blood.

PubMed

Fennrich, S; Fischer, M; Hartung, T; Lexa, P; Montag-Lessing, T; Sonntag, H G; Weigandt, M; Wendel, A

1999-01-01

When cells of the immune system, i.e. primarily blood monocytes and macrophages, come into contact with pyrogens (fever-inducing contaminations) they release mediators transmitting the fever reaction through the organism to the thermoregulatory centres of the brain. The new test discussed here exploits this reaction for the detection of pyrogens: human whole blood taken from healthy volunteers is incubated in the presence of the test sample. If there is pyrogen contamination, the endogenous pyrogen interleukin-1 is released, which is then determined by ELISA. According to the pharmacopoeia, the rabbit pyrogen test determines the fever reaction following injection of a test sample. In comparison, the new whole blood assay is more sensitive, less expensive and determines the reaction of the targeted species. Compared to the well established in vitro alternative, i.e. the limulus amebocyte lysate assay (LAL), the new blood assay is not restricted to endotoxins of gram-negative bacteria, it is not affected by endotoxin-binding blood proteins and it reflects the potency of different endotoxin preparations in mammals. Here, interim results of the ongoing optimization and pre-validation are reported and the present state of the evaluation for biological and pharmaceutical drugs are presented.

Addressing endotoxin issues in bioengineered heparin.

PubMed

Suwan, Jiraporn; Torelli, Amanda; Onishi, Akihiro; Dordick, Jonathan S; Linhardt, Robert J

2012-01-01

Heparin is a widely used clinical anticoagulant that is prepared from pig intestine. A contamination of heparin in 2008 has led to a reexamination of animal-derived pharmaceuticals. A bioengineered heparin prepared by bacterial fermentation and chemical and enzymatic processing is currently under development. This study examines the challenges of reducing or removing endotoxins associated with this process that are necessary to proceed with preclinical in vivo evaluation of bioengineered heparin. The current process is assessed for endotoxin levels, and strategies are examined for endotoxin removal from polysaccharides and enzymes involved in this process. © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Risks associated with endotoxins in feed additives produced by fermentation.

PubMed

Wallace, R John; Gropp, Jürgen; Dierick, Noël; Costa, Lucio G; Martelli, Giovanna; Brantom, Paul G; Bampidis, Vasileios; Renshaw, Derek W; Leng, Lubomir

2016-01-15

Increasingly, feed additives for livestock, such as amino acids and vitamins, are being produced by Gram-negative bacteria, particularly Escherichia coli. The potential therefore exists for animals, consumers and workers to be exposed to possibly harmful amounts of endotoxin from these products. The aim of this review was to assess the extent of the risk from endotoxins in feed additives and to calculate how such risk can be assessed from the properties of the additive. Livestock are frequently exposed to a relatively high content of endotoxin in the diet: no additional hazard to livestock would be anticipated if the endotoxin concentration of the feed additive falls in the same range as feedstuffs. Consumer exposure will be unaffected by the consumption of food derived from animals receiving endotoxin-containing feed, because the small concentrations of endotoxin absorbed do not accumulate in edible tissues. In contrast, workers processing a dusty additive may be exposed to hazardous amounts of endotoxin even if the endotoxin concentration of the product is low. A calculation method is proposed to compare the potential risk to the worker, based on the dusting potential, the endotoxin concentration and technical guidance of the European Food Safety Authority, with national exposure limits.

Equine uveitis: a UK perspective.

PubMed

Lowe, R C

2010-03-01

Uveitis in the equine population of the UK does not appear to be as prevalent or disastrous as seen across regions of Europe and the USA. Some cases perceived to be recurrent uveitis may be poorly resolved single episodes of uveitis and care should be taken not to make the diagnosis of recurrence without ensuring effective control of the initial episode. Leptospira spp. appear to play only a minor role ERU in the UK which is probably the main reason for the prevalence of the disease being much lower compared to the USA and mainland Europe. Actual data are relatively few on the ground as far as disease surveillance in concerned. This has 2 implications. Firstly unless we are able to effectively monitor the levels of uveitic disease, it will be difficult to pick up early changes in the trend which may allow quicker intervention. Secondly, it is difficult to secure funding for further research if the prevalence of the problem is poorly defined. This may leave the UK equine population at risk should the disease profile suddenly alter for the worse.

Oxidative degradation of endotoxin by advanced oxidation process (O3/H2O2 & UV/H2O2).

PubMed

Oh, Byung-Taek; Seo, Young-Suk; Sudhakar, Dega; Choe, Ji-Hyun; Lee, Sang-Myeong; Park, Youn-Jong; Cho, Min

2014-08-30

The presence of endotoxin in water environments may pose a serious public health hazard. We investigated the effectiveness of advanced oxidative processes (AOP: O3/H2O2 and UV/H2O2) in the oxidative degradation of endotoxin. In addition, we measured the release of endotoxin from Escherichia coli following typical disinfection methods, such as chlorine, ozone alone and UV, and compared it with the use of AOPs. Finally, we tested the AOP-treated samples in their ability to induce tumor necrosis factor alpha (TNF-α) in mouse peritoneal macrophages. The production of hydroxyl radical in AOPs showed superior ability to degrade endotoxin in buffered solution, as well as water samples from Korean water treatment facilities, with the ozone/H2O2 being more efficient compared to UV/H2O2. In addition, the AOPs proved effective not only in eliminating E. coli in the samples, but also in endotoxin degradation, while the standard disinfection methods lead to the release of endotoxin following the bacteria destruction. Furthermore, in the experiments with macrophages, the AOPs-deactivated endotoxin lead to the smallest induction of TNF-α, which shows the loss of inflammation activity, compared to ozone treatment alone. In conclusion, these results suggest that AOPs offer an effective and mild method for endotoxin degradation in the water systems. Copyright © 2014 Elsevier B.V. All rights reserved.

Safety and benefits of inhaled hypertonic saline following airway challenges with endotoxin and allergen in asthmatics.

PubMed

Alexis, Neil E; Bennett, William; Peden, David Blaine

2017-11-01

To determine whether induced sputum (IS) with hypertonic saline inhalation is safe to use in asthmatics within 24 hours of two commonly used airway challenges, namely endotoxin and dust mite allergen, and to assess whether IS can enhance mucociliary clearance (MCC) rates in asthmatics. IS (three 7-minute inhalation periods of 3%, 4%, and 5% hypertonic saline) was employed before (N = 29) and within 24 hours of inhaled challenges with endotoxin (N = 13) and dust mite allergen (N = 12) in a cohort of mild to moderate asthmatics. Safety was assessed by lung function (Forced Expiratory Volume in 1 second; FEV1) and MCC was measured using a radiolabeled gamma scintigraphy method (Tcm99 sulfur colloid). IS was performed pre and post MCC. No significant lung function decrement was observed before or after inhaled challenges with endotoxin or dust mite allergen. IS significantly enhanced MCC rates before and after inhaled endotoxin challenge. Based on a small cohort, IS is safe to use in mild to moderate asthmatics before and within 24 hours of inhaled challenges with endotoxin and dust mite allergen. Furthermore, IS has beneficial effects on host defense function in asthmatics by enhancing MCC rates.

Dexamethasone intravitreal implant for the treatment of noninfectious uveitis

PubMed Central

Hunter, Rebecca S; Lobo, Ann-Marie

2011-01-01

Uveitis can be a sight-threatening eye disease with significant morbidity. Corticosteroids remain the mainstay of treatment of uveitis and provide an effective treatment against ocular inflammation. However, the various modes available for corticosteroid drug delivery can carry significant ocular and systemic side effects which can limit their use in the treatment of uveitis. In an effort to avoid the damage to ocular structures that can ensue with recurrent episodes of ocular inflammation, the side effects associated with systemic steroids, and the need for repeated administration of both topical and locally injected corticosteroids, sustained-release intraocular corticosteroid implants have been developed. The dexamethasone (DEX) drug delivery system (Ozurdex®; Allergan Inc, Irvine, CA), is a biodegradable intravitreal implant. This implant has been shown to be effective in the treatment of macular edema and noninfectious posterior uveitis and has been approved by the FDA for these entities. This review will highlight the current methods available for corticosteroid delivery to the eye with a particular emphasis on the DEX intravitreal implant and the evidence currently available for its use in noninfectious uveitis. PMID:22140307

Current therapeutic approaches to autoimmune chronic uveitis in children.

PubMed

Simonini, Gabriele; Cantarini, Luca; Bresci, Cecilia; Lorusso, Monica; Galeazzi, Mauro; Cimaz, Rolando

2010-08-01

Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, non-infectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, e.g. juvenile idiopathic arthritis (JIA), a significant number of cases in children show no associated signs or symptoms, and are labelled as idiopathic. Taking into account this evidence, an anti-inflammatory therapy based on an immuno-modulatory approach seems a reasonable strategy for non-infectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive drugs are supported only at evidence level III. The aim of this review is to report currently available medical strategies for treatment of childhood sight-threatening chronic uveitis; in addition, a step-by-step approach to the use of immunosuppressants in this context is suggested. 2010 Elsevier B.V. All rights reserved.

Benefits of Systemic Anti-inflammatory Therapy versus Fluocinolone Acetonide Intraocular Implant for Intermediate Uveitis, Posterior Uveitis, and Panuveitis: Fifty-four-Month Results of the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study.

PubMed

Kempen, John H; Altaweel, Michael M; Drye, Lea T; Holbrook, Janet T; Jabs, Douglas A; Sugar, Elizabeth A; Thorne, Jennifer E

2015-10-01

To compare the benefits of fluocinolone acetonide implant therapy versus systemic corticosteroid therapy supplemented (when indicated) with immunosuppression for intermediate uveitis, posterior uveitis, and panuveitis. Additional follow-up of a randomized comparative effectiveness trial cohort. Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis randomized to implant or systemic therapy. Best-corrected visual acuity (BCVA), visual field mean deviation (MD), activity of uveitis, and presence of macular edema (per reading center grading) ascertained prospectively. Trial participants were followed-up for 54 months from original randomization. The visual function trajectory in uveitic eyes demonstrated a similar (P = 0.73) degree of modest (not statistically significant) improvement from baseline to 54 months in both groups (mean improvement in BCVA at 54 months, 2.4 and 3.1 letters in the implant and systemic groups, respectively). Many had excellent initial visual acuity, limiting the potential for improvement. The mean automated perimetry MD score remained similar to baseline throughout 48 months of follow-up in both groups. Overall control of inflammation was superior in the implant group at every time point assessed (P < 0.016), although most eyes in the systemic therapy arm also showed substantial improvement, achieving complete control or low levels of inflammation. Although macular edema improved significantly more often with implant treatment within the first 6 months, the systemic group gradually improved over time such that the proportions with macular edema converged in the 2 groups by 36 months and overlapped thereafter (P = 0.41 at 48 months). Visual outcomes of fluocinolone acetonide implant and systemic treatment for intermediate uveitis, posterior uveitis, and panuveitis were similarly favorable through 54 months. The implant maintained a clear advantage in controlling inflammation through 54 months. Nevertheless

Endotoxin- and ATP-neutralizing activity of alkaline phosphatase as a strategy to limit neuroinflammation

PubMed Central

2012-01-01

Background Alkaline phosphatase (AP) is a ubiquitously expressed enzyme which can neutralize endotoxin as well as adenosine triphosphate (ATP), an endogenous danger signal released during brain injury. In this study we assessed a potential therapeutic role for AP in inhibiting neuroinflammation using three complementary approaches. Methods Mice were immunized to induce experimental autoimmune encephalomyelitis (EAE) and treated with AP for seven days during different phases of disease. In addition, serological assays to determine AP activity, endotoxin levels and endotoxin-reactive antibodies were performed in a cohort of multiple sclerosis (MS) patients and controls. Finally, the expression of AP and related enzymes CD39 and CD73 was investigated in brain tissue from MS patients and control subjects. Results AP administration during the priming phase, but not during later stages, of EAE significantly reduced neurological signs. This was accompanied by reduced proliferation of splenocytes to the immunogen, myelin oligodendrocyte glycoprotein peptide. In MS patients, AP activity and isoenzyme distribution were similar to controls. Although endotoxin-reactive IgM was reduced in primary-progressive MS patients, plasma endotoxin levels were not different between groups. Finally, unlike AP and CD73, CD39 was highly upregulated on microglia in white matter lesions of patients with MS. Conclusions Our findings demonstrate that: 1) pre-symptomatic AP treatment reduces neurological signs of EAE; 2) MS patients do not have altered circulating levels of AP or endotoxin; and 3) the expression of the AP-like enzyme CD39 is increased on microglia in white matter lesions of MS patients. PMID:23231745

Some effects of prostaglandins E1 and E2 and of endotoxin injected into the hypothalamus of young chicks: dissociation between endotoxin fever and the effects of prostaglandins.

PubMed

Artunkal, A A; Marley, E; Stephenson, J D

1977-09-01

Prostaglandins E1 and E2 elevated body temperature of young chicks when injected into the hypothalamus at thermoneutrality (31 degrees C). In contrast, they lowered body temperature when so injected below thermoneutrality (16degreesC): the relation of the fall in body temperature to increased heat loss and decreased heat production was examined. 2 The above effects below thermoneutrality were potentiated by pretreatment with inhibitors of prostaglandin synthetase and possible reasons for this potentation are given. 3 The O-somatic antigen of Shigella dysenteriae consistently evoked hyperthermia when injected into the hypothalamus, irrespective of whether the chicks were within or below thermoneutrality. 4 Pretreatment with prostaglandin synthetase inhibitors failed to prevent the onset of endotoxin fever; however, duration of the fever, induced by intrahypothalamic injection of the O-somatic antigen of Shigella dysenteriae was reduced. 5 The intrahypothalamic injection, belwo thermoneutrality of prostaglandins E1, E2, noradrenaline, 5-hydroxytryptamine or carbachol reversed endotoxin fever, inducing even substantial falls in body temperature. 6 While the results cast some doubts on the role of prostaglandins of the E series as mediators of endotoxin fever in chicks, they cannot be eliminated as mediators until the significance of the reduction in duration of the pyrexic response by indomethacin and 5,8,11,14-eicosatetraynoic acid, and the degree of synthesis inhibition attained, are known.

Some effects of prostaglandins E1 and E2 and of endotoxin injected into the hypothalamus of young chicks: dissociation between endotoxin fever and the effects of prostaglandins.

PubMed Central

Artunkal, A A; Marley, E; Stephenson, J D

1977-01-01

Prostaglandins E1 and E2 elevated body temperature of young chicks when injected into the hypothalamus at thermoneutrality (31 degrees C). In contrast, they lowered body temperature when so injected below thermoneutrality (16degreesC): the relation of the fall in body temperature to increased heat loss and decreased heat production was examined. 2 The above effects below thermoneutrality were potentiated by pretreatment with inhibitors of prostaglandin synthetase and possible reasons for this potentation are given. 3 The O-somatic antigen of Shigella dysenteriae consistently evoked hyperthermia when injected into the hypothalamus, irrespective of whether the chicks were within or below thermoneutrality. 4 Pretreatment with prostaglandin synthetase inhibitors failed to prevent the onset of endotoxin fever; however, duration of the fever, induced by intrahypothalamic injection of the O-somatic antigen of Shigella dysenteriae was reduced. 5 The intrahypothalamic injection, belwo thermoneutrality of prostaglandins E1, E2, noradrenaline, 5-hydroxytryptamine or carbachol reversed endotoxin fever, inducing even substantial falls in body temperature. 6 While the results cast some doubts on the role of prostaglandins of the E series as mediators of endotoxin fever in chicks, they cannot be eliminated as mediators until the significance of the reduction in duration of the pyrexic response by indomethacin and 5,8,11,14-eicosatetraynoic acid, and the degree of synthesis inhibition attained, are known. PMID:334308

The future of uveitis treatment.

PubMed

Lin, Phoebe; Suhler, Eric B; Rosenbaum, James T

2014-01-01

Uveitis is a heterogeneous collection of diseases with polygenic and environmental influences. This heterogeneity presents challenges in trial design and selection of end points. Despite the multitude of causes, therapeutics targeting common inflammatory pathways are effective in treating diverse forms of uveitis. These treatments, including corticosteroids and immunomodulatory agents, although often effective, can have untoward side effects, limiting their utility. The search for drugs with equal or improved efficacy that are safe is therefore paramount. A mechanism-based approach is most likely to yield the future breakthroughs in the treatment of uveitis. We review the literature and provide examples of the nuances of immune regulation and dysregulation that can be targeted for therapeutic benefit. As our understanding of the causes of uveitis grows we will learn how to better apply antibodies designed to block interaction between inflammatory cytokines and their receptors. T-lymphocyte activation can be targeted by blocking co-stimulatory pathways or inhibiting major histocompatibility complex protein interactions. Furthermore, intracellular downstream molecules from cytokine or other pathways can be inhibited using small molecule inhibitors, which have the benefit of being orally bioavailable. An emerging field is the lipid-mediated inflammatory and regulatory pathways. Alternatively, anti-inflammatory cytokines can be provided by administering recombinant protein, and intracellular "brakes" of inflammatory pathways can be introduced potentially by gene therapy. Novel approaches of delivering a therapeutic substance include, but are not limited to, the use of small interfering RNA, viral and nonviral gene therapy, and microparticle or viscous gel sustained-release drug-delivery platforms. Copyright © 2014. Published by Elsevier Inc.

Uveitis in spondyloarthritis including psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.

PubMed

Rosenbaum, James T

2015-06-01

Uveitis is a common complication of spondyloarthritis. The "phenotype" of the uveitis characteristic of ankylosing spondylitis (sudden onset, anterior, unilateral, recurrent, more often male) may differ from the phenotype often seen with either psoriatic arthritis or inflammatory bowel disease (insidious onset, anterior and intermediate, bilateral, chronic, and/or more often female). The frequency of uveitis is also much greater in association with ankylosing spondylitis than with either inflammatory bowel disease or psoriasis. Uveitis may affect the choice of therapy and can rarely be a complication of therapy. Uveitis and arthritis also co-exist in several animal models.

Assessment of diagnostic and therapeutic vitrectomy for vitreous opacity associated with uveitis with various etiologies

PubMed Central

Sato, Tomohito; Kinoshita, Rina; Taguchi, Manzo; Sugita, Sunao; Kaburaki, Toshikatsu; Sakurai, Yutaka; Takeuchi, Masaru

2018-01-01

Abstract Vitreous opacity (VO) is a common feature of intermediate uveitis, posterior uveitis, and panuveitis. Fundus observation is critical for determining the etiology of uveitis, however, is often interfered with VO. In these clinical settings, vitrectomy contributes to a correct diagnosis and guides alternative management strategies. The purpose of this study was to evaluate the diagnostic yield and surgical outcome of vitrectomy in uveitic patients with VO and compare the visual outcome between infectious and noninfectious uveitis. Forty-five eyes with uveitis-associated VO underwent diagnostic and therapeutic vitrectomy, and etiological diagnosis of uveitis was confirmed in 34 of 45 eyes (75.6%). The diagnoses were infectious uveitis in 13 eyes (28.9%), noninfectious uveitis in 21 eyes (46.7%), and unidentified uveitis in 11 eyes (24.4%). Visual acuity (VA) improvement rates at 6 months after surgery were 69.2%, 76.2%, and 90.9% in the infectious, noninfectious, and unidentified uveitis groups, with no significant difference among 3 groups. Significant decrease in inflammation score after vitrectomy was observed only in the infectious uveitis group. This study demonstrated that diagnostic vitrectomy for inflammatory eyes with VO of unknown etiology was effective in infectious and noninfectious uveitis, and the therapeutic effect of VA improvement was observed in both types of uveitis. PMID:29480837

HL-A27 and anterior uveitis.

PubMed

Woodrow, J C; Mapstone, R; Anderson, J; Usher, N

1975-09-01

HL-A types were determined in 90 successive patients with non-granulomatous uveitis. Fifty-one were HL-A27 positive (55.7%) compared to 8.2% of controls. Of 16 patients with ankylosing spondylitis, 13 were HL-A27 positive, as were two patients with a history of Reiter's syndrome. Twenty-eight patients were HL-A27 positive but had no evidence of rheumatic disease. The findings are discussed in relation to the possible pathogenesis of uveitis.

Endotoxin removal by radio frequency gas plasma (glow discharge)

NASA Astrophysics Data System (ADS)

Poon, Angela

2011-12-01

-IR measurements were repeated after employing 3-minute RFGD treatments sequentially for more than 10 cycles to observe removal of deposited matter that correlated with diminished EU titers. The results showed that 5 cycles, for a total exposure time of 15 minutes to low-temperature gas plasma, was sufficient to reduce endotoxin titers to below 0.05 EU/ml, and correlated with concurrent reduction of major endotoxin reference standard absorption bands at 3391 cm-1, 2887 cm-1, 1646 cm -1 1342 cm-1, and 1103 cm-1 to less than 0.05 Absorbance Units. Band depletion varied from 15% to 40% per 3-minute cycle of RFGD exposure, based on peak-to-peak analyses. In some cases, 100% of all applied biomass was removed within 5 sequential 3-minute RFGD cycles. The lipid ester absorption band expected at 1725 cm-1 was not detectable until after the first RFGD cycle, suggesting an unmasking of the actual bacterial endotoxin membrane induced within the gas plasma environment. Future work must determine the applicability of this low-temperature, quick depyrogenation process to medical devices of more complicated geometry than the flat surfaces tested here.

Targeting interleukin-6 for noninfectious uveitis

PubMed Central

Lin, Phoebe

2015-01-01

Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in the pathogenesis of many immune-mediated disorders including several types of non-infectious uveitis. These uveitic conditions include Vogt-Koyanagi-Harada syndrome, uveitis associated with Behçet disease, and sarcoidosis. This review summarizes the role of IL-6 in immunity, highlighting its effect on Th17, Th1, and plasmablast differentiation. It reviews the downstream mediators activated in the process of IL-6 binding to its receptor complex. This review also summarizes the biologics targeting either IL-6 or the IL-6 receptor, including tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab, and siltuximab. The target, dosage, potential side effects, and potential uses of these biologics are summarized in this article based on the existing literature. In summary, anti-IL-6 therapy for non-infectious uveitis shows promise in terms of efficacy and side effect profile. PMID:26392750

Protective effect of aescin from the seeds of Aesculus hippocastanum on liver injury induced by endotoxin in mice.

PubMed

Jiang, Na; Xin, Wenyu; Wang, Tian; Zhang, Leiming; Fan, Huaying; Du, Yuan; Li, Chong; Fu, Fenghua

2011-11-15

To investigate the effect and underlying mechanism of aescin on acute liver injury induced by endotoxin, liver injury was established by injecting lipopolysaccharide (LPS) in mice. Animals were assigned to seven groups: the control group and groups treated with LPS (40 mg/kg), aescin (3.6 mg/kg), LPS plus dexamethasone (4 mg/kg) and LPS plus aescin (0.9, 1.8 or 3.6 mg/kg). Hepatic histopathological changes were examined under a light microscope. Activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were determined. Levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO) and antioxidative parameters in liver homogenate were measured. Glucocorticoid receptor (GR), 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expressions in liver were determined by western blotting. Treatment with escin could inhibit immigration of inflammatory cells, alleviate the degree of necrosis, and decrease serum ALT and AST activities. Aescin also down-regulated levels of inflammation mediators (TNF-α, IL-1β and NO) and 11β-HSD2 expression in liver, up-regulated GR expression, enhanced endogenous antioxidative capacity, but have no obvious effect on 11β-HSD1 expression in liver. The findings suggest aescin has protective effects on endotoxin-induced liver injury, and the underlying mechanisms were associated with its anti-inflammatory effects, up-regulating GR expression, down-regulating 11β-HSD2 experssion, and antixoidation. Copyright © 2011 Elsevier GmbH. All rights reserved.

Regulation of endotoxin-induced inhibition of macrophage migration by fresh serum.

PubMed Central

Heilman, D H

1977-01-01

Purified endotoxin (LPS) caused macrophage migration inhibition (MMI) in capillary tube cultures of guinea pig peritoneal macrophages in medium prepared with 15% fresh-frozen guinea pig serum. The inactivation of serum by heating at 56 degrees C for 30 min or by zymosan absorption prevented LPS-induced MMI. LPS was fully inhibitory in fresh C4-deficient guinea pig serum. Heat treatment of normal serum at 50 to 52 degrees C for 30 min to inactivate the alternate complement (C) pathway prevented or significantly decreased LPS-induced MMI, but heating C4-deficient serum at 50 to 52 degrees C for 30 min prevented LPS-MMI in all instances. These results suggest that the reaction was effected via the alternate C pathway but that some inhibition of migration was permitted via the classical C pathway, presumably due to antibodies for LPS in some normal sera. Pretreatment of normal serum with cobra venom factor decreased or prevented LPS-MMI in most instances, but similar results were obtained with C4-deficient serum. Experiments with chelated sera were unsuccessful because of the immobilization of macrophages by 10 mM ethylenediamine-tetraacetic acid and by 10 mM Mg-ethyleneglycol-bis (beta-aminoethyl)-N,N-tetraacetic acid. Low doses of concanavalin A and staphylococcal enterotoxin B and large doses of pokeweed mitogen caused MMI in "inactivated serum" medium, but MMI was enhanced in fresh serum. PMID:330407

Readability Assessment of Online Uveitis Patient Education Materials.

PubMed

Ayoub, Samantha; Tsui, Edmund; Mohammed, Taariq; Tseng, Joseph

2017-12-29

To evaluate the readability of online uveitis patient education materials. A Google search in November 2016 was completed using search term "uveitis" and "uveitis inflammation." The top 50 websites with patient-centered information were selected and analyzed for readability using the Flesch-Kincaid Grade Level (FKGL), Flesch Reading Ease Score (FRES), Gunning FOG Index (GFI), and Simple Measure of Gobbledygook (SMOG). Statistical analysis was performed with two-tailed t-tests. The mean word count of the top 50 websites was 1162.7 words, and averaged 16.2 words per sentence. For these websites, the mean FRES was 38.0 (range 4-66, SD = 12.0), mean FKGL was 12.3 (range 6.8-19, SD = 2.4), mean SMOG score was 14.4 (range 9.8-19, SD = 1.8), and the mean Gunning FOG index was 14.0 (range 8.6-19, SD = 2.0). The majority of online patient directed uveitis materials are at a higher reading level than that of the average American adult.

Extracorporeal Perfusion without Exogenous Anticoagulation: Its Protective Role in Endotoxin Shock.

DTIC Science & Technology

1982-02-19

lethal effects of endotoxin . Group E: Heparinized dogs given endotoxin ; no perfusion. This group served to evaluate the effects of heparin on...recovery from endotoxin shock. Group F: Heparinized dogs perfused 90 minutes; then given endotoxin . This group served to assay the effects of exogenous...stable model and is preperfusion neces- sary to provide protection against the lethal effects of endotoxin ? The first series of experiments (Group B) were

Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?

PubMed

Fazio, Francesco; Carrizzo, Albino; Lionetto, Luana; Damato, Antonio; Capocci, Luca; Ambrosio, Mariateresa; Battaglia, Giuseppe; Bruno, Valeria; Madonna, Michele; Simmaco, Maurizio; Nicoletti, Ferdinando; Vecchione, Carmine

2017-01-01

The kynurenine pathway of tryptophan metabolism is activated by pro-inflammatory cytokines. L-kynurenine, an upstream metabolite of the pathway, acts as a putative endothelium-derived relaxing factor, and has been hypothesized to play a causative role in the pathophysiology of inflammation-induced hypotension. Here, we show that xanthurenic acid (XA), the transamination product of 3-hydroxykynurenine, is more efficacious than L-kynurenine in causing relaxation of a resistance artery, but fails to relax pre-contracted aortic rings. In the mesenteric artery, XA enhanced activating phosphorylation of endothelial nitric oxide synthase (NOS), and the relaxing action of XA was abrogated by pharmacological inhibition of NOS and endothelial-derived hyperpolarizing factor. Systemic injection of XA reduced blood pressure in mice, and serum levels of XA increased by several fold in response to a pulse with the endotoxin, lipopolysaccharide (LPS). LPS-induced hypotension in mice was prevented by pre-treatment with the kynurenine monooxygenase (KMO) inhibitor, Ro-618048, which lowered serum levels of XA but enhanced serum levels of L-kynurenine. UPF 648, another KMO inhibitor, could also abrogate LPS-induced hypotension. Our data identify XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension.

Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?

PubMed Central

Fazio, Francesco; Carrizzo, Albino; Lionetto, Luana; Damato, Antonio; Capocci, Luca; Ambrosio, Mariateresa; Battaglia, Giuseppe; Bruno, Valeria; Madonna, Michele; Simmaco, Maurizio; Nicoletti, Ferdinando; Vecchione, Carmine

2017-01-01

The kynurenine pathway of tryptophan metabolism is activated by pro-inflammatory cytokines. L-kynurenine, an upstream metabolite of the pathway, acts as a putative endothelium-derived relaxing factor, and has been hypothesized to play a causative role in the pathophysiology of inflammation-induced hypotension. Here, we show that xanthurenic acid (XA), the transamination product of 3-hydroxykynurenine, is more efficacious than L-kynurenine in causing relaxation of a resistance artery, but fails to relax pre-contracted aortic rings. In the mesenteric artery, XA enhanced activating phosphorylation of endothelial nitric oxide synthase (NOS), and the relaxing action of XA was abrogated by pharmacological inhibition of NOS and endothelial-derived hyperpolarizing factor. Systemic injection of XA reduced blood pressure in mice, and serum levels of XA increased by several fold in response to a pulse with the endotoxin, lipopolysaccharide (LPS). LPS-induced hypotension in mice was prevented by pre-treatment with the kynurenine monooxygenase (KMO) inhibitor, Ro-618048, which lowered serum levels of XA but enhanced serum levels of L-kynurenine. UPF 648, another KMO inhibitor, could also abrogate LPS-induced hypotension. Our data identify XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension. PMID:28507519

Inactivation of Escherichia coli Endotoxin by Soft Hydrothermal Processing▿

PubMed Central

Miyamoto, Toru; Okano, Shinya; Kasai, Noriyuki

2009-01-01

Bacterial endotoxins, also known as lipopolysaccharides, are a fever-producing by-product of gram-negative bacteria commonly known as pyrogens. It is essential to remove endotoxins from parenteral preparations since they have multiple injurious biological activities. Because of their strong heat resistance (e.g., requiring dry-heat sterilization at 250°C for 30 min) and the formation of various supramolecular aggregates, depyrogenation is more difficult than sterilization. We report here that soft hydrothermal processing, which has many advantages in safety and cost efficiency, is sufficient to assure complete depyrogenation by the inactivation of endotoxins. The endotoxin concentration in a sample was measured by using a chromogenic limulus method with an endotoxin-specific limulus reagent. The endotoxin concentration was calculated from a standard curve obtained using a serial dilution of a standard solution. We show that endotoxins were completely inactivated by soft hydrothermal processing at 130°C for 60 min or at 140°C for 30 min in the presence of a high steam saturation ratio or with a flow system. Moreover, it is easy to remove endotoxins from water by soft hydrothermal processing similarly at 130°C for 60 min or at 140°C for 30 min, without any requirement for ultrafiltration, nonselective adsorption with a hydrophobic adsorbent, or an anion exchanger. These findings indicate that soft hydrothermal processing, applied in the presence of a high steam saturation ratio or with a flow system, can inactivate endotoxins and may be useful for the depyrogenation of parenterals, including end products and medical devices that cannot be exposed to the high temperatures of dry heat treatments. PMID:19502435

Profile of patients with uveitis referred to a multidisciplinary unit in northern Spain.

PubMed

Fanlo, P; Heras, H; Pérez, D; Tiberio, G; Espinosa, G; Adan, A

2017-05-01

To describe the main characteristics of a cohort of patients with uveitis referred to a multidisciplinary unit in northern Spain. Retrospective analysis of clinical records of patients evaluated in the Multidisciplinary Unit of the Navarra Hospital Complex from the period January 2010 until March 2015. An analysis was performed on the demographic characteristics, origin, types of uveitis, laterality, and aetiology. The present series was also compared with 2 previous series from Castilla y León and Barcelona. A total of 500 patients were identified, with a mean age of 47.9±16.4 years, with 50% women. The most frequent type of uveitis was anterior uveitis (65.4%), followed by posterior uveitis (17.6%), panuveitis (15.2%), and intermediate uveitis (1.8%). The origin was unclassifiable in 31.2%, followed by non-infectious systemic disease in 29.2%. Ankylosing spondylitis was the most frequent cause in 10.8% of patients, followed by herpes infection in 9.2%, and toxoplasmosis in 7.8%, respectively. Compared with the 2other cohorts, the present cohort showed a higher proportion of unilateral anterior uveitis. Furthermore, the patients from the Navarra series had a higher prevalence of unilateral and idiopathic uveitis compared to the series from Barcelona. The main characteristics of the present cohort of patients with uveitis are similar to those of patients from other regions of our country. Unilateral anterior uveitis and idiopathic uveitis were the most frequent in our series. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

[The clinical investigation of peripheral retinal changes of anterior uveitis].

PubMed

Guo, Chunying; Qiao, Lijun; Yang, Liu

2015-10-01

To observe the peripheral retinal changes of anterior uveitis patients using ultra-wide field fluorescein angiography. Retrospective case series study. Thirty-three eyes of 20 patients diagnosed as anterior uveitis from September to November 2013 in the ophthalmic clinic of Peking University First Hospital was included. All the patients underwent routine ocular examination, followed by ultra-wide field Fluorescein. There were 13 male patients and 7 female patients, aged 23-66, an average of 46 years old. The anterior uveitis recurrent in both eyes in 13 patients and only one eye in 7 patients. Uveitis duration ranging from months to 30 years. Twenty eyes were at the active stage of the anterior uveitis while 13 eyes in the quiescent stage. Peripheral retinal vessels leakage was detected in 57.6% (19/33) of the eyes, among which in eyes with active disease the rate of peripheral retinal vessels leakage was 75% (15/20), and in eyes with quiescent disease the rate was 30.8% (4/13). Optic disk hyperfluorescence was found in 6 of 20 eyes with active disease. Cystoid macular edema was found in 4 eyes. In addition, peripheral retinal hyperfluorescence dot and zone were detected in 2 eyes. Peripheral retinal vessels were detected to have inflammative leakage in patients of anterior uveitis by ultra-wide field fluorescein agiography. Peripheral retinal inflammation may still exist even in the quiescent stage of the anterior uveitis.

Association of leptospiral seroreactivity and breed with uveitis and blindness in horses: 372 cases (1986-1993).

PubMed

Dwyer, A E; Crockett, R S; Kalsow, C M

1995-11-15

Recurrent uveitis, a leading cause of blindness in horses, often develops as a sequela to systemic leptospirosis. Over a 7-year period, 63 of 112 (56%) horses with uveitis were seropositive for Leptospira interrogans serovar pomona, but only 23 of 260 (9%) horses without uveitis were seropositive. Odds-ratio analysis revealed that seropositive horses were 13.2 times more likely to have uveitis than were seronegative horses. Of the 63 seropositive horses with uveitis, 59% developed blindness, compared with only 24% in the 49 seronegative horses with uveitis that lost vision in 1 or both eyes during the same period. Odds-ratio analysis revealed that seropositive horses with uveitis were 4.4 times more likely to lose vision than were seronegative horses with uveitis. Of the 112 horses with uveitis, 28 (25%) were Appaloosas, compared with only 10 of the 260 (4%) horses without uveitis (odds ratio, 8.3). In addition, 19 of the 28 (68%) Appaloosas with uveitis developed blindness, compared with only 30 of the 84 (36%) non-Appaloosas with uveitis that lost vision in 1 or both eyes (odds ratio, 3.8). This field study therefore confirmed a strong positive relationship between uveitis and leptospiral seroreactivity in horses. Furthermore, the data suggested that seropositive horses with uveitis were at increased risk of losing vision, compared with that in seronegative horses with uveitis, and that Appaloosas were at increased risk of developing uveitis and associated blindness, compared with that in non-Appaloosas.

Equine recurrent uveitis: the viewpoint from the USA.

PubMed

Gilger, B C

2010-03-01

Equine recurrent uveitis (ERU) is a common disease in horses in the USA. There have been many advances in the treatment of ERU; however, frequent misdiagnosis of ERU occurs in cases of primary corneal or uveal disease. It is critical to remember that primary uveitis (i.e. one bout of inflammation) is a different disease to ERU, which is an immune mediated recurrent uveitis. Standard symptomatic anti-inflammatory therapy is effective to control most cases of ERU; however, some horses require advanced therapy, such as placement of drug delivery devices or removal of the vitreous, when they fail to respond to the standard therapy.

Response of Pediatric Uveitis to Tumor Necrosis Factor-α Inhibitors

PubMed Central

Lerman, Melissa A.; Burnham, Jon M.; Chang, Peter Y.; Daniel, Ebenezer; Foster, C. Stephen; Hennessy, Sean; Jabs, Douglas A.; Joffe, Marshall M.; Kaçmaz, R. Oktay; Levy-Clarke, Grace A.; Mills, Monte D.; Nussenblatt, Robert B.; Rosenbaum, James T.; Suhler, Eric B.; Thorne, Jennifer E.; Kempen, John H.

2013-01-01

Objectives To evaluate the outcome of TNF-alpha inhibition (anti-TNFα) for pediatric uveitis. Methods We retrospectively assessed children (≤18 years) with non-infectious uveitis receiving anti-TNFα at five uveitis centers and one pediatric-rheumatology center. Incident treatment success was defined as minimal or no uveitis activity at ≥2 consecutive ophthalmological exams ≥28 days apart while taking no oral and ≤2 eyedrops/day of corticosteroids. Eligible children had active uveitis and/or were taking higher corticosteroid doses. Results Among 56 eligible children followed over 33.73 person-years, 52% had juvenile idiopathic arthritis (JIA) and 75% had anterior uveitis (AU). The Kaplan-Meier estimated proportion achieving treatment success within 12 months was 75% (95% confidence interval [95% CI]: 62–87%). Complete absence of inflammatory signs with discontinuation of all corticosteroids was observed in an estimated 64% by 12 months (95% CI: 51–76%). Diagnoses of JIA or AU were associated with greater likelihood of success, as was the oligoarticular subtype amongst JIA cases. In a multivariable model, compared to those with JIA-associated AU, those with neither or with JIA or AU alone had a 75–80% lower rate of achieving quiescence under anti-TNFα - independent of the number of immunomodulators previously or concomitantly prescribed. Uveitis re-activated within 12 months of achieving quiescence in 14% of those continuing anti-TNFα (95% CI: 6–31%). The incidence of discontinuation for adverse effects was 8%/year (95% CI: 1–43%). Conclusion Treatment with anti-TNFα was successful and sustained in a majority of children with non-infectious uveitis and treatment-limiting toxicity was infrequent. JIA-associated AU may be especially responsive to anti-TNFα. PMID:23818712

Endotoxin inactivation by selected drinking water treatment oxidants.

PubMed

Anderson, William B; Mayfield, Colin I; Dixon, D George; Huck, Peter M

2003-11-01

Exposure to endotoxins in treated drinking water can occur through ingestion, dermal abrasions, inhalation of water vapor, intravenous injection or during dialysis. While the risks associated with endotoxin ingestion and entry through dermal abrasions are not well quantified, adverse effects of intravenous injection and dialysis are well known and some studies indicate that inhalation of moisture-laden air may impact human health. This study quantifies the inactivation of endotoxin derived from Escherichia coli O55:B5 by three substances used either as disinfectants or oxidants in drinking water treatment: chlorine, monochloramine and potassium permanganate. Inactivation rates were found to be 1.4, 1.0 and 0.7 endotoxin units (EU)/mL h, for free chlorine, potassium permanganate and monochloramine, respectively. These rates are relatively slow given that contact times in drinking water distribution systems are typically less than 48 h. While small amounts of endotoxin may be removed by oxidation the observed removals are much less than those provided by physical removal processes. The significance of this finding is important for dialysis considerations but is as yet unclear with regard to inhalation, as the risk of inhaling sufficient quantities of endotoxin-containing aerosolized water droplets to adversely affect human health has not yet been adequately quantified.

Hypo-responsiveness of interleukin-8 production in human embryonic epithelial intestine 407 cells independent of NF-{kappa}B pathway: New lessons from endotoxin and ribotoxic deoxynivalenol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moon, Yuseok; Yang, Hyun; Park, Seung-Hwan

Mucosal epithelium senses external toxic insults and transmits the danger signals into the epithelial cells in order to activate a broad range of inflammatory responses. However, pre-exposure to the commensal endotoxins can induce inflammatory tolerance and maintain the homeostasis without excessive immune responses. We recently reported that ribotoxin deoxynivalenol (DON) and its derivatives elicited the pro-inflammatory response as the mucosal insults in human epithelial cells. Taking the knowledge into consideration, we tested the hypothesis that endotoxin pre-exposure can attenuate ribotoxin-induced epithelial interleukin-8 (IL-8) production via a tolerance mechanism. Pre-exposure to endotoxin repressed IL-8 release and its gene expression. However, inflammatorymore » tolerance was not mediated by the attenuated NF-{kappa}B activation which has been generally recognized as the major mediator of LPS-mediated toll-like receptor (TLR) signaling pathway. Instead, pre-exposure to endotoxin was observed to trigger the delayed induction of peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) which contributed to the diminished IL-8 production in the human epithelial cells. Moreover, endogenous PPAR-{gamma} agonist suppressed toxicant-mediated interleukin-8 production and IL-8 mRNA stability. Taken together, endotoxin induced hypo-production of pro-inflammatory cytokine IL-8 in the human epithelial cells, which was associated with the delayed activation of PPAR-{gamma} expression by pre-existing endotoxin.« less

Personal endotoxin exposure in a panel study of school children with asthma

PubMed Central

2011-01-01

Background Endotoxin exposure has been associated with asthma exacerbations and increased asthma prevalence. However, there is little data regarding personal exposure to endotoxin in children at risk, or the relation of personal endotoxin exposure to residential or ambient airborne endotoxin. The relation between personal endotoxin and personal air pollution exposures is also unknown. Methods We characterized personal endotoxin exposures in 45 school children with asthma ages 9-18 years using 376 repeated measurements from a PM2.5 active personal exposure monitor. We also assayed endotoxin in PM2.5 samples collected from ambient regional sites (N = 97 days) and from a subset of 12 indoor and outdoor subject home sites (N = 109 and 111 days, respectively) in Riverside and Whittier, California. Endotoxin was measured using the Limulus Amoebocyte Lysate kinetic chromogenic assay. At the same time, we measured personal, home and ambient exposure to PM2.5 mass, elemental carbon (EC), and organic carbon (OC). To assess exposure relations we used both rank correlations and mixed linear regression models, adjusted for personal temperature and relative humidity. Results We found small positive correlations of personal endotoxin with personal PM2.5 EC and OC, but not personal PM2.5 mass or stationary site air pollutant measurements. Outdoor home, indoor home and ambient endotoxin were moderately to strongly correlated with each other. However, in mixed models, personal endotoxin was not associated with indoor home or outdoor home endotoxin, but was associated with ambient endotoxin. Dog and cat ownership were significantly associated with increased personal but not indoor endotoxin. Conclusions Daily fixed site measurements of endotoxin in the home environment may not predict daily personal exposure, although a larger sample size may be needed to assess this. This conclusion is relevant to short-term exposures involved in the acute exacerbation of asthma. PMID:21810249

Neural Substrate of Cold-Seeking Behavior in Endotoxin Shock

PubMed Central

Almeida, Maria C; Steiner, Alexandre A; Branco, Luiz G S; Romanovsky, Andrej A

2006-01-01

Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 µg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 µg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel (“warmth receptor”). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 (“cold receptor”). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock. PMID:17183631

Endotoxin contamination of apolipoprotein A-I: effect on macrophage proliferation--a cautionary tale.

PubMed

Jin, Xueting; Xu, Qing; Champion, Keith; Kruth, Howard S

2015-05-01

This technical report addresses the problem of endotoxin contamination of apolipoprotein reagents. Using a bromodeoxyuridine incorporation cell proliferation assay, we observed that human plasma ApoA-I as low as 1 μg/ml resulted in a >90% inhibition in macrophage proliferation. However, not all ApoA-I from different sources showed this effect. We considered the possibility that endotoxin contamination of the apolipoproteins contributed to the differential inhibition of macrophage cell proliferation. Endotoxin alone very potently inhibited macrophage proliferation (0.1 ng/ml inhibited macrophage proliferation>90%). Measurement of endotoxin levels in the apolipoprotein products, including an analysis of free versus total endotoxin, the latter which included endotoxin that was masked due to binding to protein, suggested that free endotoxin mediated inhibition of macrophage proliferation. Despite the use of an advanced endotoxin removal procedure and agents commonly used to inhibit endotoxin action, the potency of endotoxin precluded successful elimination of endotoxin effect. Our findings show that endotoxin contamination can significantly influence apparent apolipoprotein-mediated cell effects (or effects of any other biological products), especially when these products are tested on highly endotoxin-sensitive cells, such as macrophages. Published by Elsevier Ireland Ltd.

Management of cataract in uveitis patients.

PubMed

Conway, Mandi D; Stern, Ethan; Enfield, David B; Peyman, Gholam A

2018-01-01

This review is timely because the outcomes of surgical invention in uveitic eyes with cataract can be optimized with adherence to strict anti-inflammatory principles. All eyes should be free of any cell/ flare for a minimum of 3 months preoperatively. Another helpful maneuver is to place dexamethasone in the infusion fluid or triamcinolone intracamerally at the end of surgery. Recent reports about the choice of intraocular lens material or lens design are germane to the best surgical outcome. Integrating these findings will promote better visual outcomes and allow advancement in research to further refine these surgical interventions in high-risk uveitic eyes. Control of inflammation has been shown to greatly improve postoperative outcomes in patients with uveitis. Despite better outcomes, more scientific research needs to be done regarding lens placement and materials and further research needs to adhere to the standardized reporting of uveitis nomenclature. Future studies should improve postoperative outcomes in eyes with uveitis so that they approach those of eyes undergoing routine cataract procedures.

Uveitis in the elderly: epidemiological data from the National Long-term Care Survey Medicare Cohort.

PubMed

Reeves, Sherman W; Sloan, Frank A; Lee, Paul P; Jaffe, Glenn J

2006-02-01

There is a paucity of population-based data on the epidemiology of uveitis in the elderly. In the past 40 years, only 2 U.S. population-based studies have examined the epidemiology of uveitis. The conclusions of these studies on the burden of uveitis in the elderly differ greatly. In this analysis, we use Medicare claims data to define the population-based incidence and prevalence of uveitis in the United States elderly population. Cohort study. A cohort of 21644 Medicare beneficiaries drawn for the National Long-term Care Survey, a random sample of U.S. adults 65 years and older, was followed up from 1991 through 1999. The International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes specific to uveitis were queried. To decrease the inclusion of uveitis caused by surgery, diagnoses occurring within 3 months of intraocular surgery were excluded. The incidence and prevalence of uveitis by anatomic location was calculated for each year in the study. The onset of uveitis during a given year and its presence in subsequent years. The cumulative yearly incidence of uveitis ranged from 302/100000 to 424/100000 persons per year and averaged 340.9/100000 persons per year. Anterior uveitis was the most common form of uveitis in this population, with a mean incidence of 243.6 cases per 100000 persons per year. The incidence of posterior uveitis averaged 76.6/100000 and the incidence of panuveitis/endophthalmitis averaged 41.7/100000. Only 2 cases of intermediate uveitis occurred during the study period. The cumulative prevalence of uveitis doubled from 511/100000 in 1991 to 1231/100000 in 1999, with anterior uveitis accounting for most prevalent cases in every year. The burden of uveitis in the elderly is substantial and is higher than previously thought. Longitudinal analysis of Medicare claims data may provide a useful tool for monitoring uncommon diseases, such as uveitis, in the elderly population.

Successful treatment of syphilitic uveitis in HIV-positive patients.

PubMed

Nurfahzura, Mohd-Jamil; Hanizasurana, Hashim; Zunaina, Embong; Adil, Hussein

2013-01-01

We report successful treatment of syphilitic uveitis in a case series of three Human immunodeficiency virus (HIV)-positive patients at Malaysia's Selayang Hospital eye clinic. All three patients with syphilitic uveitis were male, aged from 23 to 35 years old, with a history of high-risk behaviors. Of the patients, two presented with blurring of vision and only one patient presented with floaters in the affected eye. Ocular examination revealed intermediate uveitis (case 1 and case 3) and panuveitis (case 2). Each patient showed a high Venereal Disease Research Laboratory (VDRL) titer at presentation and they were also newly diagnosed as HIV positive with variable CD4 counts. All three patients responded well to a neurosyphilis regimen of intravenous penicillin G. At 3 months posttreatment, there was reduction in VDRL titer with improvement of vision in the affected eye. Diagnosis of syphilis needs to be ruled out in all cases of uveitis. All syphilitic uveitis cases should have HIV screening and vice versa, as syphilis is one of the most common infectious diseases associated with HIV-positive patients. Early detection and treatment are important for a good visual outcome.

Quantification of endotoxins in infected root canals and acute apical abscess exudates: monitoring the effectiveness of root canal procedures in the reduction of endotoxins.

PubMed

Sousa, Ezilmara L R; Martinho, Frederico C; Nascimento, Gustavo G; Leite, Fabio R M; Gomes, Brenda P F A

2014-02-01

This clinical study was conducted to measure the endotoxin levels in infected root canals (RCs) and exudates related to acute apical abscesses (AAAs). In addition, the effectiveness of RC procedures in reducing the endotoxin levels in RCs was monitored. Paired samples of infected RCs and exudates from AAAs were collected from 10 subjects by using paper points. RCs samples were collected before (RCS1) and after chemomechanical preparation (CMP) (RCS2), after 17% EDTA (RCS3), and after 30 days of intracanal medication (Ca[OH]2 + chlorhexidine) (RCS4). A turbidimetric kinetic limulus amebocyte lysate assay was used for the measurement of endotoxins. Endotoxins were detected in 100% of the baseline samples of AAAs and RCs (RCS1) with median values of 175 EU/mL and 41.5 EU/mL, respectively (P < .05). After CMP (RCS2), endotoxins were reduced to a median value of 0.54 EU/mL (P < .05). Subsequent irrigation with EDTA (RCS3) failed to present a significant effectiveness in reducing the endotoxin levels (median= 0.37 EU/mL) (P = .07). However, intracanal medication for 30 days (RCS4) reduced endotoxins to median values of 0.03 EU/mL (P < .01). The present study revealed a strong association between the high levels of endotoxins found in AAAs and RCs collected from the same tooth. Moreover, the effectiveness of CMP in reducing the endotoxin levels from RCs in acute endodontic infection was improved by the use of RC medication. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Detoxifying Escherichia coli for endotoxin-free production of recombinant proteins.

PubMed

Mamat, Uwe; Wilke, Kathleen; Bramhill, David; Schromm, Andra Beate; Lindner, Buko; Kohl, Thomas Andreas; Corchero, José Luis; Villaverde, Antonio; Schaffer, Lana; Head, Steven Robert; Souvignier, Chad; Meredith, Timothy Charles; Woodard, Ronald Wesley

2015-04-16

Lipopolysaccharide (LPS), also referred to as endotoxin, is the major constituent of the outer leaflet of the outer membrane of virtually all Gram-negative bacteria. The lipid A moiety, which anchors the LPS molecule to the outer membrane, acts as a potent agonist for Toll-like receptor 4/myeloid differentiation factor 2-mediated pro-inflammatory activity in mammals and, thus, represents the endotoxic principle of LPS. Recombinant proteins, commonly manufactured in Escherichia coli, are generally contaminated with endotoxin. Removal of bacterial endotoxin from recombinant therapeutic proteins is a challenging and expensive process that has been necessary to ensure the safety of the final product. As an alternative strategy for common endotoxin removal methods, we have developed a series of E. coli strains that are able to grow and express recombinant proteins with the endotoxin precursor lipid IVA as the only LPS-related molecule in their outer membranes. Lipid IVA does not trigger an endotoxic response in humans typical of bacterial LPS chemotypes. Hence the engineered cells themselves, and the purified proteins expressed within these cells display extremely low endotoxin levels. This paper describes the preparation and characterization of endotoxin-free E. coli strains, and demonstrates the direct production of recombinant proteins with negligible endotoxin contamination.

General effect of endotoxin on glucocorticoid receptors in mammalian tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stith, R.D.; McCallum, R.E.

Considering the ubiquitous nature of glucocorticoid actions and the fact that endotoxin inhibits glucocorticoid action in the liver, we proposed to examine whether endotoxin affected extrahepatic actions of glucocorticoids. Fasted C57BL/6J mice were injected intraperitoneally with endotoxin (LD50) at 0800 and were killed 6 h later. Control mice were injected with an equal volume of saline. /sup 3/H-dexamethasone binding, measured by a new cytosol exchange assay utilizing molybdate plus dithiothreitol, in liver, kidney, skeletal muscle, spleen, lung, and heart tissue was significantly lower in treated than in control mice. The equilibrium dissociation constants were not significantly different, but the numbermore » of available binding sites in each tissue was reduced by endotoxin treatment. Phosphoenolpyruvate carboxykinase activity was significantly reduced in liver but not in kidney. Endotoxin treatment lowered glycogen content in liver but not in skeletal muscle. The reduction observed in the a form of liver glycogen synthase due to endotoxin was not seen in skeletal muscle glycogen synthase a. These data support the proposal that endotoxin or a mediator of its action inhibits systemic glucocorticoid action. The results also emphasize the central role of the liver in the metabolic disturbances of the endotoxin-treated mouse.« less

Uveitis induction in the rabbit by muramyl dipeptides.

PubMed Central

Waters, R V; Terrell, T G; Jones, G H

1986-01-01

Intraocular inflammation (uveitis) was produced in rabbits by intravenous or subcutaneous treatment with N-acetylmuramyl-L-alanyl-D-isoglutamine and several of its synthetic analogs at doses of greater than or equal to 0.2 mg/kg in saline. A dose-dependent increase in permeability of the ocular blood-aqueous barrier as measured by leakage of protein or fluoresceinated dextran from the serum into the eye was observed from 2 to 14 h after glycopeptide treatment. Peak response occurred at approximately 3 h postdose. The lowest dose found to produce maximal vascular leakage for the most active glycopeptide analogs was 1 mg/kg. The adjuvant-inactive L-L stereoisomer of N-acetylmuramyl-L-alanyl-D-isoglutamine was inactive, even at doses as high as 10 mg/kg. Analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine which were homologous in the lactyl side chain were found to cause less uveitis. Chronic biweekly intravenous treatment of rabbits for 1 month with either N-acetyl-L-alpha-aminobutyryl-D-isoglutamine or its lipophilic 6-O-stearoyl derivative at 1 mg/kg, but not with murabutide, resulted in leukocytic inflammatory lesions unique to the uveal tract of the eye. The uveitis was potentially reversible and occurred with decreased severity as long as 2 months after cessation of chronic treatment. Vascular leakage but not cellular infiltrate in the choroid could be modulated by pharmacologic means. Pyrogenicity but not adjuvanticity correlated with ability of glycopeptides to induce vascular leakage. Several adjuvant-active muramyl dipeptide analogs with minimal ability to cause acute vascular leakage or chronic inflammation in the rabbit eye have been identified. Images PMID:3949381

Regulation of adenosine deaminase (ADA) on induced mouse experimental autoimmune uveitis (EAU) ‡

PubMed Central

Liang, Dongchun; Zuo, Aijun; Zhao, Ronglan; Shao, Hui; Kaplan, Henry J.; Sun, Deming

2016-01-01

Adenosine is an important regulator of the immune response and adenosine deaminase (ADA) inhibits this regulatory effect by converting adenosine into functionally inactive molecules. Studies have shown that adenosine receptor (AR) agonists can be either anti- or pro-inflammatory. Clarification of the mechanisms that cause these opposing effects should provide a better guide for therapeutic intervention. In this study, we investigated the effect of ADA on the development of experimental autoimmune uveitis (EAU) induced by immunizing EAU-prone mice with a known uveitogenic peptide, IRBP1–20. Our results showed that the effective time to administer a single dose of ADA to suppress induction of EAU was 8–14 days post-immunization, shortly before EAU expression, but ADA treatment at other time points exacerbated disease. ADA preferentially inhibited Th17 responses and this effect was γδ T cell-dependent. Our results demonstrated that the existing immune status strongly influences the anti- or proinflammatory effects of ADA. Our observations should help improve the design of ADA- and AR-targeted therapies. PMID:26856700

The spectrum of presumed tubercular uveitis in Tunisia, North Africa.

PubMed

Khochtali, Sana; Gargouri, Salma; Abroug, Nesrine; Ksiaa, Imen; Attia, Sonia; Sellami, Dorra; Feki, Jamel; Khairallah, Moncef

2015-10-01

The purpose of this study was to analyze the spectrum of presumed tubercular uveitis in Tunisia, North Africa. We retrospectively reviewed the clinical records of 38 patients (65 eyes) diagnosed with presumed tubercular uveitis at two referral centers in Tunisia, between January 2009 and December 2011. Mean age at presentation was 42.7 years. Twenty-four patients were women (63.2%) and 14 (36.8%) were men. Twenty-three eyes (35.4%) had posterior uveitis, 21 eyes (32.3%) had intermediate uveitis, 13 eyes (20%) had panuveitis, and 8 eyes (12.3%) had anterior uveitis. Ocular findings included vitritis in 67.7% of eyes, posterior synechiae in 47.7%, multifocal non-serpiginoid choroiditis in 23.1%, multifocal serpiginoid choroiditis in 21.5%, periphlebitis in 21.5%, and mutton-fat keratic precipitates in 20%. Anti-tubercular treatment was prescribed in 33 patients (86.8%) and was associated with systemic corticosteroids in 20 patients (52.6%) and periocular injections of corticosteroids in four patients (10.5%). After a mean follow-up of 14.2 months (range, 10-58), inflammation was controlled, with a significant improvement in visual acuity (VA) (p = 0.028). However, recurrences developed in two patients (5.3%). Final VA was better than 20/40 in 27 eyes (41.5%) and less than 20/200 in five eyes (7.7%). In Tunisia, all anatomic types are possible in tuberculosis-associated uveitis, but posterior and intermediate uveitis are more frequent. Vitritis, posterior synechiae, multifocal serpiginoid or non-serpiginoid choroiditis, and periphlebitis are the most common manifestations.

The effects of Helicobacter pylori infection on intraocular pressure in anterior uveitis

PubMed Central

Kim, J M; Park, K H; Choi, M J; Ha, M M; Sohn, Y H; Kim, H K; Caprioli, J

2012-01-01

Purpose We investigated the influence of H. pylori infection on intraocular pressure (IOP) in anterior uveitis patients to clarify whether H. pylori infection is related to high IOP in anterior uveitis. Methods In this prospective study, 165 Korean anterior uveitis patients were examined. All patients underwent serological analysis to identify the cause of uveitis, including the presence of H. pylori infection by enzyme-linked immunosorbent assay. Serological values were compared between patients with and without high IOP. Results Seropositivity for H. pylori was 69.70% of patients with high IOP and 38.38% of patients with normal IOP (P<0.01). Conclusion This study suggests that H. pylori infection is associated with high IOP in anterior uveitis. PMID:23154495

[Amblyopia and uveitis in childhood].

PubMed

Eckstein, A; Robering, A; Rudolph, G; Esser, J

2007-06-01

Manifestations of uveitis in the sensitive period of childhood can cause amblyopia. In most of the cases band keratopathy, dense cataracts and cyclitic membranes cause deprivation amblyopia. Asymmetrical damage can result in relative amblyopia. Secondary squint can lead to suppression amblyopia. For these reasons every visit during uveitis treatment should be accompanied by a search for amblyogenic factors and visual acuity measurements. In the case of a side difference in the visual acuity, occlusion therapy should be started. The follow-up should not only contain visual acuity measurements but also cycloplegic refraction. Especially when pupil-dilating drugs are necessary for a longer period, bifocals should be prescribed.

Bilateral uveitis and Usher syndrome: a case report.

PubMed

Benson, Matthew D; MacDonald, Ian M

2015-03-15

Usher syndrome is a genetically heterogeneous condition and represents the most common cause of inherited combined vision and hearing loss. Deficits manifest as sensorineural hearing loss that typically develops at a young age and retinitis pigmentosa that can lead to peripheral vision loss and night blindness. As a result, this syndrome can have a significant impact on a patient's quality of life. Previous studies have described an association between Usher syndrome and Fuchs' heterochromic iridocyclitis, a form of non-granulomatous uveitis that generally presents in a unilateral manner. We present a rare finding of bilateral uveitis and, to the best of our knowledge, the first report of granulomatous uveitis as a feature in a patient with Usher syndrome. A 45-year-old Caucasian woman with a known history of retinitis pigmentosa presented to our clinic with suspected Usher syndrome, given her report of long-standing hearing loss. Aside from a mild loss in visual acuity, our patient was otherwise asymptomatic. Visual field testing, audiology and electroretinography findings supported the diagnosis of Usher syndrome. With slit lamp examination she was found to have bilateral keratic precipitates, with large, greasy-white, mutton-fat keratic precipitates on the endothelial surface of her left eye. A thorough work-up that included blood tests and imaging was negative for an alternative cause of her uveitis. We present a rare finding of bilateral uveitis and what we believe to be the first reported instance of mutton-fat keratic precipitates and granulomatous uveitis as a feature in a patient with Usher syndrome. By identifying atypical presentations of the disease, we hope to contribute to the range of ophthalmic conditions that may be seen in association with Usher syndrome.

Updates on the risk markers and outcomes of severe juvenile idiopathic arthritis-associated uveitis

PubMed Central

Angeles-Han, Sheila T; Yeh, Steven; Vogler, Larry B

2013-01-01

Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis, which is the most common systemic cause of uveitis in children. Known risk factors for uveitis include antinuclear antibody seropositivity, young age of arthritis onset, specific juvenile idiopathic arthritis subtype and short duration of disease. Risk markers for severe ocular disease include gender, age and complications at initial visit. Due to the risk for vision-compromising sequelae such as cataracts, band keratopathy, glaucoma, vision loss and blindness, an understanding of the risk factors for uveitis development and severe ocular disease is crucial to help prevent serious visual disability and complications. This paper reviews the pathogenesis of uveitis, known risk factors for uveitis development and severe visual outcome, and addresses the need for additional biomarkers of uveitis risk, prognosis and remission. PMID:24187594

Multiple etiologies of equine recurrent uveitis--A natural model for human autoimmune uveitis: A brief review.

PubMed

Witkowski, Lucjan; Cywinska, Anna; Paschalis-Trela, Katarzyna; Crisman, Mark; Kita, Jerzy

2016-02-01

Equine recurrent uveitis (ERU) has various etiologies, with Leptospira infection and genetic predisposition being the leading risk factors. Regardless of etiology, expression of ocular proteins associated with maintenance of the blood-ocular barrier is impaired in ERU. The recurring-remitting cycle of ERU repeatedly disrupts the blood-ocular barrier, allowing the previously immune-privileged ocular environment to become the site of a progressive local autoimmune pathology that ultimately results in tissue destruction and vision loss. The immune-mediated process involves humoral and cellular mechanisms. Intraocular antibodies either produced in the eye or that leak through the blood-ocular barrier, are often present at higher levels than in serum and react with antigens in ocular tissue of horses with ERU. Ocular infiltration of auto-aggressive lymphocytes occurs with each uveitis episode and is the most crucial contributor to inflammation and eye damage. Recurring uveitis episodes may be initiated when epitopes of an ocular antigen become visible to the immune system (intramolecular spreading) or another autoantigen (intermolecular spreading), resulting in a new inflammatory reaction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Treatment of pediatric uveitis with adalimumab: the MERSI experience.

PubMed

Castiblanco, Claudia; Meese, Halea; Foster, C Stephen

2016-04-01

To evaluate adalimumab therapy in children with uveitis. The electronic health records of pediatric patients diagnosed with uveitis and treated with adalimumab therapy were reviewed retrospectively. Demographic information, site and degree of intraocular inflammation, visual acuity, underlying systemic disorders, duration of therapy, side effects, and ability to obtain steroid-free remission were recorded. A total of 17 patients were included, 16 patients with anterior uveitis and 1 with panuveitis; 14 patients had bilateral disease. Juvenile idiopathic arthritis had been diagnosed in 14 patients, sarcoidosis in 1 patient, and idiopathic etiology in 2 patients. Of the 17 patients, 13 (about 77%) achieved steroid-free remission, and 4 did not. Six patients flared after discontinuation of adalimumab, with evidence of inflammation noted 3-7 months later. Adalimumab therapy was of 12-64 months' duration (mean, 36 months). At the time of initiation, 14 patients were using other agents concomitantly with adalimumab; 3 patients were on adalimumab monotherapy. At 1 year's follow-up, 12 patients were using combination therapy, and 3 patients were on adalimumab monotherapy: 11 patients had no evidence of inflammation. Side effects included pain at site of injection in 3 patients, anemia in 1 patient, and depression in 1 patient. In our study cohort, adalimumab was effective in inducing steroid-free remission. It was well tolerated, especially in combination with other immunomodulatory agents. The dosing and the interval can be adjusted to further improve inflammation control. Copyright © 2016 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature.

PubMed

Carvounis, Petros E; Herman, David C; Cha, Stephen; Burke, James P

2006-03-01

Juvenile rheumatoid arthritis (JRA) is the most common systemic cause of pediatric uveitis in Europe and North America. Uveitis is commonly perceived as a frequent sequela of JRA and JRA-associated uveitis is commonly considered to have a complicated course with frequent adverse visual outcomes. We performed a systematic literature search for series of consecutive patients with JRA (as defined by the American College of Rheumatology criteria) reporting on the frequency of uveitis and/or complications of uveitis, published between January 1980 and December 2004. The main outcome measures were: the cumulative incidence of uveitis in JRA, the cumulative incidence of adverse visual outcome and that of complications in JRA-associated uveitis. Additionally, the influence of gender, presence of antinuclear antibody (ANA) and disease onset subtype to the likelihood of developing uveitis were examined. Analysis of pooled data from the 26 eligible series suggested a cumulative incidence of uveitis in JRA of 8.3% [95% confidence intervals (CI), 7.5-9.1%]. The cumulative incidence of uveitis varied according to geographic location, being highest in Scandinavia, then the US, then Asia and lowest in India. JRA-associated uveitis was more common in pauciarticular than polyarticular onset patients [odds ratio (OR) = 3.2, 95% CI, 2.33-4.36] and in ANA-positive than ANA-negative patients (OR = 3.18, 95% CI, 2.22-4.54). Female gender was only a weak risk factor for the development of uveitis in JRA patients (OR = 1.69, 95% CI 1.09-2.62) and was not statistically significant after considering disease onset subtypes. In JRA-associated uveitis the cumulative incidence of cumulative incidence of adverse outcome (visual acuity < 20/40 OU) was 9.2% (95% CI: 4.7-15.8) of cataracts 20.5% (95% CI: 15.5-26.3), of glaucoma 18.9% (95% CI: 14.4-24.2) and of band keratopathy 15.7% (95% CI: 10.9-21.7). The cumulative incidence of uveitis in JRA varies according to geographic location, presence of

[Effect of inducers and inhibitors of mixed function oxidases on body resistance to endotoxins of gram-negative bacteria].

PubMed

Liniuchev, M N; Zubik, T M; Kovelenov, A Iu; Bulyko, V I; Sergeev, V V

1989-06-01

Experimental typhoid intoxication in white mice leads to the inhibition of microsomal oxidation in the liver, which is manifested by the prolongation of hexenal-induced sleep and a decrease in the toxic action of parathion. Phenobarbital, capable of inducing oxidases with mixed function (OMF), enhances the process of the detoxification of endotoxin injected into the animals, which is manifested by the increase of its LD50. Soluble levomycetin succinate, widely used for the treatment of typhoid-paratyphoid infections, is a powerful inhibitor of OMF (as shown by the hexenal test). Benzonal, the analog of phenobarbital, removes the inhibitory effect of the antibiotic. Experimental studies carried out in the course of this investigation make it possible to substantiate the clinical trial of these preparations (OMF inducers) used in the complex therapy of typhoid-paratyphoid infections for the stimulation of natural detoxification mechanisms of the body. Benzonal is the preparation of choice for use in clinical practice.

Indoor airborne endotoxin assessment in homes of Paris newborn babies.

PubMed

Dassonville, C; Demattei, C; Vacquier, B; Bex-Capelle, V; Seta, N; Momas, I

2008-12-01

The aims of this study were first to assess airborne endotoxin levels in the dwellings of 162 newborns living in Paris twice during a 1-year period, and second, to identify predictors for endotoxin concentrations using questionnaire data in relation to housing factors and living conditions. Air samples were collected on a glass fiber filter in polystyrene filter holders, using a pump at a flow rate of 3.5 l/min for 24 h placed in the main room of the home. Endotoxin levels were measured using a chromogenic kinetic Limulus Amoebocyte Lysate test. Geometric means (geometric standard deviation) of airborne endotoxin levels at two different visits were respectively 0.509 (4.289) EU/m3 and 0.557 (3.029) EU/m3. Airborne endotoxin levels were significantly increased: (i) in cold season (P = 0.024), with (ii) the presence of visible cockroaches in the previous 12 months at home (P < 0.001), (iii) increased number of inhabitants per square meter (P = 0.012), (iv) the high frequency of cleaning with the floor cloths (P = 0.0014), and (v) the low frequency of vacuuming (P = 0.0045). This study provided for the first time airborne endotoxin levels issued from repeated measurements in Paris dwellings. PRACTICAL IMPLICATIONS This analysis contributed to identify a few factors that determined indoor airborne endotoxin levels. However, the predictive model including housing factors and living conditions poorly estimated endotoxin levels. Consequently, multiple samples and longer sampling periods might improve the estimate of long-term airborne endotoxin exposure especially its variability, in cohort studies.

Uveitis and Juvenile Psoriatic Arthritis or Psoriasis.

PubMed

Salek, Sherveen S; Pradeep, Archana; Guly, Catherine; Ramanan, Athimalaipet V; Rosenbaum, James T

2018-01-01

To describe the phenotype of the uveitis that accompanies juvenile psoriatic arthritis or psoriasis. Observational case series. Setting: Two university-based referral clinics: 1 in England, 1 in the United States. Five children with uveitis and psoriatic arthritis and 1 with uveitis and psoriasis Observational Procedure: Retrospective chart review. Demographics of subjects such as age and sex; description of ocular and joint disease; surgical and other complications; medical treatment. Five of the 6 children in this series had the onset of disease at or before age 6 (P = .0008 compared to expected age of onset for psoriatic arthritis in childhood). All children in this series had an inadequate response to topical corticosteroids. Most of the children were treated with systemic corticosteroids for many months, yet all of them went on to require methotrexate. Therapy with systemic methotrexate did not suffice, as all the patients also required some form of biologic therapy. Five of 6 had surgeries such as vitrectomy, cataract extraction, or a procedure for glaucoma control. The observations suggest that the uveitis that accompanies juvenile psoriatic arthritis might be a distinct disease that is particularly severe when its onset affects children aged 6 years or younger. Copyright © 2017 Elsevier Inc. All rights reserved.

Renal excretion of prostaglandin metabolites, arginine vasopressin, and sodium during endotoxin and endogenous pyrogen induced fever in the goat.

PubMed

Jónasson, H; Basu, S; Andersson, B; Kindahl, H

1984-04-01

Responses to intravenous injections of an endotoxin (E. coli-lipopolysaccharide, 1 microgram/kg b.wt.) and endogenous pyrogen were studied in euhydrated and hyperhydrated goats. The biphasic febrile response to the endotoxin was associated with a pronounced increase in the renal excretion of measured prostaglandin (PG) metabolites (11-ketotetranor PGF metabolites). This increase was time-correlated with the elevation of the rectal temperature, and (in hyperhydrated animals) with an inhibition of the water diuresis and an increase in renal excretion of arginine vasopressin (AVP). Other effects of the endotoxin were an immediate depression of renal Na and K excretion followed by the development of pronounced natriuresis, and a reduction of plasma Fe and Zn concentrations. The appearance of the febrile reactions (peripheral vasoconstriction and shivering) was accompanied by miosis. The maximum elevation of the rectal temperature was significantly greater during euhydration than during hyperhydration. Also endogenous pyrogen elicited miosis concomitant with febrile reactions, and an elevation of the renal excretion of PG metabolites which was closely correlated in time with the monophasic febrile response, and (during hyperhydration) with temporary inhibition of the water diuresis and an increase in the renal AVP excretion. However, the responses were much weaker than the corresponding endotoxin effects. No appreciable changes in renal excretion of Na and K were observed in response to the endogenous pyrogen. It is concluded that the observed effects on renal cation excretion were manifestations of direct endotoxin influences on kidney function.(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal supplementation with fishmeal protects against late gestation endotoxin-induced fetal programming of the ovine hypothalamic-pituitary-adrenal axis.

PubMed

Fisher, R E; Or'Rashid, M; Quinton, M; AlZahal, O; Boermans, H J; McBride, B W; Karrow, N A

2014-06-01

Adverse uterine environments caused by maternal stress (such as bacterial endotoxin) can alter programming of the fetal hypothalamic-pituitary-adrenal axis (HPAA) rendering offspring susceptible to various adulthood diseases. Thus, protection against this type of stress may be critical for ensuring offspring health. The present study was designed to determine if maternal supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) during pregnancy helps to protect against stress-induced fetal programming. Briefly, 53 ewes were fed a diet supplemented with fishmeal (FM) or soybean meal (SM) from day 100 of gestation (gd100) through lactation. On gd135, half the ewes from each dietary group were challenged with either 1.2 μg/kg Escherichia coli lipopolysaccharide (LPS) endotoxin, or saline as the control. The offspring's cortisol response to weaning stress was assessed 50 days postpartum by measuring serum cortisol concentrations 0, 6 and 24 h post weaning. Twenty-four hours post-weaning, lambs were subjected to an adrenocorticotropic hormone (ACTH) challenge (0.5 μg/kg) and serum cortisol concentrations were measured 0, 0.25, 0.5, 1 and 2 h post injection. At 5.5 months of age, offspring were also challenged with 400 ng/kg of LPS, and serum cortisol concentrations were measured 0, 2, 4 and 6 h post challenge. Interestingly, female offspring born to FM+LPS mothers had a greater cortisol response to weaning and endotoxin challenge compared with the other treatments, while female offspring born to SM+LPS mothers had a faster cortisol response to the ACTH stressor. Additionally, males born to FM+LPS mothers had a greater cortisol response to the ACTH challenge than the other treatments. Overall, FM supplementation during gestation combined with LPS challenge alters HPAA responsiveness of the offspring into adulthood.

Detection of Endotoxin Contamination of Graphene Based Materials Using the TNF-α Expression Test and Guidelines for Endotoxin-Free Graphene Oxide Production.

PubMed

Mukherjee, Sourav P; Lozano, Neus; Kucki, Melanie; Del Rio-Castillo, Antonio E; Newman, Leon; Vázquez, Ester; Kostarelos, Kostas; Wick, Peter; Fadeel, Bengt

2016-01-01

Nanomaterials may be contaminated with bacterial endotoxin during production and handling, which may confound toxicological testing of these materials, not least when assessing for immunotoxicity. In the present study, we evaluated the conventional Limulus amebocyte lysate (LAL) assay for endotoxin detection in graphene based material (GBM) samples, including graphene oxide (GO) and few-layered graphene (FLG). Our results showed that some GO samples interfered with various formats of the LAL assay. To overcome this problem, we developed a TNF-α expression test (TET) using primary human monocyte-derived macrophages incubated in the presence or absence of the endotoxin inhibitor, polymyxin B sulfate, and found that this assay, performed with non-cytotoxic doses of the GBM samples, enabled unequivocal detection of endotoxin with a sensitivity that is comparable to the LAL assay. FLG also triggered TNF-α production in the presence of the LPS inhibitor, pointing to an intrinsic pro-inflammatory effect. Finally, we present guidelines for the preparation of endotoxin-free GO, validated by using the TET.

Endotoxin in Size-Separated Metal Working Fluid Aerosol Particles.

PubMed

Dahlman-Höglund, Anna; Lindgren, Åsa; Mattsby-Baltzer, Inger

2016-08-01

Patients with airway symptoms working in metal working industries are increasing, despite efforts to improve the environmental air surrounding the machines. Our aim was to analyse the amount of endotoxin in size-separated airborne particles of metal working fluid (MWF) aerosol, by using the personal sampler Sioutas cascade impactor, to compare filter types, and to compare the concentration of airborne endotoxin to that of the corresponding MWFs. In a pilot field study, aerosols were collected in two separate machine halls on totally 10 occasions, using glass fibre and polytetrafluoroethylene (PTFE) filters in parallel at each station. Airborne endotoxin was distributed over all size fractions. While a major part was found in the largest size fraction (72%, 2.5-10 µm), up to 8% of the airborne endotoxin was detected in the smallest size fraction (<0.25 µm). Comparing the efficiency of the filter types, a significantly higher median endotoxin level was found with glass fibres filters collecting the largest particle-size fraction (1.2-fold) and with PTFE filters collecting the smallest ones (5-fold). The levels of endotoxin in the size-separated airborne particle fractions correlated to those of the MWFs supporting the aerosol-generating machines. Our study indicates that a significant part of inhalable aerosols of MWFs consists of endotoxin-containing particles below the size of intact bacteria, and thus small enough to readily reach the deepest part of the lung. Combined with other chemical irritants of the MWF, exposure to MWF aerosols containing endotoxin pose a risk to respiratory health problems. © The Author 2016. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Ultrasensitive detection of endotoxins using computationally designed nanoMIPs.

PubMed

Altintas, Zeynep; Abdin, Mohammed J; Tothill, Alexander M; Karim, Kal; Tothill, Ibtisam E

2016-09-07

Novel molecularly imprinted polymer nanoparticles (nanoMIPs) were designed for endotoxin from Escherichia coli 0111:B4, using computational modeling. The screening process based on binding energy between endotoxin and each monomer was performed with 21 commonly used monomers, resulting in the selection of itaconic acid, methacrylic acid and acrylamide as functional monomers due to their strong binding interaction with the endotoxin template. The nanoMIPs were successfully synthesized with functional groups on the outer surface to aid in the immobilization onto sensor surface. The solid phase photopolymerization approach used for the synthesis of nanoMIPs ranging from 200 to 235 nm in diameter. The limit of detection and KD were significantly improved when endotoxin samples were prepared using a novel triethylamine method. This improved the efficiency of gold nanoparticle functionalization by targeting the subunits of the endotoxin. Compared to the vancomycin MIP control, the endotoxin MIPs displayed outstanding affinity and selectivity towards the endotoxin with KD values in the range of 4.4-5.3 × 10(-10) M, with limits of detection of 0.44 ± 0.02 ng mL(-1) as determined by surface plasmon resonance (SPR) sensor when itaconic acid was used as the functional monomer. The MIP surface can be regenerated >30 times without significant loss of binding activity making this approach highly cost effective for expensive analyte templates. The combination of molecular modeling and solid phase synthesis enabled the successful synthesis of nanoMIPs capable of recognition and ultrasensitive detection of endotoxins using the highly sensitive SPR biosensor with triethylamine method. Copyright © 2016 Elsevier B.V. All rights reserved.

Endotoxin contamination: a key element in the interpretation of nanosafety studies.

PubMed

Li, Yang; Boraschi, Diana

2016-02-01

The study of toxicity and potential risks of engineered nanoparticles is of particular importance in nanomedicine. Endotoxin, a common contaminant of bacterial origin, has biological effects that can mask the true biological effects of nanoparticles, if its presence is overlooked. In this review, we report the features of nanoparticle contamination by endotoxin, and the different biological effects of endotoxin-contaminated nanoparticles. We will describe different methods for endotoxin detection applied to nanoparticles, and discuss their pros and cons. Eventually, we describe various methods for eliminating endotoxin contamination in nanoparticles. Although there is no universal technique for efficiently removing endotoxin from nanoparticles, specific solutions can be found case by case, which can allow us to perform nanosafety studies in biologically relevant conditions.

Corticosteroid implants for chronic non-infectious uveitis

PubMed Central

Brady, Christopher J; Villanti, Andrea C; Law, Hua Andrew; Rahimy, Ehsan; Reddy, Rahul; Sieving, Pamela C; Garg, Sunir J; Tang, Johnny

2016-01-01

Background Uveitis is a term used to describe a heterogeneous group of intraocular inflammatory diseases of the anterior, intermediate, and posterior uveal tract (iris, ciliary body, choroid). Uveitis is the fifth most common cause of vision loss in high-income countries, accounting for 5% to 20% of legal blindness, with the highest incidence of disease in the working-age population. Corticosteroids are the mainstay of acute treatment for all anatomical subtypes of non-infectious uveitis and can be administered orally, topically with drops or ointments, by periocular (around the eye) or intravitreal (inside the eye) injection, or by surgical implantation. Objectives To determine the efficacy and safety of steroid implants in people with chronic non-infectious posterior uveitis, intermediate uveitis, and panuveitis. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlledtrials.com) (last searched 15 April 2013), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform(ICTRP) (www.who.int/ictrp/search/en).We did not use any date or language restrictions in the electronic search for studies. We last searched the electronic databases on 6 November 2015. We also searched reference lists of included study reports, citation databases, and abstracts and clinical study presentations from professional meetings. Selection criteria We included randomized controlled trials comparing either fluocinolone acetonide (FA) or dexamethasone intravitreal implants with standard

Bacterial endotoxin in the endometrium and its clinical significance in reproduction.

PubMed

Kamiyama, Shigeru; Teruya, Yoko; Nohara, Makoto; Kanazawa, Koji

2004-10-01

Bacterial endotoxin was detected in menstrual effluent from infertile women. Endometrial endotoxin appears to influence reproductive process because the pregnancy rate after IVF-ET was significantly associated with an endotoxin level.

Fluorescent nanodiamonds as highly stable biomarker for endotoxin verification

NASA Astrophysics Data System (ADS)

Bergmann, Thorsten; Burg, Jan Michael; Lilholt, Maria; Maeder, Ulf; Beer, Sebastian; Salzig, Denise; Ebrahimi, Mehrdad; Czermak, Peter; Fiebich, Martin

2012-03-01

Fluorescent nanodiamonds (ND) provide advantageous properties as a fluorescent biomarker for in vitro and in vivo studies. The maximum fluorescence occurs around 700 nm, they do not show photobleaching or blinking and seem to be nontoxic. After a pretreatment with strong acid fluorescent ND can be functionalized and coupled to endotoxin. Endotoxin is a decay product of bacteria and causes strong immune reactions. Therefore endotoxin has to be removed for most applications. An effective removal procedure is membrane filtration. The endotoxin, coupled to fluorescent ND can be visualized by using confocal microscopy which allows the investigation of the separation mechanisms of the filtration process within the membranes.

Computer-controlled closed-loop drug infusion system for automated hemodynamic resuscitation in endotoxin-induced shock.

PubMed

Uemura, Kazunori; Kawada, Toru; Zheng, Can; Li, Meihua; Sugimachi, Masaru

2017-10-23

Hemodynamic resuscitation in septic shock requires aggressive fluid replacement and appropriate use of vasopressors to optimize arterial pressure (AP) and cardiac output (CO). Because responses to these drugs vary between patients and within patient over time, strict monitoring of patient condition and repetitive adjustment of drug dose are required. This task is time and labor consuming, and is associated with poor adherence to resuscitation guidelines. To overcome this issue, we developed a computer-controlled closed-loop drug infusion system for automated hemodynamic resuscitation in septic shock, and evaluated the performance of the system in a canine model of endotoxin shock. Our system monitors AP, CO and central venous pressure, and computes arterial resistance (R), stressed blood volume (V) and Frank-Starling slope of left ventricle (S). The system controls R with noradrenaline (NA), and V with Ringer's acetate solution (RiA), thereby controlling AP and CO. In 4 dogs, AP and CO were measured invasively. In another 4 dogs, AP and CO were measured less invasively using clinically acceptable modalities, aiming to make the system clinically feasible. In all 8 dogs, endotoxin shock was induced by injecting Escherichia coli lipopolysaccharide, which significantly decreased AP from 95 (91-108) to 43 (39-45) mmHg, and CO from 112 (104-142) to 62 (51-73) ml·min -1 ·kg -1 . The system was then connected to the dogs, and activated. System performance was observed over a period of 4 h. Our system immediately started infusions of NA and RiA. Within 40 min, RiA increased V to target level, and NA maintained R at target level, while S was concomitantly increased. These resulted in restoration of AP to 70 (69-71) mmHg and CO to 130 (125-138) ml·min -1 ·kg -1 . Median of absolute performance error, an index of precision of control, was small in AP [2.5 (2.1-4.5) %] and CO [2.4 (1.4-5.5) %], which were not increased even when the variables were measured less invasively

Uveitis in juvenile idiopathic arthritis.

PubMed

Heiligenhaus, Arnd; Minden, Kirsten; Föll, Dirk; Pleyer, Uwe

2015-02-06

Juvenile idiopathic arthritis (JIA) is the most common systemic disease causing uveitis in childhood, with a prevalence of 10 per 100 000 persons. JIA often takes a severe inflammatory course, and its complications often endanger vision. This review is based on pertinent articles retrieved by a selective literature search up to 18 August 2014 and on the current interdisciplinary S2k guideline on the diagnostic evaluation and anti-inflammatory treatment of juvenile idiopathic uveitis. Uveitis arises in roughly 1 in 10 patients with JIA. Regular eye check-ups should be performed starting as soon as JIA is diagnosed. 75-80% of patients are girls; antinuclear antibodies are found in 70-90%. The risk to vision is higher if JIA begins in the preschool years. As for treatment, only a single, small-scale randomized controlled trial (RCT) and a small number of prospective trials have been published to date. Topical corticosteroids should be given as the initial treatment. Systemic immunosuppression is needed if irritation persists despite topical corticosteroids, if new complications arise, or if the topical steroids have to be given in excessively high doses or have unacceptable side effects. If the therapeutic effect remains inadequate, conventional and biological immune modulators can be given as add-on (escalation) therapy. Treatment lowers the risk of uveitis and its complications and thereby improves the prognosis for good visual function. Severely affected patients should be treated in competence centers to optimize their long-term outcome. Multidisciplinary, individualized treatment is needed because of the chronic course of active inflammation and the ensuing high risk of complications that can endanger vision. Future improvements in therapy will be aided by prospective, population-based registries and by basic research on biomarkers for the prediction of disease onset, prognosis, tissue damage, and therapeutic response.

Noninvasive Ocular Drug Delivery System of Dexamethasone Sodium Phosphate in the Treatment of Experimental Uveitis Rabbit.

PubMed

Papangkorn, Kongnara; Prendergast, Eri; Higuchi, John W; Brar, Balbir; Higuchi, William I

2017-12-01

To investigate the efficacy and safety of dexamethasone sodium phosphate administered through Visulex system (DSP-Visulex) in treating experimental uveitis. Uveitis was induced in rabbits by subcutaneous injections of complete Freund's adjuvant and an intravitreal injection of H37RA antigen. After induction, the animals of the control group received no treatment and the others received various treatment regimens of DSP-Visulex. Each regimen was different in DSP strength (4%, 8%, and 15%), application time, or treatment frequency. Efficacy and safety of DSP-Visulex were evaluated by ophthalmic observations and histopathological examinations for ocular inflammations and pathology. The control group exhibited panuveitis with significant inflammation in the vitreous, choroid, and retina, but less in the conjunctiva, cornea, and anterior chamber. The uveitis occurred within 24 h after induction and persisted throughout the study in the control group. All treatments showed some reduction in inflammation in the vitreous, choroid, and retina. The higher dose regimens generally showed more rapid and higher degree of resolution than the lower dose regimens. The posterior eye tissues of the 15% and 8% DSP-Visulex appeared normal with minimal or no inflammation, whereas the untreated eye and the 4% DSP-Visulex eyes showed minimal response. All DSP-Visulex regimens suppressed the signs of inflammation and were well tolerated over the course of a 29-day study. The 8% and 15% DSP-Visulex treatment regimens were safe and efficacious for anterior, intermediate, and posterior uveitis. On the other hand, the 4% DSP-Visulex regimen may only be considered for anterior and intermediate uveitis.

Anti-inflammatory effect of conditioned medium from human uterine cervical stem cells in uveitis.

PubMed

Bermudez, Maria A; Sendon-Lago, Juan; Seoane, Samuel; Eiro, Noemi; Gonzalez, Francisco; Saa, Jorge; Vizoso, Francisco; Perez-Fernandez, Roman

2016-08-01

The aim of the present study was to evaluate the effect of conditioned medium from human uterine cervical stem cells (CM-hUCESCs) in uveitis. To do that, uveitis was induced in rats after footpad injection of Escherichia coli lipopolysaccaride (LPS). Human retinal pigment epithelial (ARPE-19) cells after LPS challenge were used to test anti-inflammatory effect of CM-hUCESCs 'ìn vitro'. Real-time PCR was used to evaluate mRNA expression levels of the pro-inflammatory cytokines interkeukin-6, interkeukin-8, macrophage inflammatory protein-1 alpha, tumor necrosis factor alpha, and the anti-inflammatory interkeukin-10. Leucocytes from aqueous humor (AqH) were quantified in a Neubauer chamber, and eye histopathological analysis was done with hematoxylin-eosin staining. Additionally, using a human cytokine antibody array we evaluated CM-hUCESCs to determine mediating proteins. Results showed that administration of CM-hUCESCs significantly reduced LPS-induced pro-inflammatory cytokines both 'in vitro' and 'in vivo', and decreased leucocytes in AqH and ocular tissues. High levels of cytokines with anti-inflammatory effects were found in CM-hUCESCs, suggesting a possible role of these factors in reducing intraocular inflammation. In summary, treatment with CM-hUCESCs significantly reduces inflammation in uveitis. Our data indicate that CM-hUCESCs could be regarded as a potential therapeutic agent for patients suffering from ocular inflammation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Temporal and spatial patterns of ambient endotoxin concentrations in Fresno, California.

PubMed

Tager, Ira B; Lurmann, Frederick W; Haight, Thaddeus; Alcorn, Siana; Penfold, Bryan; Hammond, S Katharine

2010-10-01

Endotoxins are found in indoor dust generated by human activity and pets, in soil, and adsorbed onto the surfaces of ambient combustion particles. Endotoxin concentrations have been associated with respiratory symptoms and the risk of atopy and asthma in children. We characterized the temporal and spatial variability of ambient endotoxin in Fresno/Clovis, California, located in California's Central Valley, to identify correlates and potential predictors of ambient endotoxin concentrations in a cohort of children with asthma [Fresno Asthmatic Children's Environment Study (FACES)]. Between May 2001 and October 2004, daily ambient endotoxin and air pollutants were collected at the central ambient monitoring site of the California Air Resources Board in Fresno and, for shorter time periods, at 10 schools and indoors and outdoors at 84 residences in the community. Analyses were restricted to May-October, the dry months during which endotoxin concentrations are highest. Daily endotoxin concentration patterns were determined mainly by meteorologic factors, particularly the degree of air stagnation. Overall concentrations were lowest in areas distant from agricultural activities. Highest concentrations were found in areas immediately downwind from agricultural/pasture land. Among three other measured air pollutants [fine particulate matter, elemental carbon (a marker of traffic in Fresno), and coarse particulate matter (PMc)], PMc was the only pollutant correlated with endotoxin. Endotoxin, however, was the most spatially variable. Our data support the need to evaluate the spatial/temporal variability of endotoxin concentrations, rather than relying on a few measurements made at one location, in studies of exposure and and respiratory health effects, particularly in children with asthma and other chronic respiratory diseases.

Overview and recent developments in the medical management of paediatric uveitis.

PubMed

Pilly, Bertrand; Heath, Greg; Tschuor, Patrizia; Lightman, Susan; Gale, Richard P

2013-09-01

Although rarer than its adult counterpart, non-infectious uveitis remains a significant cause of ocular morbidity in children. Owing to the chronicity of the disorder and when refractory to first-line treatment, namely corticosteroids, systemic immunosuppressive treatment may be required to control the disease. Following a literature search using the keywords 'paediatric uveitis', 'juvenile idiopathic arthritis-associated uveitis', 'immunosuppression' and 'treatment', we reviewed the range and effectiveness of treatments employed in the management of non-infectious, paediatric uveitis. Corticosteroids (topical, periocular, intraocular or systemic) remain the initial drug of choice in ameliorating the signs and symptoms of non-infectious paediatric uveitis. Failure to control the disease and/or failure to reduce the oral dose of prednisolone at least 0.15 mg/kg within 4 weeks often requires additional immunosuppressant therapy. Methotrexate and azathioprine have shown to be effective in the management of juvenile idiopathic arthritis (JIA)-associated uveitis with the former considered the first-line corticosteroid-sparing agent. Biologic therapies are increasingly used earlier in the disease with investigators in the UK currently recruiting patients for the SYCAMORE trial evaluating the efficacy of methotrexate and adalimumab vs methotrexate alone for the treatment for JIA-associated uveitis. Until further randomised controlled trials are conducted, the use of other biologic agents should only be used with an appreciation that there are potentially unknown side-effects and that there is not a full knowledge of their efficacy.

Endotoxin Contamination of Apolipoprotein A-I: Effect on Macrophage Proliferation – A Cautionary Tale

PubMed Central

Jin, Xueting; Xu, Qing; Champion, Keith; Kruth, Howard S.

2015-01-01

This technical report addresses the problem of endotoxin contamination of apolipoprotein reagents. Using a bromodeoxyuridine incorporation cell proliferation assay, we observed that human plasma ApoA-I as low as 1 μg/ml resulted in a >90% inhibition in macrophage proliferation. However, not all ApoA-I from different sources showed this effect. We considered the possibility that endotoxin contamination of the apolipoproteins contributed to the differential inhibition of macrophage cell proliferation. Endotoxin alone very potently inhibited macrophage proliferation (0.1 ng/ml inhibited macrophage proliferation >90%). Measurement of endotoxin levels in the apolipoprotein products, including an analysis of free versus total endotoxin, the latter which included endotoxin that was masked due to binding to protein, suggested that free endotoxin mediated inhibition of macrophage proliferation. Despite the use of an advanced endotoxin removal procedure and agents commonly used to inhibit endotoxin action, the potency of endotoxin precluded successful elimination of endotoxin effect. Our findings show that endotoxin contamination can significantly influence apparent apolipoprotein-mediated cell effects (or effects of any other biological products), especially when these products are tested on highly endotoxin-sensitive cells, such as macrophages. PMID:25778625

Patterns of uveitis in a tertiary eye care center in Iran.

PubMed

Soheilian, Masood; Heidari, Kumars; Yazdani, Shahin; Shahsavari, Mohsen; Ahmadieh, Hamid; Dehghan, Mohammad

2004-12-01

To identify the distribution and characteristics of new uveitis referrals to a tertiary eye care center in Tehran. A three-year prospective study was carried out to obtain information on 544 new patients referred with uveitis. A complete ophthalmologic examination was performed in all cases; a routine set of tests and an additional battery of directed workup were conducted when indicated. Mean age was 32.3 years. There was no significant sex predominance. The most common forms of uveitis were anterior (38.4%) vs. other anatomical forms, chronic (62.1%) vs. acute (28.3%), nongranulomatous (85.5%) vs. granulomatous (14.5%), and noninfectious (83.5%) vs. infectious (16.5%). With regard to etiology, 45.5% were idiopathic, 19.9% were due to specific ocular disease, and 37.3% were associated with systemic disorders. Behcet's disease was the most common noninfectious disease and toxoplasmosis the most common infectious entity. The most prevalent causes were idiopathic, Fuchs' heterochromic iridocylitis, and seronegative spondyloarthropathies in anterior uveitis; toxoplasmosis, Eales disease, and toxocariasis in posterior uveitis; idiopathic, sarcoidosis, and multiple sclerosis in intermediate uveitis; and, finally, Behcet's disease, idiopathic, and Vogt-Koyanagi-Harada syndrome in panuveitis. The most frequent cause in patients under 16 years of age was pars planitis. Over 80% of the patients belonged to middle-to-upper socioeconomic classes. Uveitis significantly affected patients' lives in 63.1% of the cases. Although the current study was performed at a referral center, it may reflect to some extent the different distribution of uveitis in Iran and probably other Middle Eastern countries. Some entities such as presumed ocular histoplasmosis were not found, cytomegalovirus retinitis and birdshot chorioretinopathy were extremely rare, and HLA-B27-associated iridocyclitis was less commonly observed. In contrast, Behcet's disease, Fuchs' heterochromic iridocyclitis, Eales

Biomarkers and Surrogate Endpoints in Uveitis: The Impact of Quantitative Imaging.

PubMed

Denniston, Alastair K; Keane, Pearse A; Srivastava, Sunil K

2017-05-01

Uveitis is a major cause of sight loss across the world. The reliable assessment of intraocular inflammation in uveitis ('disease activity') is essential in order to score disease severity and response to treatment. In this review, we describe how 'quantitative imaging', the approach of using automated analysis and measurement algorithms across both standard and emerging imaging modalities, can develop objective instrument-based measures of disease activity. This is a narrative review based on searches of the current world literature using terms related to quantitative imaging techniques in uveitis, supplemented by clinical trial registry data, and expert knowledge of surrogate endpoints and outcome measures in ophthalmology. Current measures of disease activity are largely based on subjective clinical estimation, and are relatively insensitive, with poor discrimination and reliability. The development of quantitative imaging in uveitis is most established in the use of optical coherence tomographic (OCT) measurement of central macular thickness (CMT) to measure severity of macular edema (ME). The transformative effect of CMT in clinical assessment of patients with ME provides a paradigm for the development and impact of other forms of quantitative imaging. Quantitative imaging approaches are now being developed and validated for other key inflammatory parameters such as anterior chamber cells, vitreous haze, retinovascular leakage, and chorioretinal infiltrates. As new forms of quantitative imaging in uveitis are proposed, the uveitis community will need to evaluate these tools against the current subjective clinical estimates and reach a new consensus for how disease activity in uveitis should be measured. The development, validation, and adoption of sensitive and discriminatory measures of disease activity is an unmet need that has the potential to transform both drug development and routine clinical care for the patient with uveitis.

The Future Is Now: Biologics for Non-Infectious Pediatric Anterior Uveitis.

PubMed

Lerman, Melissa A; Rabinovich, C Egla

2015-08-01

Anterior uveitis (AU), inflammation of the iris, choroid or ciliary body, can cause significant eye morbidity, including visual loss. In the pediatric age group, the most common underlying diagnosis for AU is juvenile idiopathic associated uveitis and idiopathic AU, which are the focus of this paper. AU is often resistant to medications such as topical corticosteroids and methotrexate. In the past 15 years, biologic agents (biologics) have transformed treatment. In this review, we discuss those in widespread use and those with more theoretical applications for anterior uveitis. Tumor necrosis factor alpha inhibitors (anti-TNFα) have been available the longest and are used widely to treat pediatric uveitis. The effects of anti-TNFα in children are described mostly in small retrospective case series. Together, the literature suggests that the majority of children treated with anti-TNFα achieve decreased uveitis activity and reduced corticosteroid burden. However, many will have disease flares even on treatment. Only a few small studies directly compare outcomes between alternate anti-TNFα (infliximab and adalimumab). The use of different uveitis grading systems, inclusion criteria, and outcome measures makes cross-study comparisons difficult. Whether the achievement and maintenance of inactive disease occurs more frequently with certain anti-TNFα remains controversial. Newer biologics that modulate the immune system differently (e.g., interfere with Th17 activation through IL-17a and IL-6 blockade, limit T lymphocyte costimulation, and deplete B lymphocytes), have shown promise for uveitis. Studies of these agents are small and include mostly adults. Additional biologics are also being explored to treat uveitis. With their advent, we are hopeful that outcomes will ultimately be improved for children with AU. With many biologics available, much work remains to identify the optimal inflammatory pathway to target in AU.

Peripherally administered orexin improves survival of mice with endotoxin shock

PubMed Central

Ogawa, Yasuhiro; Irukayama-Tomobe, Yoko; Murakoshi, Nobuyuki; Kiyama, Maiko; Ishikawa, Yui; Hosokawa, Naoto; Tominaga, Hiromu; Uchida, Shuntaro; Kimura, Saki; Kanuka, Mika; Morita, Miho; Hamada, Michito; Takahashi, Satoru; Hayashi, Yu; Yanagisawa, Masashi

2016-01-01

Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin’s direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock. DOI: http://dx.doi.org/10.7554/eLife.21055.001 PMID:28035899

Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Yan; College of Food Safety, Guizhou Medical University, Guiyang 550025; Ruan, Zheng, E-mail: ruanzheng@ncu.edu.cn

Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes thatmore » are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.« less

Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation

PubMed Central

Rocksén, D; Lilliehöök, B; Larsson, R; Johansson, T; Bucht, A

2000-01-01

Inhalation of bacterial endotoxin induces an acute inflammation in the lower respiratory tract. In this study, the anti-inflammatory effects of the anti-oxidant N-acetylcysteine (NAC) and the glucocorticoid dexamethasone were investigated in mice exposed to aerosolized endotoxin (lipopolysaccharide (LPS)). Powerful reduction of neutrophils in bronchoalveolar lavage fluid (BALF) was obtained by a single i.p. injection of dexamethasone (10 mg/kg), whereas treatment with NAC only resulted in reduction of neutrophils when administered at a high dose (500 mg/kg). Measurement of cytokine and chemokine expression in lung tissue revealed a significant decrease of tumour necrosis factor-alpha, IL-1α, IL-1β, IL-6, IL-12p40, and MIP-1α mRNA when mice where treated with dexamethasone but not when treated with NAC. Analysis of oxidative burst demonstrated a remarkable reduction of oxygen radicals in BALF neutrophils after treatment with dexamethasone, whereas the effect of NAC was not significantly different from that in untreated animals. In conclusion, dexamethasone exerted both anti-inflammatory and anti-oxidative effects in acute airway inflammation, probably by blocking early events in the inflammatory cascade. In contrast, treatment with NAC resulted in a weak reduction of the inflammatory response but no inhibition of proinflammatory cytokines or reduction of oxidative burst in neutrophils. These results demonstrate dramatic differences in efficiency and also indicate that the two drugs have different actions. Combined treatment with NAC and dexamethasone revealed an additive action but no synergy was observed. PMID:11091282

Temporal and Spatial Patterns of Ambient Endotoxin Concentrations in Fresno, California

PubMed Central

Tager, Ira B.; Lurmann, Frederick W.; Haight, Thaddeus; Alcorn, Siana; Penfold, Bryan; Hammond, S. Katharine

2010-01-01

Background Endotoxins are found in indoor dust generated by human activity and pets, in soil, and adsorbed onto the surfaces of ambient combustion particles. Endotoxin concentrations have been associated with respiratory symptoms and the risk of atopy and asthma in children. Objective We characterized the temporal and spatial variability of ambient endotoxin in Fresno/Clovis, California, located in California’s Central Valley, to identify correlates and potential predictors of ambient endotoxin concentrations in a cohort of children with asthma [Fresno Asthmatic Children’s Environment Study (FACES)]. Methods Between May 2001 and October 2004, daily ambient endotoxin and air pollutants were collected at the central ambient monitoring site of the California Air Resources Board in Fresno and, for shorter time periods, at 10 schools and indoors and outdoors at 84 residences in the community. Analyses were restricted to May–October, the dry months during which endotoxin concentrations are highest. Results Daily endotoxin concentration patterns were determined mainly by meteorologic factors, particularly the degree of air stagnation. Overall concentrations were lowest in areas distant from agricultural activities. Highest concentrations were found in areas immediately downwind from agricultural/pasture land. Among three other measured air pollutants [fine particulate matter, elemental carbon (a marker of traffic in Fresno), and coarse particulate matter (PMc)], PMc was the only pollutant correlated with endotoxin. Endotoxin, however, was the most spatially variable. Conclusions Our data support the need to evaluate the spatial/temporal variability of endotoxin concentrations, rather than relying on a few measurements made at one location, in studies of exposure and and respiratory health effects, particularly in children with asthma and other chronic respiratory diseases. PMID:20494854

Clinical Manifestations and Outcome of Syphilitic Uveitis.

PubMed

Bollemeijer, Jan G; Wieringa, Wietse G; Missotten, Tom O A R; Meenken, Ina; ten Dam-van Loon, Ninette H; Rothova, Aniki; Los, Leonoor I

2016-02-01

To analyze visual outcome, effectiveness of various modes of antibiotic treatment, and prognostic factors in patients with serologically proven syphilitic uveitis. The clinical records of 85 patients (139 eyes) diagnosed with syphilitic uveitis between 1984 and 2013 at tertiary centers in The Netherlands were retrospectively analyzed. Mean age was 47 years (range, 27-73 years), 82.4% were male. HIV positivity was found in 28 (35.9%) patients; 13 were newly diagnosed. Most patients had pan (45.9%) or posterior (31.8%) uveitis. On average, logMAR visual acuity (VA) improved significantly from 0.55 at the start of syphilis treatment to 0.34 at 1 month and to 0.27 at 6 months follow-up. Most patients (86.7%) reached disease remission. No differences in efficacy between the various treatment regimens were found. A high logMAR VA at the start of syphilis treatment and a treatment delay of more than 12 weeks were prognostic for a high logMAR VA at 6 months follow-up. Chronicity was not related to any form of treatment, HIV status, or Venereal Disease Research Laboratory test outcome. In this large cohort of 85 patients with syphilitic uveitis, visual outcomes were favorable in the majority of cases. Visual outcome was dependent on VA at the start of syphilis treatment and treatment delay.

[HLA-B27 Positive Acute Anterior Uveitis - A Translational Perspective].

PubMed

Heiligenhaus, Arnd; Kasper, Maren; Grajewski, Rafael

2017-05-01

Background HLA-B27 positive acute anterior uveitis is the most common type of uveitis, and it is an autoimmune disease that can be triggered by infections. The precise mechanism of the interaction between involved microbes (mostly gram negative bacteria) and the host immune system is not clear. The disease probably results from an imbalance between pro- and anti-inflammatory components. Project description This article gives a compact overview about the current knowledge of the clinic and the etiopathogenesis of acute anterior uveitis as a basis for future research approaches. The goal of the current research is to classify the cellular and molecular pathogenetic factors in acute anterior uveitis. In this regard, a project on uveitis within the clinical research unit FOR 2240 "(Lymph)Angiogenesis and Cellular Immunity in Inflammatory Diseases of the Eye", examines the hypothesis that dysregulation of regulatory cell populations and anti-inflammatory cytokines, such as interleukin-10 (IL-10), might contribute to the development of ocular autoimmunity following infections. The goal is to establish new markers for individual susceptibility in the risk group of the HLA-B27 positive population, because only about 1% of the HLA-B27 positive population will eventually develop acute anterior uveitis. Conclusions Translational research approaches to identify predisposed risk groups from the HLA-B27 population could improve patient care both on a prophylactic and a therapeutic level. Georg Thieme Verlag KG Stuttgart · New York.

[Equine recurrent uveitis].

PubMed

Spiess, B M

1997-01-01

Equine recurrent uveitis is an important ocular disease and the most common cause for blindness in horses and mules worldwide. The anatomy, physiology, immunology and inflammatory reactions of the uveal tract are discussed. Possible etiologies and the clinical signs are described. A detailed description of possible therapies is given and the prognosis is discussed.

Detection of Endotoxin Contamination of Graphene Based Materials Using the TNF-α Expression Test and Guidelines for Endotoxin-Free Graphene Oxide Production

PubMed Central

Del Rio-Castillo, Antonio E.; Newman, Leon; Vázquez, Ester; Kostarelos, Kostas; Wick, Peter; Fadeel, Bengt

2016-01-01

Nanomaterials may be contaminated with bacterial endotoxin during production and handling, which may confound toxicological testing of these materials, not least when assessing for immunotoxicity. In the present study, we evaluated the conventional Limulus amebocyte lysate (LAL) assay for endotoxin detection in graphene based material (GBM) samples, including graphene oxide (GO) and few-layered graphene (FLG). Our results showed that some GO samples interfered with various formats of the LAL assay. To overcome this problem, we developed a TNF-α expression test (TET) using primary human monocyte-derived macrophages incubated in the presence or absence of the endotoxin inhibitor, polymyxin B sulfate, and found that this assay, performed with non-cytotoxic doses of the GBM samples, enabled unequivocal detection of endotoxin with a sensitivity that is comparable to the LAL assay. FLG also triggered TNF-α production in the presence of the LPS inhibitor, pointing to an intrinsic pro-inflammatory effect. Finally, we present guidelines for the preparation of endotoxin-free GO, validated by using the TET. PMID:27880838

Endotoxin Elimination in Patients with Septic Shock: An Observation Study.

PubMed

Adamik, Barbara; Zielinski, Stanislaw; Smiechowicz, Jakub; Kübler, Andrzej

2015-12-01

To evaluate the effectiveness of endotoxin elimination with an adsorption column in patients with septic shock and endotoxemia. The elimination therapy was guided by a new bedside method of measuring endotoxin activity (EA). Intensive care unit (ICU) patients with septic shock and suspected Gram-negative infection were consecutively added to the study group within the first 24 h. Endotoxin elimination was performed using hemoperfusion with the Alteco LPS Adsorber. The primary endpoint was improvement in organ function within the first 24 h of treatment. A secondary objective was to assess the usefulness of a new method of measuring EA to help guide endotoxin elimination therapy. Out of 64 patients 18 had a high baseline EA [0.70 EA units (0.66-0.77)]. Those patients had endotoxin elimination treatment in addition to conventional medical therapy. At 24 h after endotoxin elimination, the EA had decreased to 0.56 EA units (0.43-0.77), (p = 0.005); MAP increased from 69 (62-80) to 80 mm Hg (68-88), (p = 0.002), and noradrenaline use decreased from 0.28 (0.15-0.80) to 0.1 μg/kg/min (0.00-0.70) at the same time (p = 0.04). The SOFA score had decreased from 11 (9-15) to 9 (7-14) points 24 h after endotoxin elimination (p = 0.01) with a median delta SOFA -2 points. Endotoxin elimination did not have a significant effect on the ICU length of stay or ICU mortality. Effective endotoxin elimination resulted in a significant improvement in hemodynamic parameters and of organ function. The application of the EA assay was useful for the bedside monitoring of endotoxemia in critically ill ICU patients.

Interobserver Agreement Among Uveitis Experts on Uveitic Diagnoses: The Standardization of Uveitis Nomenclature Experience.

PubMed

Jabs, Douglas A; Dick, Andrew; Doucette, John T; Gupta, Amod; Lightman, Susan; McCluskey, Peter; Okada, Annabelle A; Palestine, Alan G; Rosenbaum, James T; Saleem, Sophia M; Thorne, Jennifer; Trusko, Brett

2018-02-01

To evaluate the interobserver agreement among uveitis experts on the diagnosis of the specific uveitic disease. Interobserver agreement analysis. Five committees, each comprised of 9 individuals and working in parallel, reviewed cases from a preliminary database of 25 uveitic diseases, collected by disease, and voted independently online whether the case was the disease in question or not. The agreement statistic, κ, was calculated for the 36 pairwise comparisons for each disease, and a mean κ was calculated for each disease. After the independent online voting, committee consensus conference calls, using nominal group techniques, reviewed all cases not achieving supermajority agreement (>75%) on the diagnosis in the online voting to attempt to arrive at a supermajority agreement. A total of 5766 cases for the 25 diseases were evaluated. The overall mean κ for the entire project was 0.39, with disease-specific variation ranging from 0.23 to 0.79. After the formalized consensus conference calls to address cases that did not achieve supermajority agreement in the online voting, supermajority agreement overall was reached on approximately 99% of cases, with disease-specific variation ranging from 96% to 100%. Agreement among uveitis experts on diagnosis is moderate at best but can be improved by discussion among them. These data suggest the need for validated and widely used classification criteria in the field of uveitis. Copyright © 2017 Elsevier Inc. All rights reserved.

Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis.

PubMed

Kalinina Ayuso, Viera; van de Winkel, Evelyne Leonce; Rothova, Aniki; de Boer, Joke Helena

2011-02-01

To evaluate the efficacy of methotrexate (MTX) and the effect of its withdrawal on relapse rate of uveitis associated with juvenile idiopathic arthritis (JIA). Retrospective case series. Data of 22 pediatric JIA patients who were being treated with MTX for active uveitis were studied retrospectively. Relapse rate after the withdrawal of MTX was established. Anterior chamber (AC) inflammation, topical steroid use during the first year of MTX treatment, and associations of relapses after the withdrawal were evaluated statistically. Duration of MTX treatment and its withdrawal was determined individually in collaboration with a rheumatologist with an intention to continue the treatment for at least 1 year and to withdraw in case of inactivity of uveitis and arthritis. Inactivity of uveitis was defined as the presence of ≤0.5+ cells in the AC. Eighteen patients (18/22; 82%) showed improvement of their uveitis with a significant decrease in activity of AC inflammation after a minimal period of 3 months of MTX treatment. A topical steroid-sparing effect was observed when MTX was administered for a period of 3 to 9 months. MTX was discontinued because of inactive uveitis in 13 patients. In 9 patients (8/13; 69%) a relapse of uveitis was observed after a mean time of 7.5 months (± SD 7.3). Six patients (6/13; 46%) had a relapse within the first year after the withdrawal. Relapse-free survival after withdrawal of MTX was significantly longer in patients who had been treated with MTX for more than 3 years (P = .009), children who were older than 8 years at the moment of withdrawal (P = .003), and patients who had an inactivity of uveitis of longer than 2 years before withdrawal of MTX (P = .033). Longer inactivity under MTX therapy was independently protective for relapses after the withdrawal (hazard ratio = 0.07; 95% confidence interval 0.01-0.86; P = .038), which means that 1-year increase of duration of inactive uveitis before the withdrawal of MTX results in a

Efficacy of golimumab on recurrent uveitis in HLA-B27-positive ankylosing spondylitis.

PubMed

Yazgan, Serpil; Celik, Ugur; Işık, Metin; Yeşil, Nesibe Karahan; Baki, Ali Erdem; Şahin, Hatice; Gencer, Ercan; Doğan, İsmail

2017-02-01

To evaluate the efficacy of golimumab on severe and frequent recurrent anterior uveitis in patients with HLA-B27-positive ankylosing spondylitis. In this study, 15 eyes of 12 HLA-B27-positive AS patients with resistant anterior uveitis who received 50 mg of subcutaneous golimumab (Gol) per month due to frequent uveitis recurrences were analyzed retrospectively between May 2013 and October 2015. Assessment criteria were uveitis activity, the number of recurrence of uveitis, visual acuity, systemic corticosteroid, or other drug requirement for maintenance of remission of AU. Twelve patients (15 eyes) with HLA-B27-positive ankylosing spondylitis and anterior uveitis have been treated with golimumab 50 mg/month. Remission of uveitis was observed in 12 eyes out of 15. Malign hypertension developed in one subject after the second dose of golimumab therefore the treatment was stopped and this subject was excluded from the study. Median follow-up time was 11 months (interquartile range: 8-18). No uveitic reaction was seen except in the patient who stopped treatment. No topical or systemic steroid necessity was needed except in two cases with oral 4 mg systemic maintenance. Visual acuity was significantly increased (p = 0.002). Golimumab may be a new and effective choice for maintaining remission and the prevention of recurrences of severe, resistant anterior uveitis in patients with HLA-B27-positive ankylosing spondylitis.

Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis.

PubMed

Foeldvari, Ivan; Wierk, Angela

2005-02-01

To assess the effectiveness of methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) associated uveitis, which is still one of the most common causes of visual impairment. A retrospective chart review of patients with the diagnosis of uveitis associated with JIA between July 1, 2002, and December 31, 2002. Four hundred sixty-seven patients with JIA were followed. Thirty-eight had uveitis: 31 associated with oligoarticular JIA and 7 with psoriatic JIA. Twenty-five of the 38 patients received MTX; in 23 patients uveitis was the indication for MTX therapy. In the MTX treated group 46/50 eyes had uveitis, the mean (range) age at onset of uveitis was 7.82 years (1.8-15.8), and the mean age at onset of arthritis was 7.25 years (1.25-15.7). MTX treatment was started an average of 11.4 months (0-72) after the onset of uveitis. The mean MTX dose was 15.6 mg/m2. Remission occurred after 4.25 months (1-12). Mean duration of remission was 10.3 months (3-27). The total duration of MTX therapy was 661 months and patients were in remission for 417/661 months. In 6 patients MTX was discontinued after 12 months of remission. Four patients were still in remission after 7.5 months (1-14). MTX seems to be an effective therapy for JIA associated uveitis.

Endotoxin treatment protects rats against ozone-induced lung edema: with evidence for the role of manganese superoxide dismutase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rahman, I.; Massaro, D.

Ozone is a strong oxidizing agent that can cause lung damage and edema. There is evidence that it does so by causing peroxidation of membrane lipids. However, the elevation in lung activity of copper, zinc superoxide dismutase (Cu, ZnSOD), and manganese superoxide dismutase (MnSOD) during exposure to ozone suggests that increased production of superoxide could contribute to lung edema caused by ozone. This latter observation, and preliminary evidence that treatment of rats with endotoxin elevates lung activity of MnSOD without elevation of the activity of Cu, ZnSOD, catalase (CAT), or glutathione peroxidase (GP), led to the present study. We treatedmore » rats with endotoxin, exposed them to different concentrations of ozone, measured lung wet weight to dry weight ratio, thiobarbituric acid-reactive material (TBAR), and assayed lung tissue for Cu, ZnSOD, MnSOD, CAT, and GP activity. Our major findings are, (1) a strongly edemogenic concentration of ozone-lowered MnSOD activity; (2) endotoxin treatment of air-breathing rats did not decrease lipid peroxidation as indicated by the lung concentration of TBAR; (3) induction of increased MnSOD activity in lung by treatment with endotoxin was associated with virtually complete protection against an otherwise edemogenic concentration of ozone, with less lipid peroxidation, and with less loss of weight; and (4) this protection occurred without elevated Cu, ZnSOD, CAT, or GP activity.« less

Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock

NASA Astrophysics Data System (ADS)

Prasad, Karothu Durga; Trinath, Jamma; Biswas, Ansuman; Sekar, Kanagaraj; Balaji, Kithiganahalli N.; Guru Row, Tayur N.

2014-11-01

Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.

Indoor dust and air concentrations of endotoxin in urban and rural environments.

PubMed

Barnig, C; Reboux, G; Roussel, S; Casset, A; Sohy, C; Dalphin, J-C; de Blay, F

2013-03-01

Rural dairy farming is associated with high exposure to indoor endotoxins as compared to rural nonfarming houses and urban houses. The time spent on the mattress (7 h for an adult) and of the proximity of the contaminated source should be taken into account with the other causes of exposure. Studies in European children from a farming background have shown that these children have a reduced risk of asthma and atopic sensitization compared to their urban counterparts. It has been suggested that this might be due to exposure to high levels of endotoxin in the farming environment. The aim of this study was to compare indoor endotoxin concentrations in air and dust samples from randomly selected urban and rural dwellings. In the rural area, endotoxins were analysed in farmhouses and nonfarmhouses as well as housing characteristics, lifestyle factors and agricultural practices likely to influence air and dust endotoxin levels. Endotoxin levels were significantly higher in floor (6600 ± 6100 vs 3600 ± 5600 and 3800 ± 17,000 ng g⁻¹; P < 0·001) and mattress dust (2900 ± 4100 vs 1100 ± 2400 and 800 ± 2600 ng g⁻¹; P < 0·001) from farmhouses compared to other rural and urban homes. However, no difference was observed between endotoxin concentrations in the air of urban and rural houses, and airborne endotoxin levels did not correlate to dust levels. Lack of ventilation and direct entry into the house were correlated with an increase in dust endotoxin levels. These results confirm that dairy farming is associated with high exposure to endotoxins in indoor dust samples. No difference was observed between indoor airborne concentrations between urban and rural houses. These results suggest that measuring endotoxin in dust is the most relevant method to assess endotoxin exposure. © 2012 The Society for Applied Microbiology.

Exposure and Sensitization to Pets Modify Endotoxin Association with Asthma and Wheeze.

PubMed

Mendy, Angelico; Wilkerson, Jesse; Salo, Päivi M; Cohn, Richard D; Zeldin, Darryl C; Thorne, Peter S

2018-04-21

Pets are major contributors of endotoxin in homes, but whether they influence endotoxin association with respiratory outcomes is unclear. To examine whether exposure and sensitization to dog and cat modify the relationship between endotoxin exposure and asthma and wheeze. We analyzed data from 6051 participants in the 2005-2006 cycle of the National Health and Nutrition Examination Survey (NHANES). House dust from bedroom floor and bedding was evaluated for endotoxin and for dog (Canis familiaris 1) and cat (Feline domesticus 1) allergens. The NHANES also collected data on respiratory outcomes and measured IgE specific to allergens. Associations of log-endotoxin and pet exposure with respiratory outcomes were examined, adjusting for covariates including pet avoidance. Dog and cat ownership among participants was 48.3% and 37.5%, respectively. Endotoxin geometric mean (SE) was 15.49 (0.50) EU/mg. Endotoxin and pet allergen levels were significantly higher in households with a dog or cat. Overall, endotoxin was positively associated with wheeze (odds ratio [OR], 1.30; 95% CI, 1.04-1.62), but not with asthma. However, in participants nonsensitized to dog, the odds of endotoxin association with wheeze were higher with exposure to dog allergen (OR, 1.80; 95% CI, 1.27-2.53; P interaction  = .048). In participants sensitized to cat and exposed to cat allergen, endotoxin became positively associated with asthma (OR, 1.92; 95% CI, 1.21-3.0; P interaction  = .040). With coexposure to dog and cat allergens, endotoxin association with asthma and wheeze was exacerbated (OR, 2.00; 95% CI, 1.04-3.83; P interaction  = .012 and OR, 1.88; 95% CI, 1.32-2.66; P interaction  = .016, respectively). Exposure to dog and cat allergens enhances the association of endotoxin with asthma and wheeze. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.

Endotoxin increases pulmonary vascular protein permeability in the dog

DOE Office of Scientific and Technical Information (OSTI.GOV)

Welsh, C.H.; Dauber, I.M.; Weil, J.V.

Endotoxin increases pulmonary vascular permeability consistently in some species but fails to reliably cause injury in the dog. We wondered whether this phenomenon depended on the method of injury assessment, as others have relied on edema measurement; we quantified injury by monitoring the rate of extravascular protein accumulation. /sup 113m/In-labeled protein and /sup 99m/Tc-labeled erythrocytes were injected into anesthetized dogs and monitored by an externally placed lung probe. A protein leak index, the rate of extravascular protein accumulation, was derived from the rate of increase in lung protein counts corrected for changes in intravascular protein activity. After administration of Salmonellamore » enteriditis endotoxin (4 micrograms/kg), the protein leak index was elevated 2.5-fold (41.1 +/- 4.6 X 10(-4) min-1) compared with control (16.0 +/- 2.8 X 10(-4) min-1). In contrast, wet-to-dry weight ratios failed to increase after endotoxin (4.6 +/- 0.8 vs. control values of 4.2 +/- 0.5 g/g dry bloodless lung). However, we observed that endotoxin increased lung dry weight (per unit body weight), which may have attenuated the change in wet-to-dry weight ratios. To determine whether low microvascular pressures following endotoxin attenuated edema formation, we increased pulmonary arterial wedge pressures in five dogs by saline infusion, which caused an increase in wet-to-dry weight ratios following endotoxin but no change in the five controls. We conclude that low dose endotoxin causes pulmonary vascular protein leak in the dog while edema formation is minimal or absent.« less

Determinants of endotoxin levels in carpets in New Zealand homes.

PubMed

Wickens, K; Douwes, J; Siebers, R; Fitzharris, P; Wouters, I; Doekes, G; Mason, K; Hearfield, M; Cunningham, M; Crane, J

2003-06-01

Endotoxin in house dust has been shown to be associated with asthma severity. Little is known about the influence of housing characteristics on endotoxin distribution. Using standardized methods, dust was sampled from a 1m(2) site and the whole accessible carpet area in selected Wellington, New Zealand homes (n = 77). Endotoxin was measured using a Limulus Amoebocyte Lysate assay. Relative humidity and temperature were recorded using sensors placed in carpet bases. Questionnaires were used to collect information on housing characteristics. All analyses were performed for endotoxin units (EU)/mg and EU/m2 for each site. Geometric mean endotoxin levels were 22.7 EU/mg [geometric standard deviation (GSD) = 2.4] or 30,544 EU/m2 (GSD = 3.2) from the 1m(2) site, and 28.4 EU/mg (GSD = 3.4) or 5653 EU/m2 (GSD = 6.4) from the whole room. After controlling for confounding, endotoxin was positively associated with dogs inside [geometric mean ratio (GMR): 0.9-2.0], total household occupants (GMR: 1.7-2.0, for 1 m2 sample only), vacuum cleaners <1-year old (GMR: 2.3-2.7), reusing vacuum dust collection bags (GMR: 1.4-3.1), steamcleaning or shampooing the carpet (GMR: 1.4-2.2) and high relative humidity (GMR: 1.4-1.6). Lower endotoxin was associated with floor insulation (GMR: 0.4-0.8), and north-facing living rooms (GMR: 0.4-0.8). This study has identified home characteristics that could be modified to reduce endotoxin exposure.

Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients

PubMed Central

2012-01-01

Background Uveitis is an autoimmune disease of the eye that refers to any of a number of intraocular inflammatory conditions. Because it is a rare disease, uveitis is often overlooked, and the possible associations between uveitis and extra-ocular disease manifestations are not well known. The aim of this study was to characterize uveitis in a large sample of patients and to evaluate the relationship between uveitis and systemic diseases. Methods The present study is a cross-sectional study of a cohort of patients with uveitis. Records from consecutive uveitis patients who were seen by the Uveitis Service in the Department of Ophthalmology at the Medical University of Vienna between 1995 and 2009 were selected from the clinical databases. The cases were classified according to the Standardization of Uveitis Nomenclature Study Group criteria for Uveitis. Results Data were available for 2619 patients, of whom 59.9% suffered from anterior, 14.8% from intermediate, 18.3% from posterior and 7.0% from panuveitis. 37.2% of all cases showed an association between uveitis and extra-organ diseases; diseases with primarily arthritic manifestations were seen in 10.1% of all cases, non-infectious systemic diseases (i.e., Behçet´s disease, sarcoidosis or multiple sclerosis) in 8.4% and infectious uveitis in 18.7%. 49.4% of subjects suffering from anterior uveitis tested positively for the HLA-B27 antigen. In posterior uveitis cases 29% were caused by ocular toxoplasmosis and 17.7% by multifocal choroiditis. Conclusion Ophthalmologists, rheumatologists, infectiologists, neurologists and general practitioners should be familiar with the differential diagnosis of uveitis. A better interdisciplinary approach could help in tailoring of the work-up, earlier diagnosis of co-existing diseases and management of uveitis patients. PMID:22932001

Masking of endotoxin in surfactant samples: Effects on Limulus-based detection systems.

PubMed

Reich, Johannes; Lang, Pierre; Grallert, Holger; Motschmann, Hubert

2016-09-01

Over the last few decades Limulus Amebocyte Lysate (LAL) has been the most sensitive method for the detection of endotoxins (Lipopolysaccharides) and is well accepted in a broad field of applications. Recently, Low Endotoxin Recovery (LER) in biopharmaceutical drug products has been noticed, whereby the detection of potential endotoxin contaminations is not ensured. Notably, most of these drug products contain surfactants, which can have crucial effects on the detectability of endotoxin. In order to analyze the driving forces of LER, endotoxin detection in samples containing nonionic surfactants in various buffer systems was investigated. The results show that the process of LER is kinetically controlled and temperature-dependent. Furthermore, only the simultaneous presence of nonionic surfactants and components capable of forming metal complexes resulted in LER. In addition, capacity experiments show that even hazardous amounts of endotoxin can remain undetectable within such formulation compositions. In conclusion, the LER phenomenon is caused by endotoxin masking and not by test interference. In this process, the supramolecular structure of endotoxin is altered and exhibits only a limited susceptibility in binding to the Factor C of Limulus-based detection systems. We propose a two-step mechanism of endotoxin masking by complex forming agents and nonionic surfactants. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Domestic exposure to endotoxin and respiratory morbidity in former smokers with COPD

PubMed Central

Bose, S; Rivera-Mariani, F; Chen, R; Williams, D; Belli, A; Aloe, C; McCormack, MC; Breysse, PN; Hansel, NN

2016-01-01

Indoor air pollution has been linked to adverse COPD health, but specific causative agents have not yet been identified. We evaluated the role of indoor endotoxin exposure upon respiratory health in former smokers with COPD. Eighty-four adults with moderate to severe COPD were followed longitudinally and indoor air and dust samples collected at baseline, 3 and 6 months. Respiratory outcomes were repeatedly assessed at each time point. The associations between endotoxin exposure in air and settled dust and health outcomes were explored using generalizing estimating equations in multivariate models accounting for confounders. Dust endotoxin concentrations in the main living area were highest in spring and lowest in fall, while airborne endotoxins remained steady across seasons. Airborne and dust endotoxin concentrations were weakly correlated with one another (rs=+0.24, p = 0.005). Endotoxin concentrations were not significantly associated with respiratory symptoms, rescue medication use, quality of life, or severe exacerbations. In-vitro whole blood assays of the pro-inflammatory capacity of PM10 filters with and without endotoxin depletion demonstrated that the endotoxin component of indoor air pollution was not the primary trigger for IL-1β release Our findings support that endotoxin is not the major driver in the adverse effects of indoor PM upon COPD morbidity. PMID:26547489

Regulatory T Cell Therapy for Uveitis: A New Promising Challenge.

PubMed

Foussat, Arnaud; Gregoire, Sylvie; Clerget-Chossat, Nathalie; Terrada, Celine; Asnagli, Hélène; Lemoine, François M; Klatzmann, David; LeHoang, Phuc; Forte, Miguel; Bodaghi, Bahram

2017-05-01

Uveitis is a sight-threatening primary intraocular inflammation of various origins in mainly young and active patients. Due to the absence of biomarkers in most of the cases, the current treatment of noninfectious entities remains nonspecific, using corticosteroids, conventional immunosuppressors, and more recently biological agents. Identification of regulatory T cells in different models of autoimmune uveitis together with the evaluation of this important subpopulation in different entities paved the way for new therapeutic strategies, in addition to exclusive pharmaceutical approaches. Upregulation of regulatory T cells induced by biological agents has been recently highlighted. Development of cell therapy in autoimmune diseases is at its stammering needing more experimental data and robust clinical trials to demonstrate safety and efficacy before larger developments. Specific or polyclonal Tregs may be used, but it is of utmost importance to determine the method of selection, the level of activation, and the route of administration. Mastering immune cell therapy remains a challenging goal in patients with autoimmune diseases, but it may significantly enlarge our therapeutic possibilities in severe and refractory situations.

Endotoxin and β-1,3-d-Glucan in Concentrated Ambient Particles Induce Rapid Increase in Blood Pressure in Controlled Human Exposures.

PubMed

Zhong, Jia; Urch, Bruce; Speck, Mary; Coull, Brent A; Koutrakis, Petros; Thorne, Peter S; Scott, James; Liu, Ling; Brook, Robert D; Behbod, Behrooz; Gibson, Heike; Silverman, Frances; Mittleman, Murray A; Baccarelli, Andrea A; Gold, Diane R

2015-09-01

Short-term exposure to particulate matter (PM) is associated with increased blood pressure (BP) in epidemiological studies. Understanding the impact of specific PM components on BP is essential in developing effective risk-reduction strategies. We investigated the association between endotoxin and β-1,3-d-Glucan-two major biological PM components-and BP. We also examined whether vascular endothelial growth factor, a vasodilatory inflammatory marker, modified these associations. We conducted a single-blind, randomized, crossover trial of controlled human exposure to concentrated ambient particles with 50 healthy adults. Particle-associated-endotoxin and β-1,3-d-Glucan were sampled using polycarbonate-membrane-filters. Supine resting systolic BP and diastolic BP were measured pre-, 0.5-hour post-, and 20-hour postexposure. Urine vascular endothelial growth factor concentration was determined using enzyme-linked immunosorbant assay and creatinine-corrected. Exposures to endotoxin and β-1,3-d-Glucan for 130 minutes were associated with increases in BPs: at 0.5-hour postexposure, every doubling in endotoxin concentration was associated with 1.73 mm Hg higher systolic BP (95% confidence interval, 0.28, 3.18; P=0.02) and 2.07 mm Hg higher diastolic BP (95% confidence interval, 0.74, 3.39; P=0.003); every doubling in β-1,3-d-Glucan concentration was associated with 0.80 mm Hg higher systolic BP (95% confidence interval, -0.07, 1.67; P=0.07) and 0.88 mm Hg higher diastolic BP (95% confidence interval, 0.09, 1.66; P=0.03). Vascular endothelial growth factor rose after concentrated ambient particle endotoxin exposure and attenuated the association between endotoxin and 0.5-hour postexposure diastolic BP (Pinteraction=0.02). In healthy adults, short-term endotoxin and β-1,3-d-Glucan exposures were associated with increased BP. Our findings suggest that the biological PM components contribute to PM-related cardiovascular outcomes, and postexposure vascular endothelial

Ultra-Widefield Fluorescein Angiography in Intermediate Uveitis.

PubMed

Laovirojjanakul, Wipada; Acharya, Nisha; Gonzales, John A

2017-10-17

To examine associations between pattern of vascular leakage on ultrawide-field fluorescein angiography (UWFFA) and visual acuity, cystoid macular edema (CME), and inflammatory activity in intermediate uveitis. Single center cross-sectional, retrospective review of medical records, spectral domain optical coherence tomography (SD-OCT) and angiographic images of intermediate uveitis patients who underwent UWFFA over a 12-month period. Forty-one eyes from 24 patients were included. Twelve eyes (29%) exhibited peripheral leakage, 26 eyes (64%) had diffuse leakage and three eyes (7%) had no leakage. Diffuse leakage was associated with 0.2 logMAR worse visual acuity than peripheral leakage (p = 0.02). There was no statistically significant difference in the odds of having CME when diffuse leakage was compared to peripheral leakage. UWFFA identifies retinal vascular pathology in intermediate uveitis not present on clinical examination. Diffuse retinal vascular leakage was associated with worse visual acuity when compared to peripheral and no leakage patterns.

Equine recurrent uveitis: Human and equine perspectives.

PubMed

Malalana, Fernando; Stylianides, Amira; McGowan, Catherine

2015-10-01

Equine recurrent uveitis (ERU) is a spontaneous disease characterised by repeated episodes of intraocular inflammation. The epidemiology of ERU has not been fully elucidated, but the condition appears to be much more common in horses than is recurrent uveitis in humans, especially in certain breeds and geographical regions. Both humans and horses show a similarly altered immune response and a marked autoimmune response as the primary disease pathophysiology. However, an inciting cause is not always clear. Potential inciting factors in horses include microbial agents such as Leptospira spp. Microbial factors and genetic predisposition to the disease may provide clues as to why the horse appears so susceptible to this disease. The aim of this review is to discuss the immunology and genetics of ERU, compare the disease in horses with autoimmune anterior uveitis in humans, and discuss potential reasons for the increased prevalence in the horse. Copyright © 2015 Elsevier Ltd. All rights reserved.

Airborne endotoxin concentrations at a large open-lot dairy in southern idaho.

PubMed

Dungan, Robert S; Leytem, April B

2009-01-01

Endotoxins are derived from gram-negative bacteria and are a potential respiratory health risk for animals and humans. To determine the potential for endotoxin transport from a large open-lot dairy, total airborne endotoxin concentrations were determined at an upwind location (background) and five downwind locations on three separate days. The downwind locations were situated at of the edge of the lot, 200 and 1390 m downwind from the lot, and downwind from a manure composting area and wastewater holding pond. When the wind was predominantly from the west, the average endotoxin concentration at the upwind location was 24 endotoxin units (EU) m(-3), whereas at the edge of the lot on the downwind side it was 259 EU m(-3). At 200 and 1390 m downwind from the edge of the lot, the average endotoxin concentrations were 168 and 49 EU m(-3), respectively. Average airborne endotoxin concentrations downwind from the composting site (36 EU m(-3)) and wastewater holding pond (89 EU m(-3)) and 1390 m from the edge of the lot were not significantly different from the upwind location. There were no significant correlations between ambient weather data collected and endotoxin concentrations over the experimental period. The downwind data show that the airborne endotoxin concentrations decreased exponentially with distance from the lot edge. Decreasing an individual's proximity to the dairy should lower their risk of airborne endotoxin exposure and associated health effects.

Abatacept in the treatment of severe, longstanding, and refractory uveitis associated with juvenile idiopathic arthritis.

PubMed

Tappeiner, Christoph; Miserocchi, Elisabetta; Bodaghi, Bahram; Kotaniemi, Kaisu; Mackensen, Friederike; Gerloni, Valeria; Quartier, Pierre; Lutz, Thomas; Heiligenhaus, Arnd

2015-04-01

Abatacept (ABA), a selective T cell costimulation modulator that binds to CD80 and CD86 on antigen-presenting cells, was investigated for its antiinflammatory effect in treating severe chronic uveitis associated with juvenile idiopathic arthritis (JIA). Our retrospective study was conducted by members of the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC). Patients with JIA who are receiving ABA treatment for active uveitis were included. In all patients, uveitis had been refractory to previous topical and systemic corticosteroids, immunosuppressives, and at least 1 tumor necrosis factor-α inhibitor. A standardized protocol was used to document uveitis (MIWGUC) and arthritis. Baseline visit and visits at 3, 6, 9, and 12 months before and after ABA start were evaluated. Primary outcome measure was defined as achievement of uveitis inactivity; secondary outcome measures were tapering of corticosteroid and/or immunosuppressive treatment, and occurrence of complications. In all, 21 patients (16 female) with active uveitis (n = 21) and arthritis (n = 18) were included (mean age 11.8 ± 3.6 yrs). In 7 of 18 patients with active arthritis at baseline, inactivity was achieved following ABA treatment. Uveitis inactivity was achieved in 11 patients, but recurred later in 8 of them, and remained active in another 10 cases. Systemic corticosteroids or immunosuppression were tapered in 3 patients, but uveitis recurred in all of them during further followup. Ocular complications secondary to uveitis were present in 17 patients at baseline, while 3 patients developed new ocular complications during followup. A sustained response to ABA was uncommon in patients with severe and refractory uveitis.

Predictors of Airborne Endotoxin Concentrations in Inner City Homes

PubMed Central

Mazique, D; Diette, GB; Breysse, PN; Matsui, EC; McCormack, MC; Curtin-Brosnan, J; Williams, D; Peng, RD; Hansel, NN

2011-01-01

Few studies have assessed in-home factors which contribute to airborne endotoxin concentrations. In 85 inner-city Baltimore homes, we found no significant correlation between settled dust and airborne endotoxin concentrations. Certain household activities and characteristics, including frequency of dusting, air conditioner use and type of flooring, explained 36–42% of the variability of airborne concentrations. Measurements of both airborne and settled dust endotoxin concentrations may be needed to fully characterize domestic exposure in epidemiologic investigations. PMID:21429483

Effects of endotoxin on monoamine metabolism in the rat.

NASA Technical Reports Server (NTRS)

Pohorecky, L. A.; Wurtman, R. J.; Taam, D.; Fine, J.

1972-01-01

Examination of effects of administered endotoxin on catecholamine metabolism in the rat brain, sympathetic neurons, and adrenal medulla. It is found that endotoxin, administered intraperitoneally, lowers the norepinephrine content in peripheral sympathetic neurons and the brain, and the catecholamine content in the adrenal medulla. It also accelerates the disappearance of H3-norepinephrine from all these tissues. It is therefore suggested that the effects of endotoxin on body temperature may be mediated in part by central non-adrenergic neurons.

Epidemiology of uveitis in a Western urban multiethnic population. The challenge of globalization.

PubMed

Llorenç, Victor; Mesquida, Marina; Sainz de la Maza, Maite; Keller, Johannes; Molins, Blanca; Espinosa, Gerard; Hernandez, María V; Gonzalez-Martín, Julian; Adán, Alfredo

2015-09-01

To report the anatomical pattern and etiological spectrum of uveitis in an urban multi-ethnic population from Barcelona, Spain. General and specific epidemiological data for the most prevalent aetiologies are also calculated. A cross-sectional study of consecutive uveitis cases was performed between 1 January 2009 and 31 December 2012. Exogenous endophthalmitis, surgery-related, post-traumatic and toxic uveitis along with masquerade syndromes were excluded. Anatomical (Standard Uveitis Nomenclature criteria) and aetiological patterns (by tailored tests), age, sex, geographical origin and laterality were analysed. Mean incidence and prevalence were calculated for a mid-period reference population. From 1022 patients included, 52% were anterior uveitis (AU), 23% posterior, 15% panuveitis and 9% intermediate uveitis. Aetiologically, 26% were unclassifiable, 29% infectious, 25% associated with systemic immune diseases, and 20% corresponded to ocular-specific syndromes. Among classified causes, herpesvirus (12%), toxoplasma (7%), Behçet's disease (BD) (5%), HLA-B27-isolated AU (5%), ankylosing spondylitis (5%), tuberculosis-related uveitis (TRU) (5%), birdshot chorioretinopathy (3%) and sarcoidosis (3%) were the most frequent. Non-Spanish origin was recorded in 22%, with 47% of Vogt-Koyanagi-Harada and 36% of toxoplasma cases coming from South America, 10% of BD and 11% of TRU from Africa and 24% of TRU cases from Asia. A mean annual incidence of 51.91 cases/100,000 inhabitants was found for the referral population. In our referral area, 74% of the uveitis cases can be correctly classified. A large myriad of uveitis aetiologies with a strong geographical origin burden are found in Western urban multi-ethnic populations. © 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Review and update of intraocular therapy in noninfectious uveitis.

PubMed

Sallam, Ahmed; Taylor, Simon R J; Lightman, Sue

2011-11-01

To review new clinically relevant data regarding the intraocular treatment of noninfectious uveitis. Triamcinolone acetonide, the most commonly used intravitreal corticosteroid for treatment of uveitis and uveitic macular oedema has a limited duration of action and is associated with a high risk of corticosteroid-induced intraocular pressure (IOP) rise and cataract. Recent advances have led to the development of sustained-release corticosteroid devices using different corticosteroids such as dexamethasone and fluocinolone acetonide. Treatment options for patients who have previously exhibited corticosteroid hypertensive response have also expanded through the use of new noncorticosteroid intravitreal therapeutics such as methotrexate and antivascular endothelial growth factor (anti-VEGF) agents. Ozurdex dexamethasone implant appears to have a better safety profile, and a slightly long-lasting effect than triamcinolone acetonide. The Retisert implant allows the release of corticosteroids at a constant rate for 2.5 years, but it requires surgical placement and its use is associated with a very high risk of cataract and requirement for IOP-lowering surgery. For patients who are steroid responders, methotrexate may offer a better alternative to corticosteroid treatment than anti-VEGF agents, but controlled trials are required to confirm this.

Mycophenolate sodium for the treatment of chronic non-infectious uveitis of childhood.

PubMed

Doycheva, Deshka; Zierhut, Manfred; Blumenstock, Gunnar; Sobolewska, Bianka; Voykov, Bogomil; Hohmann, Johanna; Spitzer, Martin S; Deuter, Christoph

2016-08-01

To assess the efficacy and tolerability of mycophenolate sodium (MPS) in the therapy of children with chronic non-infectious uveitis. Retrospective analysis of 23 children with chronic uveitis, treated with MPS, with a follow-up of at least 6 months. The main outcome measures were time to uveitis reactivation and corticosteroid-sparing effect under MPS treatment. The secondary outcome measures were best-corrected visual acuity (BCVA) and treatment-related side effects. From 23 patients included in the study, 2 patients had anterior uveitis, 19 had intermediate uveitis and 2 had panuveitis. The probability of reactivation-free survival after MPS initiation was estimated as 65% at both 1 and 2 years. The probability of discontinuing systemic corticosteroids after 1 year of treatment was 39% and after 2 years 51%. The probability to taper corticosteroids to a daily dosage of ≤0.1 mg/kg after 1 and 2 years was 62% and 85%, respectively. BCVA improved or remained stable in 96% of eyes after 1 year of therapy. Treatment-related side effects were found in nine children (rate: 0.17/patient-year). No therapy discontinuation because of side effects was needed. Our data suggest that MPS is useful and well tolerated in children with chronic uveitis. MPS seems to be an effective drug for the treatment of chronic non-infectious uveitis of childhood and may be preferred as a first-line steroid-sparing agent in this form of uveitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

[Therapy for childhood uveitis: biologics: too often--too late?].

PubMed

Mackensen, F; Lutz, T

2011-03-01

Pediatric uveitis differs from uveitis seen in adulthood not only because of the uveitis presentation and severity of disease but also by a worse prognosis and age-specific problems that may occur under therapy. Biologics are selective acting proteins that are manufactured by biotechnology. The greatest amount of knowledge to date exists for the TNF alpha blocking agents. Experimental and clinical studies showed that TNF alpha plays a significant role in the process of intraocular inflammation, so it was a logical step to use TNF blocking agents in uveitis therapy. Randomized controlled studies are rare, but pooled data (as presented here) of case series published show good evidence for the efficacy especially of infliximab and adalimumab. It is to be hoped that blindness and severe sight disabilities can be further reduced by this treatment in the future. From pediatric rheumatology we have learned about even newer biologics. With this review we want to show the weaknesses and strengths of therapy with biologics and want to help in choosing this treatment at the indicated time point in the disease.

Detection of Leptospira spp. in the aqueous humor of horses with naturally acquired recurrent uveitis.

PubMed

Faber, N A; Crawford, M; LeFebvre, R B; Buyukmihci, N C; Madigan, J E; Willits, N H

2000-07-01

Leptospiral organisms have long been presumed to be associated with the presence of equine recurrent uveitis. This project was undertaken to determine the presence of Leptospira spp. in the aqueous humor of horses with uveitis to determine if there was an association with inflammation. Thirty horses were determined to have recurrent uveitis based on clinical evaluation or history. Sixteen horses were judged clinically and historically to be free of uveitis and were used as controls. Aqueous humor samples were cultured and evaluated by PCR for the presence of Leptospira DNA. Serum was collected and evaluated for the presence of antibodies against five serovars in a leptospirosis panel. Twenty-one of 30 horses with recurrent uveitis and one of 16 uveitis-free horses were positive by PCR for the presence of Leptospira DNA. Six of these 21 horses with uveitis were culture positive for leptospires from the aqueous humor. Serologic results did not correlate well with the presence of Leptospira DNA or organisms in the aqueous humor. Leptospira spp. are present in a high percentage of horses with naturally occurring recurrent uveitis.

Detection of Leptospira spp. in the Aqueous Humor of Horses with Naturally Acquired Recurrent Uveitis

PubMed Central

Faber, Nick A.; Crawford, Melissa; LeFebvre, Rance B.; Buyukmihci, Nedim C.; Madigan, John E.; Willits, Neil H.

2000-01-01

Leptospiral organisms have long been presumed to be associated with the presence of equine recurrent uveitis. This project was undertaken to determine the presence of Leptospira spp. in the aqueous humor of horses with uveitis to determine if there was an association with inflammation. Thirty horses were determined to have recurrent uveitis based on clinical evaluation or history. Sixteen horses were judged clinically and historically to be free of uveitis and were used as controls. Aqueous humor samples were cultured and evaluated by PCR for the presence of Leptospira DNA. Serum was collected and evaluated for the presence of antibodies against five serovars in a leptospirosis panel. Twenty-one of 30 horses with recurrent uveitis and one of 16 uveitis-free horses were positive by PCR for the presence of Leptospira DNA. Six of these 21 horses with uveitis were culture positive for leptospires from the aqueous humor. Serologic results did not correlate well with the presence of Leptospira DNA or organisms in the aqueous humor. Leptospira spp. are present in a high percentage of horses with naturally occurring recurrent uveitis. PMID:10878072

Endotoxin Neutralization as a Biomonitor for Inflammatory Bowel Disease

PubMed Central

Champion, Keith; Chiu, Laura; Ferbas, John; Pepe, Michael

2013-01-01

Gram-negative bacterial endotoxin is a potent immunostimulant implicated in the development and/or progression of a variety of diseases. The mammalian immune system has both innate and adaptive immune responses to neutralize endotoxin. In this study, a system was developed to monitor bacterial exposure by measuring the extent and nature of endotoxin neutralization in plasma. In control patients, females had higher levels of endotoxin neutralization than males, mirroring clinical outcomes from bacterial infection and sepsis. In addition to the total amount of neutralization, we used inactivation techniques to elucidate the nature of this activity and develop a system to compare early and late immune responses. Using this method to monitor patients with inflammatory bowel disease, we found a more robust total response that relies more on long-term, adaptive components of the immune system and less on early, innate components. Our results indicate that endotoxin neutralization is a valuable method to discern inflammatory bowel disease patients from a control population. Additionally, the nature of neutralization may be valuable in monitoring disease severity and/or the role of medication. PMID:23826338

In silico designed nanoMIP based optical sensor for endotoxins monitoring.

PubMed

Abdin, M J; Altintas, Z; Tothill, I E

2015-05-15

Molecular modelling was used to select specific monomers suitable for the design of molecularly imprinted polymers (MIPs) with high affinity towards endotoxins. MIPs were synthesised using solid-phase photopolymerisation with endotoxins from Escherichia coli 0111:B4 as the template. This technique also allowed the endotoxin template to be reused successfully. Particle size of ~190-220 nm was achieved with low polydispersity index, which confirms the quality of the produced MIPs. For the development of the optical sensor, SPR-2 biosensor system was used by functionalising the gold sensor chip with the MIP nanoparticles using EDC/NHS coupling procedure. The affinity based-endotoxin assay can detect endotoxins in the concentration range of 15.6-500 ng mL(-1). MIP surfaces were regenerated showing stability of the method for subsequent analysis and dissociation constants were calculated as 3.24-5.24×10(-8) M. The developed SPR sensor with the novel endotoxins nanoMIP showed the potential of the technology for endotoxins capture, detection and risk management and also the importance of computational modelling to design the artificial affinity ligands. Copyright © 2014 Elsevier B.V. All rights reserved.

Myocardial and vascular adrenergic alterations in a rat model of endotoxin shock: reversal by an anti-tumor necrosis factor-alpha monoclonal antibody.

PubMed

Boillot, A; Massol, J; Maupoil, V; Grelier, R; Bernard, B; Capellier, G; Berthelot, A; Barale, F

1997-03-01

a) To investigate responsiveness to exogenous catecholamines in rat endotoxin shock by studying both myocardial and vascular functional parameters, and to determine the relationship of these parameters with other relevant biological parameters of the adrenergic pathway, such as myocardial beta-adrenergic receptors and cyclic adenosine monophosphate (cAMP); b) to investigate the role of tumor necrosis factor (TNF)-alpha via prophylactic anti-TNF-alpha monoclonal antibody administration. Experimental, comparative hospital. Laboratory in a university hospital. Male Sprague-Dawley rats, weighing 280 to 340 g. Intravenous injection of Escherichia coli endotoxin (5 mg/100 g) in the first group; injection of the same dose of endotoxin preceded by 2 mg/100 g of anti-TNF-alpha monoclonal antibody in the second group; injection of saline in the third (control) group. TNF-alpha concentration was measured before and during the first 3 hrs in all three groups. Myocardial and vascular functional parameters were obtained, respectively, from Langendorff perfused hearts and isolated aortic rings. Adrenergic biochemical parameters (catecholamines, density and affinity of beta-receptors, and isoproterenol-stimulated myocardial cAMP) were determined 3 hrs after injections in the three groups. After endotoxin injection, serum TNF-alpha concentrations peaked at 60 mins (2496 +/- 412 pg/mL) and returned slowly to control values at 3 hrs; serum TNF-alpha concentrations remained under the limit of detection in the other two groups. When compared with the control group, plasma concentrations of epinephrine and norepinephrine were significantly (p < .05) increased. Baseline values for differential left ventricular pressure and coronary flow were significantly (p < .001, p < .01, respectively) reduced in the endotoxin group; heart rate remained unchanged. In the endotoxin and control groups, isoproterenol induced a similar increase in differential left ventricular pressure and in heart rate

Diagnosis and treatment of tuberculous uveitis in a low endemic setting.

PubMed

Vos, A G; Wassenberg, M W M; de Hoog, J; Oosterheert, J J

2013-11-01

To determine factors associated with the diagnosis of tuberculous uveitis and the response to anti-tuberculous treatment (ATT). A retrospective case study was performed at the University Medical Centre Utrecht between October 2007 and December 2009. Patients with possible tuberculous uveitis (TBU) were selected from all patients with an unexplained uveitis. Demographics, ethnicity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tuberculin skin test (TST), QuantiFERON (QFT) test, and ocular findings were evaluated. An interdisciplinary panel discussed if there was a presumed TBU and decided to start treatment. When there was a decrease in intraocular cell count and/or improvement in visual acuity after ATT, the confirmation of presumed TBU was made. Of 585 patients with unexplained uveitis, 66 (11.3%) fulfilled the definition of possible TBU. Ten (15.4%) patients were regarded as having presumed TBU and received ATT. All of them had latent tuberculosis (LTB). The ocular situation improved in seven patients (70%). A history of TB contact, abnormalities on chest radiology, and extraocular manifestations of TB were associated with a good response to ATT in the case of presumed tuberculous uveitis. Tuberculous uveitis remains difficult to diagnose. No clearly correlating factors that predicted the response to ATT, including ocular parameters, could be identified. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Endotoxin depletion of recombinant protein preparations through their preferential binding to histidine tags.

PubMed

Mack, Laura; Brill, Boris; Delis, Natalia; Groner, Bernd

2014-12-01

The presence of endotoxins in preparations of recombinantly produced therapeutic proteins poses serious problems for patients. Endotoxins can cause fever, respiratory distress syndromes, intravascular coagulation, or endotoxic shock. A number of methods have been devised to remove endotoxins from protein preparations using separation procedures based on molecular mass or charge properties. Most of the methods are limited in their endotoxin removal capacities and lack general applicability. We are describing a biotechnological approach for endotoxin removal. This strategy exploits the observation that endotoxins form micelles that expose negative charges on their surface, leading to preferential binding of endotoxins to cationic surfaces, allowing the separation from their resident protein. Endotoxins exhibit high affinity to stretches of histidines, which are widely used tools to facilitate the purification of recombinant proteins. They bind to nickel ions and are the basis for protein purification from cellular extracts by immobilized metal affinity chromatography. We show that the thrombin-mediated cleavage of two histidine tags from the purified recombinant protein and the adsorption of these histidine tags and their associated endotoxins to a nickel affinity column result in an appreciable depletion of the endotoxins in the purified protein fraction. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Retinitis pigmentosa, Coats disease and uveitis.

PubMed

Solomon, A; Banin, E; Anteby, I; Benezra, D

1999-01-01

To study the anamnestic immune response to retinal specific antigens of two patients suffering from a rare triad of retinitis pigmentosa, Coats disease and uveitis. 17-year-old girl presented with an acute episode of panuveitis, and her 19-year-old brother suffered from chronic uveitis. On examination, both patients showed retinal vascular changes and subretinal exudations typical of Coats disease, with bone-spicule pigmentary changes as observed in retinitis pigmentosa. All routine examinations were unrevealing. However, the peripheral lymphocytes from these two siblings gave a specific anamnestic response to retinal antigens in vitro. A stimulation index of 4.6 was obtained when the sister's lymphocytes were stimulated with interphotoreceptor binding protein, IRBP--during the acute stage of the uveitis. The brother's lymphocytes showed a stimulation index of 2.7 towards S-Ag during the chronic phase of his uveitic condition. These results indicate that autoimmunity towards retinal antigens may play some role in specific types of retinitis pigmentosa. Whether these autoimmune reactions are a primary pathological mechanism or are secondary to the extensive destruction of the photoreceptor layer resulting from the retinitis pigmentosa remains debatable.

Tocilizumab treatment for refractory uveitis-related cystoid macular edema.

PubMed

Adán, Alfredo; Mesquida, Marina; Llorenç, Victor; Espinosa, Gerard; Molins, Blanca; Hernández, Maria V; Pelegrín, Laura

2013-11-01

This retrospective study investigated the efficacy of tocilizumab (TCZ), a fully humanized antibody that binds both to soluble and membrane bound IL-6 receptors, for the treatment of uveitis-related cystoid macular edema (CME) refractory to immunomodulatory therapy. Five refractory patients with uveitis-related CME who received TCZ between January and August 2012 were included. All patients received 8 mg/kg TCZ at 4-week intervals. Data regarding patient demographics, use of immunosuppressive drugs, biologic agents or intravitreal therapies prior to TCZ infusions were collected. Main outcome measure was central foveal thickness (CFT) measured by optical coherence tomography at 6 months. Secondary outcome measures were degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria) and visual acuity (logarithm of the minimum angle of resolution [log-MAR]) at month 6. Adverse events (AEs) related to TCZ therapy were also assessed. Eight eyes from five patients (all females) were included. Mean age was 49.4 years (range, 30-68). Mean follow-up was 8.4 months (range, 6-12). Before TCZ, all patients received and failed conventional immunosuppressive therapy and had received at least another biologic agent. Uveitis diagnoses were Birdshot chorioretinopathy (n = 3), juvenile idiopathic arthritis (JIA)-associated uveitis (n = 1), and idiopathic panuveitis (n = 1). Mean evolution of CME was 13.4 years (range, 2-30). Mean baseline CFT (95% confidence interval) was 602 ± 236 μm at baseline, 386 ± 113 μm at month 1 (p = 0.006), 323 ± 103 μm at month 3 (p = 0.026), and 294.5 ± 94.5 μm at month 6 (p = 0.014). Median best-corrected visual acuity (BCVA) improved from 0.66 ± 0.57 at baseline to 0.47 ± 0.62 at month 6 (p = 0.035). After 6 months, an improvement of ≥ 2 lines of BCVA was observed in 50% of eyes (p = 0.028) remained stable in 25% and worsened in none of the patients. Sustained uveitis remission was

Endotoxin Contamination in Nanomaterials Leads to the Misinterpretation of Immunosafety Results

PubMed Central

Li, Yang; Fujita, Mayumi; Boraschi, Diana

2017-01-01

Given the presence of engineered nanomaterials in consumers’ products and their application in nanomedicine, nanosafety assessment is becoming increasingly important. In particular, immunosafety aspects are being actively investigated. In nanomaterial immunosafety testing strategies, it is important to consider that nanomaterials and nanoparticles are very easy to become contaminated with endotoxin, which is a widespread contaminant coming from the Gram-negative bacterial cell membrane. Because of the potent inflammatory activity of endotoxin, contaminated nanomaterials can show inflammatory/toxic effects due to endotoxin, which may mask or misidentify the real biological effects (or lack thereof) of nanomaterials. Therefore, before running immunosafety assays, either in vitro or in vivo, the presence of endotoxin in nanomaterials must be evaluated. This calls for using appropriate assays with proper controls, because many nanomaterials interfere at various levels with the commercially available endotoxin detection methods. This also underlines the need to develop robust and bespoke strategies for endotoxin evaluation in nanomaterials. PMID:28533772

Imaging Phenotype of Occupational Endotoxin-Related Lung Function Decline.

PubMed

Lai, Peggy S; Hang, Jing-Qing; Zhang, Feng-Ying; Sun, J; Zheng, Bu-Yong; Su, Li; Washko, George R; Christiani, David C

2016-09-01

Although occupational exposures contribute to a significant proportion of obstructive lung disease, the phenotype of obstructive lung disease associated with work-related organic dust exposure independent of smoking remains poorly defined. We identified the relative contributions of smoking and occupational endotoxin exposure to parenchymal and airway remodeling as defined by quantitative computed tomography (CT). The Shanghai Textile Worker Study is a longitudinal study of endotoxin-exposed cotton workers and endotoxin-unexposed silk workers that was initiated in 1981. Spirometry, occupational endotoxin exposure, and smoking habits were assessed at 5-year intervals. High-resolution computed tomography (CT) was performed in 464 retired workers in 2011, along with quantitative lung densitometric and airway analysis. Significant differences in all CT measures were noted across exposure groups. Occupational endotoxin exposure was associated with a decrease (-1.3%) in percent emphysema (LAAI-950), a 3.3-Hounsfield unit increase in 15th percentile density, an 18.1-g increase in lung mass, and a 2.3% increase in wall area percent. Current but not former smoking was associated with a similar CT phenotype. Changes in LAAI-950 were highly correlated with 15th percentile density (correlation -1.0). Lung mass was the only measure associated with forced expiratory volume in 1 sec (FEV1) decline, with each 10-g increase in lung mass associated with an additional loss (-6.1 mL) of FEV1 (p = 0.001) between 1981 and 2011. There are many similarities between the effects of occupational endotoxin exposure and those of tobacco smoke exposure on lung parenchyma and airway remodeling. The effects of occupational endotoxin exposure appear to persist even after the cessation of exposure. LAAI-950 may not be a reliable indicator of emphysema in subjects without spirometric impairment. Lung mass is a CT-based biomarker of accelerated lung function decline. Lai PS, Hang J, Zhang F, Sun J

Domestic exposure to endotoxin and respiratory morbidity in former smokers with COPD.

PubMed

Bose, S; Rivera-Mariani, F; Chen, R; Williams, D; Belli, A; Aloe, C; McCormack, M C; Breysse, P N; Hansel, N N

2016-10-01

Indoor air pollution has been linked to adverse chronic obstructive pulmonary disease (COPD) health, but specific causative agents have not yet been identified. We evaluated the role of indoor endotoxin exposure upon respiratory health in former smokers with COPD. Eighty-four adults with moderate to severe COPD were followed longitudinally and indoor air and dust samples collected at baseline, 3 and 6 months. Respiratory outcomes were repeatedly assessed at each time point. The associations between endotoxin exposure in air and settled dust and health outcomes were explored using generalizing estimating equations in multivariate models accounting for confounders. Dust endotoxin concentrations in the main living area were highest in spring and lowest in fall, while airborne endotoxins remained steady across seasons. Airborne and dust endotoxin concentrations were weakly correlated with one another (rs  = +0.24, P = 0.005). Endotoxin concentrations were not significantly associated with respiratory symptoms, rescue medication use, quality of life, or severe exacerbations. In vitro whole-blood assays of the pro-inflammatory capacity of PM10 filters with and without endotoxin depletion demonstrated that the endotoxin component of indoor air pollution was not the primary trigger for interleukin-1β release. Our findings support that endotoxin is not the major driver in the adverse effects of indoor PM upon COPD morbidity. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Uveitis associated with juvenile idiopathic arthritis : Optimization of immunomodulatory therapy].

PubMed

Heiligenhaus, A; Tappeiner, C; Walscheid, K; Heinz, C

2016-05-01

Uveitis associated with juvenile idiopathic arthritis (JIA-associated uveitis) is a vision-threatening disorder with a high complication rate. Besides early diagnosis within screening programs an adequate therapy is essential for improvement of the long-term prognosis. Corticosteroid therapy is often insufficient. In addition to conventional immunosuppression, immunomodulatory drugs, so-called biologicals, are novel highly effective treatment modalities. A systematic search of the literature was carried out for biologicals currently used in the treatment of JIA-associated uveitis. Review of current publications, summary of treatment guidelines and discussion of treatment options for therapy refractive patients. In accordance with the current recommendations tumor necrosis factor (TNF) inhibitors are administered if uveitis inactivity cannot be achieved with topical corticosteroids and in the next stage with immunosuppressants (methotrexate preferred). According to the currently available data adalimumab is then preferred. When the effectiveness of TNF inhibitors ceases during long-term administration and/or recurrences, other biological response modifiers are attractive treatment options (e. g. lymphocyte inhibitors or specific receptor antagonists). The TNF inhibitors are of major importance for the treatment of JIA-associated uveitis. Prospective studies and registries would be desirable in order to be able to compare the value of TNF inhibitors and other biologicals and for optimization of treatment recommendations.

A new method for concentration analysis of bacterial endotoxins in perfluorocarbon

NASA Astrophysics Data System (ADS)

Chen, Dan-Dan; Feng, Xiao-Ming; Wang, Chun-Ren; Huang, Qing-Quan; Yang, Zhao-Peng; Meng, Qing-Yuan

2014-12-01

This communication demonstrates the feasibility of the gel-clot method for the analysis of bacterial endotoxins in water extracts of perfluorocarbon which is a water insoluble liquid medical device. Perfluorocarbon (10 mL) was shaken with 10mL water for 15 min at 2000 r/min and the endotoxin present was extracted to the aqueous phase without interference inhibition/enhancement of the product and the recovery of endotoxin added to perfluorocarbon was determined. A validation study confirmed that endotoxins presented in perfluorocarbon pass over into the aqueous phase at concentrations of 20, 10 and 5 EU/mL with recoveries from 86.8% to 96.8%. Therefore, the gel-clot test is suitable for detecting bacterial endotoxins in perfluorocarbon which is a water insoluble medical device.

Biofilm Growth Increases Phosphorylcholine Content and Decreases Potency of Nontypeable Haemophilus influenzae Endotoxins

PubMed Central

West-Barnette, Shayla; Rockel, Andrea; Swords, W. Edward

2006-01-01

Nontypeable Haemophilus influenzae (NTHI) is a common respiratory commensal and opportunistic pathogen. NTHI is normally contained within the airways by host innate defenses that include recognition of bacterial endotoxins by Toll-like receptor 4 (TLR4). NTHI produces lipooligosaccharide (LOS) endotoxins which lack polymeric O side chains and which may contain host glycolipids. We recently showed that NTHI biofilms contain variants with sialylated LOS glycoforms that are essential to biofilm formation. In this study, we show that NTHI forms biofilms on epithelial cell layers. Confocal analysis revealed that sialylated variants were distributed throughout the biofilm, while variants expressing phosphorylcholine (PCho) were found within the biofilm. Consistent with this observation, PCho content of LOS purified from NTHI biofilms was increased compared to LOS from planktonic cultures. Hypothesizing that the observed changes in endotoxin composition could affect bioactivity, we compared inflammatory responses to NTHI LOS purified from biofilm and planktonic cultures. Our results show that endotoxins from biofilms induced weaker host innate responses. While we observed a minimal effect of sialylation on LOS bioactivity, there was a significant decrease in bioactivity associated with PCho substitutions. We thus conclude that biofilm growth increases the proportion of PCho+ variants in an NTHI population, resulting in a net decrease in LOS bioactivity. Thus, in addition to their well-documented resistance phenotypes, our data show that biofilm communities of NTHI bacteria contain variants that evoke less potent host responses. PMID:16495557

Association between intermediate uveitis and toxocariasis in the Korean population

PubMed Central

Kwon, Jin-woo; Sim, Yoonseob; Jee, Donghyun

2017-01-01

Abstract The aim of the study was to investigate the characteristics of ocular toxocariasis (OT) presenting with intermediate uveitis in the Korean population. We studied intermediate uveitis patients using ocular and systemic evaluations and a Toxocara IgG serology test. Of 50 intermediate uveitis patients, 19 were seropositive for Toxocara IgG. Of the 19 OT patients, 4 presented with recurrence within 6 months and were significantly younger than nonrecurrence patients (P = 0.009). Thirteen patients had a history of eating raw cow liver. There were 14 males and 5 females in the OT group, and 11 males and 20 females in the non-OT group (P = 0.009). There was bilateral involvement in 7 out of 19 patients in the OT group, and 20 out of 31 patients in non-OT group (P = 0.033). Intermediate uveitis patients in OT were predominately male and had more unilateral presentation than non-OT patients. PMID:28151857

Association between intermediate uveitis and toxocariasis in the Korean population.

PubMed

Kwon, Jin-Woo; Sim, Yoonseob; Jee, Donghyun

2017-02-01

The aim of the study was to investigate the characteristics of ocular toxocariasis (OT) presenting with intermediate uveitis in the Korean population.We studied intermediate uveitis patients using ocular and systemic evaluations and a Toxocara IgG serology test.Of 50 intermediate uveitis patients, 19 were seropositive for Toxocara IgG. Of the 19 OT patients, 4 presented with recurrence within 6 months and were significantly younger than nonrecurrence patients (P = 0.009). Thirteen patients had a history of eating raw cow liver.There were 14 males and 5 females in the OT group, and 11 males and 20 females in the non-OT group (P = 0.009). There was bilateral involvement in 7 out of 19 patients in the OT group, and 20 out of 31 patients in non-OT group (P = 0.033).Intermediate uveitis patients in OT were predominately male and had more unilateral presentation than non-OT patients.

Emerging Role of Antioxidants in the Protection of Uveitis Complications

PubMed Central

Yadav, Umesh C S; Kalariya, Nilesh M; Ramana, Kota V

2011-01-01

Current understanding of the role of oxidative stress in ocular inflammatory diseases indicates that antioxidant therapy may be important to optimize the treatment. Recently investigated antioxidant therapies for ocular inflammatory diseases include various vitamins, plant products and reactive oxygen species scavengers. Oxidative stress plays a causative role in both non-infectious and infectious uveitis complications, and novel strategies to diminish tissue damage and dysfunction with antioxidant therapy may ameliorate visual complications. Preclinical studies with experimental animals and cell culture demonstrate significance of anti-inflammatory effects of a number of promising antioxidant agents. Many of these antioxidants are under clinical trial for various inflammatory diseases other than uveitis such as cardiovascular, rheumatoid arthritis and cancer. Well planned interventional clinical studies of the ocular inflammation will be necessary to sufficiently investigate the potential medical benefits of antioxidant therapies for uveitis. This review summarizes the recent investigation of novel antioxidant agents for ocular inflammation, with selected studies focused on uveitis. PMID:21182473

Chronic Non-infectious Uveitis in Patients with Juvenile Idiopathic Arthritis.

PubMed

Kolomeyer, Anton M; Tu, Yufei; Miserocchi, Elisabetta; Ranjan, Mangala; Davidow, Amy; Chu, David S

2016-08-01

To describe clinical findings and analyze treatment evolution of chronic, non-infectious uveitis in patients with juvenile idiopathic arthritis (JIA). A total of 82 patients (147 eyes) with JIA-related uveitis treated for ≥2 months were included (78% females; 79% bilateral uveitis; 74% anterior uveitis). Outcome measures were visual acuity (VA), inflammation control, side-effects, and surgical procedures. Mean ± SD age at diagnosis was 4.9 ± 3.8 years; mean ± SD follow-up time was 8.7 ± 7.8 years. Mean VA did not significantly change throughout the study. Three (2%) eyes resulted in no light perception (NLP) vision. Thirty (37%) patients underwent 69 procedures. In total, 41 (50%) patients achieved inflammation control. TNF-α inhibitors were significantly associated with inflammation control. Seven (8.5%) patients stopped treatment due to side-effects. JIA is a cause of significant ocular morbidity. TNF-α inhibitor use was associated with inflammation control. Prospective, randomized, double blind clinical trials in this regard are warranted.

Levels of thrombopoietin in aqueous humor of patients with noninfectious acute anterior uveitis

PubMed Central

Mondejar, José-Juan; Salom, David; Garcia-Delpech, Salvador; Diaz-Llopis, Manuel

2015-01-01

Purpose To measure thrombopoietin (TPO) levels in the serum and aqueous humors of patients with noninfectious acute anterior uveitis. Methods A prospective, comparative, controlled study. Serum and aqueous humors were obtained from the eyes of 16 patients with noninfectious acute anterior uveitis. TPO levels were measured using an enzyme-linked immunosorbent assay (ELISA). The results obtained were compared with those of a control group. Results Serum concentrations of TPO were not significantly different between control individuals and patients with active anterior uveitis. Aqueous humor TPO levels were 54.46±16.24 pg/mL in the eyes of patients with uveitis, and 34.32±11.63 pg/mL in the eyes of controls. The difference between the two groups was significant (Mann–Whitney U-test for independent data, P=0.0008), with uveitis patients exhibiting significantly higher levels of TPO. Conclusion The high levels of TPO in the aqueous humors of uveitis patients points toward a cytoprotective role of this factor in inflammatory repair processes and the recovery of tissue homeostasis. PMID:26203218

The molecular adsorption-type endotoxin detection system using immobilized ɛ-polylysine

NASA Astrophysics Data System (ADS)

Ooe, Katsutoshi; Tsuji, Akihito; Nishishita, Naoki; Hirano, Yoshiaki

2007-12-01

Hemodialysis for chronic renal failure is the most popular treatment method with artificial organs. However, hemodialysis patients must continue the treatment throughout their life, the results of long term extracorporeal dialysis, those patients develop the various complications and diseases, for example, dialysis amyloidosis etc. Dialysis amyloidosis is one of the refractory complications, and endotoxin is thought to be the most likely cause of it, recently. Endotoxin is one of the major cell wall components of gram-negative bacteria, and it has various biological activities. In addition, it is known that a mount of endotoxin exists in living environment, and medicine is often contaminated with endotoxin. When contaminated dialyzing fluids are used to hemodialysis, above-mentioned dialysis amyloidosis is developed. Therefore, it is important that the detection and removal of endotoxin from dialyzing fluids. Until now, the measurement methods using Limulus Amebosyte Lysate (LAL) reagent were carried out as the tests for the presence of endtoxin. However, these methods include several different varieties of measurement techniques. The following are examples of them, gelatinization method, turbidimetric assay method, colorimetric assay method and fluoroscopic method. However, these techniques needed 30-60 minutes for the measurement. From these facts, they are not able to use as a "real-time endotoxin detector". The detection of endotoxin has needed to carry out immediately, for that reason, a new detection method is desired. In this research, we focused attention to adsorption reaction between ɛ-polylysine and endotoxin. ɛ-polylysine has the structure of straight chain molecule composed by 25-30 residues made by lysine, and it is used as an antimicrobial agent, moreover, cellulose beads with immobilized ɛ-polylysine is used as the barrier filter for endotoxin removal. The endotoxin is adsorbed to immobilized ɛ-polylysine, as the result of this reaction, the

Long-term treatment with rituximab in severe juvenile idiopathic arthritis-associated uveitis.

PubMed

Miserocchi, Elisabetta; Modorati, Giulio; Berchicci, Luigi; Pontikaki, Irene; Meroni, Pierluigi; Gerloni, Valeria

2016-06-01

To evaluate retrospectively the long-term efficacy of rituximab in patients with severe juvenile idiopathic arthritis (JIA)-associated uveitis. Eight patients (15 eyes) with severe and longstanding JIA uveitis, who had an inadequate response in controlling uveitis to one or more biologic agents including tumour necrosis factor blockers and abatacept, received rituximab therapy. Rituximab was given at a dose of 1000 mg per infusion on days 1 and 15 and then every 6 months. Clinical responses to treatment, including decrease in uveitis activity, visual acuity changes, reduction of concomitant local and systemic corticosteroid and/or immunosuppressants, and occurrence of adverse events, were assessed. Eight patients with a mean±SD age of 22.8±5.5 years were treated. The mean ocular disease duration was 17.7 years; the mean±SD follow-up time on rituximab was 44.75±4.9 months; and the mean number of rituximab infusions received was 8.75 (range 6-12). All patients achieved complete control of uveitis, but in two patients rituximab was discontinued due to inefficacy in treating arthritis. The decrease in uveitis activity was evident 4-5 months after the first infusion. Systemic corticosteroids and immunosuppressants used in association with rituximab were discontinued in five patients at the end of follow-up. None of the patients experienced visual worsening during the follow-up. No drug-related complications were encountered. Rituximab may be a promising effective treatment option for refractory uveitis associated with JIA leading to long-term quiescence of uveitis, particularly for patients who have not previously responded to other biologic therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The Future is Now – Biologics for Non-Infectious Pediatric Anterior Uveitis

PubMed Central

Lerman, Melissa A.; Rabinovich, C. Egla

2015-01-01

Anterior uveitis (AU), inflammation of the iris, choroid, or ciliary body, can cause significant eye morbidity, including visual loss. In the pediatric age group, the most common underlying diagnosis for AU is juvenile idiopathic associated uveitis and idiopathic AU, which are the focus of this paper. AU is often resistant to medications such as topical corticosteroids and methotrexate. In the past 15 years, biologic agents (biologics) have transformed treatment. In this review, we discuss those in widespread use and those with more theoretical applications for anterior uveitis. Tumor Necrosis Factor alpha inhibitors (anti-TNFα) have been available the longest and are used widely to treat pediatric uveitis. The effects of anti-TNFα in children are described mostly in small retrospective case series. Together, the literature suggests that the majority of children treated with anti-TNFα achieve decreased uveitis activity and reduce corticosteroid burden. However, many will have disease flares even on treatment. Only a few small studies directly compare outcomes between alternate anti-TNFα (infliximab and adalimumab). The use of different uveitis grading systems, inclusion criteria, and outcome measures, makes cross-study comparisons difficult. Whether the achievement and maintenance of inactive disease occurs more frequently with certain anti-TNFα remains controversial. Newer biologics that modulate the immune system differently (e.g., interfere with TH17 activation through IL-17a and IL-6 blockade, limit T lymphocyte costimulation, and deplete B lymphocytes), have shown promise for uveitis. Studies of these agents are small and include mostly adults. Additional biologics are also being explored to treat uveitis. With their advent, we are hopeful that outcomes will ultimately be improved for children with AU. With many biologics available, much work remains to identify the optimal inflammatory pathway to target in AU. PMID:25893479

Marine aerosol as a possible source for endotoxins in coastal areas.

PubMed

Lang-Yona, Naama; Lehahn, Yoav; Herut, Barak; Burshtein, Noa; Rudich, Yinon

2014-11-15

Marine aerosols, that are very common in the highly populated coastal cities and communities, may contain biological constituents. Some of this biological fraction of marine aerosols, such as cyanobacteria and plankton debris, may influence human health by inflammation and allergic reactions when inhaled. In this study we identify and compare sources for endotoxins sampled on filters in an on-shore and more-inland site. Filter analysis included endotoxin content, total bacteria, gram-negative bacteria and cyanobacteria genome concentrations as well as ion content in order to identify possible sources for the endotoxins. Satellite images of chlorophyll-a levels and back trajectory analysis were used to further study the cyanobacteria blooms in the sea, close to the trajectory of the sampled air. The highest endotoxin concentrations found in the shoreline site were during winter (3.23±0.17 EU/m(3)), together with the highest cyanobacteria genome (1065.5 genome/m(3)). The elevated endotoxin concentrations were significantly correlated with cyanobacterial levels scaled to the presence of marine aerosol (r=0.90), as well as to chlorophyll-a (r=0.96). Filters sampled further inland showed lower and non-significant correlation between endotoxin and cyanobacteria (r=0.70, P value=0.19), suggesting decrease in marine-originated endotoxin, with possible contributions from other sources of gram-negative non-cyanobacteria. We conclude that marine cyanobacteria may be a dominant contributor to elevated endotoxin levels in coastal areas. Copyright © 2014 Elsevier B.V. All rights reserved.

Ascorbic acid deficiency increases endotoxin influx to portal blood and liver inflammatory gene expressions in ODS rats.

PubMed

Tokuda, Yuki; Miura, Natsuko; Kobayashi, Misato; Hoshinaga, Yukiko; Murai, Atsushi; Aoyama, Hiroaki; Ito, Hiroyuki; Morita, Tatsuya; Horio, Fumihiko

2015-02-01

The aim of this study was to determine whether ascorbic acid (AsA) deficiency-induced endotoxin influx into portal blood from the gastrointestinal tract contributes to the inflammatory changes in the liver. The mechanisms by which AsA deficiency provokes inflammatory changes in the liver were investigated in Osteogenic Disorder Shionogi (ODS) rats (which are unable to synthesize AsA). Male ODS rats (6-wk-old) were fed a diet containing sufficient (300 mg/kg) AsA (control group) or a diet without AsA (AsA-deficient group) for 14 or 18 d. On day 14, the hepatic mRNA levels of acute-phase proteins and inflammation-related genes were significantly higher in the AsA-deficient group than the control group, and these elevations by AsA deficiency were exacerbated on day 18. The serum concentrations of interleukin (IL)-1β and IL-6, which induce acute-phase proteins in the liver, were also significantly elevated on day 14 in the AsA-deficient group compared with the respective values in the control group. IL-1β mRNA levels in the liver, spleen, and lung were increased by AsA deficiency. Moreover, on both days 14 and 18, the portal blood endotoxin concentration was significantly higher in the AsA-deficient group than in the control group, and a significant correlation between serum IL-1β concentrations and portal endotoxin concentrations was found in AsA-deficient rats. In the histologic analysis of the ileum tissues, the number of goblet cells per villi was increased by AsA deficiency. These results suggest that AsA deficiency-induced endotoxin influx into portal blood from the gastrointestinal tract contributes to the inflammatory changes in the liver. Copyright © 2015 Elsevier Inc. All rights reserved.

Experimental uveitis can be maintained in rabbits for a period of six weeks after a safe sensitization method.

PubMed

Eperon, S; Balaskas, K; Vaudaux, J; Guex-Crosier, Y

2013-03-01

New treatments against long-lasting uveitis need to be tested. Our aim was to develop a six-week model of uveitis in rabbits. Rabbits were presensitized with an s.c. injection of Mycobacterium tuberculosis H37RA emulsified with TiterMax Gold adjuvant. Uveitis was induced at day 28 and 50, by intravitreal challenges of antigen suspension. Ocular inflammation was assessed till euthanasia at day 71 after s.c. injection of M. tuberculosis H37RA by: (a) the number of inflammatory cells in aqueous humor (AH); (b) the protein concentration in AH; (c) the clinical score (mean of conjunctival hyperaemia, conjunctival chemosis, oedema and secretion); (d) the microscopical score (mean presence of fibrin and synechiae, aqueous cell density and aqueous flare grade, as scored by slit lamp). At the sites of presensitization injection, rabbits presented flat nodules which progressively vanished. The first challenge induced a significant increase in the four parameters (p < 0.05 the Wilcoxon/Kruskal-Wallis test). The AH contained 764 ± 82 cells/µl and 32 ± 0.77 mg protein/ml. During the following days, inflammatory parameters decreased slightly. The second intravitreal challenge increased inflammation (3564 ± 228 cells/µl AH and 31 ± 1 mg protein/ml), which remained at a high level for a longer period of time. We developed a model of long-term uveitis, which could be maintained in rabbits for at least six weeks. Such a model could be used to test the efficacy of either new drugs or various drug delivery systems intended to deliver active agents during a few months.

Changes in patterns of uveitis at a tertiary referral center in Northern Italy: analysis of 990 consecutive cases.

PubMed

Luca, Cimino; Raffaella, Aldigeri; Sylvia, Marchi; Valentina, Mastrofilippo; Fabiana, Viscogliosi; Marco, Coassin; Annamaria, Soldani; Luisa, Savoldi; Alessandro, De Fanti; Lucia, Belloni; Alessandro, Zerbini; Maria, Parmeggiani; Matthew, Chersich; Alessandra, Soriano; Carlo, Salvarani; Luigi, Fontana

2018-02-01

The role of uveitis, an uncommon ocular disease, is often neglected in research and treatment of autoimmune conditions. The study described the spectrum of uveitis at a referral center in North Italy, and compared that to a previously published series of patients. We reviewed all patients with uveitis diagnosed from 2013 to 2015 at the Immunology Eye Unit, Arcispedale S. M. Nuova-IRCCS, Reggio Emilia, Italy. We examined patient characteristics, disease spectrum, and etiologies. In total, 990 cases of uveitis were identified, who were mostly female (59%) with a median age at presentation of 44 years (interquartile range = 29-57). Anterior uveitis was most frequent (53.5%), followed by panuveitis (22.8%), posterior (16.2%), and intermediate uveitis (5.5%). Anterior herpetic uveitis (15.6%), Fuchs uveitis (9.7%), and HLA-B27 positive anterior uveitis (7.7%) were the most common specific diagnoses. Compared with the previous series, we observed an increased incidence of uveitis, and a different pattern of diagnoses. Rates of herpetic, HLA-B27 positive uveitis, and presumed ocular tuberculosis were higher, but Fuchs uveitis was less frequent. The pattern of uveitis appears to be changing, very likely due to population-level increases in infectious diseases, to the availability of new diagnostic tests and to the interdisciplinary approach used in patient diagnosis.

Primary (Month-6) Outcomes of the STOP-Uveitis Study: Evaluating the Safety, Tolerability, and Efficacy of Tocilizumab in Patients With Noninfectious Uveitis.

PubMed

Sepah, Yasir Jamal; Sadiq, Mohammad Ali; Chu, David S; Dacey, Mark; Gallemore, Ron; Dayani, Pouya; Hanout, Mostafa; Hassan, Muhammad; Afridi, Rubbia; Agarwal, Aniruddha; Halim, Muhammad Sohail; Do, Diana V; Nguyen, Quan Dong

2017-11-01

To report the primary endpoint analyses of the safety and efficacy of 2 different doses of intravenous (IV) infusions of tocilizumab (TCZ), an IL-6 inhibitor, in eyes with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Randomized, controlled, multicenter clinical trial. STOP-Uveitis is a randomized, open-label safety, efficacy, and bioactivity clinical trial conducted at 5 clinical centers across the United States. The study evaluated the role of TCZ in patients with noninfectious uveitis (NIU). Thirty-seven patients with NIU were randomized into one of 2 treatment groups in a ratio of 1:1. Group 1 received IV infusions of 4 mg/kg TCZ and group 2 received IV infusions of 8 mg/kg TCZ. Infusions were given every 4 weeks in both groups until month 6 (primary endpoint). Primary outcome measure was incidence and severity of systemic and ocular adverse events through month 6. Secondary outcome measures included mean change in visual acuity (VA), vitreous haze (VH), and central macular thickness (CMT) at month 6. A total of 37 patients were randomized in the study. At month 6, 43.5% of patients who had the potential for a 2-step decrease in VH demonstrated a 2-step decrease (40% in Group 1 and 46.1% in Group 2). Mean change in CMT was -83.88 ± 136.1 μm at month 6 (-131.5 ± 41.56 μm in Group 1 and -38.92 ± 13.7 μm in Group 2). Mean change in VA was +8.22 ± 11.83 ETDRS letters at month 6 (10.9 ± 14.6 in Group 1 and 5.5 ± 7.8 in Group 2). Repeated infusions of TCZ were well tolerated. Repeated IV administrations of TCZ are well tolerated. TCZ (both 4 and 8 mg/kg) is effective in improving VA and reducing VH and CMT in eyes with noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of endotoxin on mammary secretion of lactating cows. [Escherichia coli

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lengemann, F.W.; Pitzrick, M.

The objectives were to describe the magnitude and time course of changes in milk pH, Na, K, lactose, and somatic cells and to determine if paracellular pathways were altered after infusion of Escherichia coli endotoxin (serotype 0128:AB12) to produce inflammation in one-half of the udder of the goat. Intramammary infusion of endotoxin increased pH, number of somatic cells, and Na and decreased K and lactose in milk. Sodium and number of somatic cells were increased by as little as .1..mu..g of endotoxin; .25 ..mu..g produced changes in most of the other parameters; maximal effect was elicited by 1..mu..g of endotoxin.more » The gland response peaked from 5 to 7 h after infusion of endotoxin with an increase in milk cellularity as the only significant effect noted in the control gland. Infusion of (/sup 14/C)lactose into the gland and (/sup 99m/Tc)albumin into the blood demonstrated that large molecules were more able to cross into and out of udder halves after endotoxin treatment. It is suggested that ion interchange rather than bulk flow across paracellular paths is responsible for changes. In addition, endotoxin appeared to reduce lactose secretion and synthesis.« less

Endotoxins in indoor air and settled dust in primary schools in a subtropical climate.

PubMed

Salonen, Heidi; Duchaine, Caroline; Létourneau, Valérie; Mazaheri, Mandana; Clifford, Sam; Morawska, Lidia

2013-09-03

Endotoxins can significantly affect the air quality in school environments. However, there is currently no reliable method for the measurement of endotoxins, and there is a lack of reference values for endotoxin concentrations to aid in the interpretation of measurement results in school settings. We benchmarked the "baseline" range of endotoxin concentration in indoor air, together with endotoxin load in floor dust, and evaluated the correlation between endotoxin levels in indoor air and settled dust, as well as the effects of temperature and humidity on these levels in subtropical school settings. Bayesian hierarchical modeling indicated that the concentration in indoor air and the load in floor dust were generally (<95th percentile) <13 EU/m(3) and <24,570 EU/m(2), respectively. Exceeding these levels would indicate abnormal sources of endotoxins in the school environment and the need for further investigation. Metaregression indicated no relationship between endotoxin concentration and load, which points to the necessity for measuring endotoxin levels in both the air and settled dust. Temperature increases were associated with lower concentrations in indoor air and higher loads in floor dust. Higher levels of humidity may be associated with lower airborne endotoxin concentrations.

In vitro reduction of endotoxin concentrations with the 5S fragment of immunoglobulin G.

PubMed Central

Xuan, D; Nicolau, D P; Tessier, P R; Bow, L; Quintiliani, R; Nightingale, C H

1997-01-01

Endotoxin has long been implicated as an inducer for the development and progression of gram-negative sepsis. Accordingly, antiendotoxin therapy has been considered one of the major targets for the treatment of sepsis. To investigate the influence of a human immunoglobulin G (IgG) derivative, the 5S fragment of IgG (5S-IgG; Gamma-Venin, Centeon Pharma GmbH, Frankfurt-Niederrad, Germany), on endotoxin release during bacterial proliferation and under antibiotic bactericidal action, time-kill studies were performed by using Escherichia coli ATCC 25922 starting inocula of 10(3), 10(5), and 10(7) CFU/ml with cefotaxime (120 microg/ml) alone and in combination with 5S-IgG (2,100 microg/ml). Samples were collected for bacterial colony count and endotoxin concentration determinations; the area under the free endotoxin concentration curve (AUFEC) was calculated by using the trapezoidal rule. Colony counts showed that cefotaxime had a rapid bactericidal effect because it achieved greater than a 4-log decrease in the numbers of E. coli CFU per milliliter over the first 2 h; the addition of 5S-IgG did not appear to alter the kinetics of killing. Comparison of the AUFEC revealed that the addition of 5S-IgG resulted in a mean reduction of 50, 66, and 27% in the free endotoxin concentration at starting inocula of 10(3), 10(5), and 10(7) CFU/ml, respectively. Moreover, experiments were conducted with a starting inoculum of 10(5) CFU/ml and various amounts of 5S-IgG (2 to 20 mg/ml) to further investigate the dose-effect relation of 5S-IgG on endotoxin release. Decreased AUFECs were observed with increasing concentrations of 5S-IgG, suggesting the dose-dependent antiendotoxin activity of 5S-IgG. Further study is required to investigate the mechanism(s) responsible for this observation, the biological significance of this antiendotoxin activity, and the potential utility of 5S-IgG as an adjuvant therapy in the treatment of gram-negative sepsis. PMID:9210676

A comparative study of different strategies for removal of endotoxins from bacteriophage preparations.

PubMed

Van Belleghem, Jonas D; Merabishvili, Maya; Vergauwen, Bjorn; Lavigne, Rob; Vaneechoutte, Mario

2017-01-01

Bacterial endotoxins have high immunogenicity. Phage biology studies as well as therapeutic phage applications necessitate highly purified phage particles. In this study, we compared combinations of seven different endotoxin removal strategies and validated their endotoxin removal efficacy for five different phages (i.e. four Pseudomonas aeruginosa phages and one Staphylococcus aureus phage). These purification strategies included Endotrap HD column purification and/or CsCl density centrifugation in combination with Endotrap purification, followed by organic solvent (1-octanol), detergent (Triton X-100), enzymatic inactivation of the endotoxin using alkaline phosphatase and CIM monolytic anion exchange chromatography. We show that CsCl density purification of the P. aeruginosa phages, at an initial concentration of 10 12 -10 13 pfu/ml, led to the strongest reduction of endotoxins, with an endotoxin removal efficacy of up to 99%, whereas additional purification methods did not result in a complete removal of endotoxins from the phage preparations and only yielded an additional endotoxin removal efficacy of 23 to 99%, sometimes accompanied with strong losses in phage titer. Copyright © 2016 Elsevier B.V. All rights reserved.

Visual Functioning and Health-related Quality-of-Life are Compromised in Patients with Uveitis.

PubMed

Hui, Michelle M; Wakefield, Denis; Patel, Ilesh; Cvejic, Erin; McCluskey, Peter J; Chang, John H

2017-08-01

To assess the vision-related (VR) and health-related (HR) quality-of-life (QoL) of patients with uveitis. In total, 60 patients with uveitis, 81 patients with diabetic retinopathy (DR), and 70 healthy subjects completed the National Eye Institute Visual Functioning Questionnaire and the Medical Outcome Study 36-Item Short Form. Patients with uveitis reported lower HR- and VR-QoL than healthy subjects (p<0.05) and lower VR-QoL (p<0.001) than patients with DR. For patients with uveitis, multiple linear regression analyses indicated that lower HR-QoL scores were predicted by younger age (p<0.01), while lower VR-QoL scores were predicted by poorer visual acuity (p<0.001), ocular comorbidities (p<0.05), and female sex (p<0.05). Patients with uveitis have significantly poorer VR- and HR-QoL than healthy control subjects. Uveitis has a more debilitating impact on VR-QoL than DR.