Guía internacional para una dosificación más segura de la clozapina en adultos mediante el uso de 6 titulaciones personalizadas de dosis basados en la etnicidad, la proteína C reactiva y los niveles de clozapina / An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels

Esta guía internacional propone mejorar los prospectos de la clozapina en todo el mundo mediante la inclusion de información sobre la titulación del fármaco en función de la ascendencia del paciente. Las bases de datos de reacciones adversas a medicamentos (RAM) sugieren que la clozapina es el tercer fármaco más tóxico en los Estados Unidos de América (EE. UU.) y que produce una mortalidad por neumonía en todo el mundo 4 veces mayor que la correspondiente a la agranulocitosis o la miocarditis. El rango terapéutico de referencia para las concentraciones séricas estables de clozapina es estrecho, de 350 a 600 ng/ml, con potencial de toxicidad y reacciones adversas más fecuentes a medida que aumentan las concentraciones. La clozapina se metaboliza principalmente por CYP1A2 (las mujeres no fumadoras requieren la dosis más baja y los hombres fumadores la dosis más alta). A través de la conversión fenotípica, la prescripción conjunta de inhibidores del metabolismo de la clozapina (incluidos los anticonceptivos orales y el valproato), la obesidad o la inflamación con elevaciones de la proteína C reactiva (PCR), pueden convertir al paciente en un metabolizador lento/pobre (MP). Las personas de ascendencia asiática (de Pakistán a Japón) o los habitantes originarios de las Américas tienen menor actividad de CYP1A2 y requieren dosis más bajas de clozapina para alcanzar concentraciones de 350 ng/ml. En los EE. UU. se recomiendan dosis diarias de 300-600 mg/día. La dosificación personalizada lenta puede prevenir RAM tempranas (incluidos el síncope, la miocarditis y la neumonía). La esencia de esta guía se fundamenta en 6 esquemas de titulaciones personalizadas para pacientes hospitalizados...(AU)

This is the Spanish translation of an international guideline which proposes improving clozapine package inserts worldwide by using ancestry-based: 1) dosing and 2) titration. Adverse drug reaction (ADR) databases suggest clozapine: 1) is the third most toxic drug in the United States (US), and 2) produces worldwide pneumonia mortality four times greater than that of agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers require the lowest dose and male smokers the highest dose). Poor metabolizer (PM) status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity or inflammation with C-reactive protein (CRP) elevations. People with ancestry from Asia (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/ml. Daily doses of 300-600 mg/day are recommended in the US. Slow personalized titration may prevent early ADRs (including syncope, myocarditis and pneumonia). The core of this guideline consists of six personalized titration schedules for inpatients...(AU)

Inflamación y adecuación de la hemodiálisis: ¿están los niveles de proteína C reactiva influidos por la dosis de diálisis recibida? / Inflammation and hemodialysis adequacy: Are C-reactive protein levels influenced by dialysis dose?

Introducción : La inflamación crónica y la subyacente comorbilidad cardiovascular aún son problemas vigentes en los pacientes en hemodiálisis crónica. Existen pocos estudios que comparen la «dosis de diálisis» (Kt/V) con el grado de inflamación del paciente. Nuestro objetivo principal fue determinar si existe una relación entre los niveles séricos de proteína C reactiva (PCR) y el Kt/V utilizando la dialisancia iónica.Métodos : Estudio transversal multicéntrico. Se incluyeron 536 pacientes prevalentes en hemodiálisis crónica. Se recogieron los niveles de PCR, el índice neutrófilo-linfocito y el índice plaqueta-linfocito. Se obtuvo el Kt por dialisancia iónica y el volumen de distribución de la urea mediante la fórmula de Watson. Se dividió la muestra en 2 grupos tomando como punto de corte la mediana de PCR y se comparó la adecuación de diálisis en cada uno. Finalmente, se realizó un modelo de regresión logística para determinar las variables de mayor influencia.Resultados : La mediana de PCR fue 4,10mg/L (q25-q75: 1,67-10). El Kt/V medio fue de 1,48±0,308. El Kt/V fue menor en los pacientes incluidos en el grupo de inflamación alta (p=0,01). En la regresión logística multivariante, los niveles «altos» de PCR tuvieron una correlación directa con el Log índice neutrófilo-linfocito (p<0,001) e inversamente proporcional con los valores de albúmina sérica (p=0,014), Kt/V (p=0,037) y hierro sérico (p<0,001).Conclusión : La peor adecuación en términos de dosis de diálisis (valores de Kt/V más bajos) puede contribuir a un mayor grado de inflamación en los pacientes en hemodiálisis crónica. (AU)

Introduction : Chronic inflammation and the underlying cardiovascular comorbidity are still current problems in chronic hemodialysis patients. There are few studies comparing the “dialysis dose” (Kt/V) with the degree of inflammation in the patient. Our main objective was to determine whether there is a relationship between serum C-reactive protein (CRP) levels and the Kt/V using ionic dialysance.Methods : Multicenter cross-sectional study. A total of 536 prevalent chronic hemodialysis patients were included. CRP levels, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were collected. Kt was obtained by ionic dialysance and urea distribution volume was calculated from the Watson's formula. The sample was divided into 2 groups, taking the median CRP as the cut-off point. Dialysis adequacy obtained in each group was compared. Finally, a logistic regression model was carried out to determine the variables with the greatest influence.Results : Median CRP was 4.10mg/L (q25-q75: 1.67-10) and mean Kt/V was 1.48±0.308. Kt/V was lower in the patients included in the high inflammation group (P=.01). In the multivariate logistic regression, the “high” levels of CRP were directly correlated with the Log neutrophil-lymphocyte ratio (P<.001) and inversely proportional with serum albumin values (P=.014), Kt/V (P=.037) and serum iron (P<.001).Conclusion : The poorer adequacy in terms of dialysis doses (lower Kt/V values) may contribute to a higher degree of inflammation in chronic hemodialysis patients. (AU)

Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies.

Muscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

Monomeric C-reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype-dependent pattern: A risk factor for Alzheimer's disease?

In chronic peripheral inflammation, endothelia in brain capillary beds could play a role for the apolipoprotein E4 (ApoE4)-mediated risk for Alzheimer's disease (AD) risk. Using human brain tissues, here we demonstrate that the interactions of endothelial CD31 with monomeric C-reactive protein (mCRP) versus ApoE were linked with shortened neurovasculature for AD pathology and cognition. Using ApoE knock-in mice, we discovered that intraperitoneal injection of mCRP, via binding to CD31 on endothelial surface and increased CD31 phosphorylation (pCD31), leading to cerebrovascular damage and the extravasation of T lymphocytes into the ApoE4 brain. While mCRP was bound to endothelial CD31 in a dose- and time-dependent manner, knockdown of CD31 significantly decreased mCRP binding and altered the expressions of vascular-inflammatory factors including vWF, NF-κB and p-eNOS. RNAseq revealed endothelial pathways related to oxidative phosphorylation and AD pathogenesis were enhanced, but endothelial pathways involving in epigenetics and vasculogenesis were inhibited in ApoE4. This is the first report providing some evidence on the ApoE4-mCRP-CD31 pathway for the cross talk between peripheral inflammation and cerebrovasculature leading to AD risk.

Biphasic roles of pentraxin 3 in cerebrovascular function after white matter stroke.

Recent clinical studies suggest that pentraxin 3 (PTX3), which is known as an acute-phase protein that is produced rapidly at local sites of inflammation, may be a new biomarker of disease risk for central nervous system disorders, including stroke. However, the effects of PTX3 on cerebrovascular function in the neurovascular unit (NVU) after stroke are mostly unknown, and the basic research regarding the roles of PTX3 in NVU function is still limited. In this reverse translational study, we prepared mouse models of white matter stroke by vasoconstrictor (ET-1 or L-Nio) injection into the corpus callosum region to examine the roles of PTX3 in the pathology of cerebral white matter stroke. PTX3 expression was upregulated in GFAP-positive astrocytes around the affected region in white matter for at least 21 days after vasoconstrictor injection. When PTX3 expression was reduced by PTX3 siRNA, blood-brain barrier (BBB) damage at day 3 after white matter stroke was exacerbated. In contrast, when PTX3 siRNA was administered at day 7 after white matter stroke, compensatory angiogenesis at day 21 was promoted. In vitro cell culture experiments confirmed the inhibitory effect of PTX3 in angiogenesis, that is, recombinant PTX3 suppressed the tube formation of cultured endothelial cells in a Matrigel-based in vitro angiogenesis assay. Taken together, our findings may support a novel concept that astrocyte-derived PTX3 plays biphasic roles in cerebrovascular function after white matter stroke; additionally, it may also provide a proof-of-concept that PTX3 could be a therapeutic target for white matter-related diseases, including stroke.

Pentraxin 3 inhibits fibroblast growth factor 2 induced osteoclastogenesis in rheumatoid arthritis.

BACKGROUND: Synovial fibroblasts (SFs) act as key effector cells mediating synovial inflammation and joint destruction in rheumatoid arthritis (RA). Fibroblast growth factor 2 (FGF2) and its receptors (FGFRs) play important roles in RASF-mediated osteoclastogenesis. Pentraxin 3 (PTX3) is a soluble pattern recognition receptor with nonredundant roles in inflammation and innate immunity. PTX3 is produced by various cell types, including SFs and is highly expressed in RA. However, the role of PTX3 in FGF2-induced osteoclastogenesis in RA and the underlying mechanism have been poorly elucidated. METHODS: We first determined the expression of FGF2 and RANKL in synovial tissue and synovial fluid of RA patients. We then examined the effect of PTX3 on RASF osteoclastogenesis induced by endogenous and exogenous FGF2 in isolated RASF cells treated with FGF2 and/or recombinant PTX3 (rPTX3). Thirdly, we analyzed the effect of PTX3 on FGF2 binding to FGFR-1 and HSPG receptors on RASFs. Lastly, we evaluated joint morphology after injection of rPTX3 into collagen-induced arthritis (CIA) mice. RESULTS: FGF2 was confirmed to be highly expressed in both synovial tissue and synovial fluid of RA patients. FGF2 promoted cell proliferation and increased the expressions of RANKL and ICAM-1 and RANKL/OPG to induce osteoclastogenesis in RASF, while anti-FGF2 neutralized this effect. PTX3 significantly inhibited FGF2-induced RASF cell growth and osteoclastogenesis by preventing the interaction of 125I-FGF2 and FGFRs on the same cells. In addition, administration of rPTX3 significantly ameliorated cartilage and bone destruction in mice with CIA. CONCLUSIONS: PTX3 exhibited an inhibitory effect on the autocrine and paracrine stimulation of FGF2 on SFs, and ameliorated bone destruction in CIA mice. PTX3 may be implicated in bone destruction in RA, which may provide theoretical evidence and potential therapeutic targets for RA treatment.

C-Reactive Protein-Based Strategy to Reduce Antibiotic Dosing for the Treatment of Pneumococcal Infection.

C-reactive protein (CRP) is a component of innate immunity. The concentration of CRP in serum increases in microbial infections including Streptococcus pneumoniae infection. Employing a mouse model of pneumococcal infection, it has been shown that passively administered human wild-type CRP protects mice against infection, provided that CRP is injected into mice within two hours of administering pneumococci. Engineered CRP (E-CRP) molecules have been reported recently; unlike wild-type CRP, passively administered E-CRP protected mice against infection even when E-CRP was injected into mice after twelve hours of administering pneumococci. The current study was aimed at comparing the protective capacity of E-CRP with that of an antibiotic clarithromycin. We established a mouse model of pneumococcal infection in which both E-CRP and clarithromycin, when used alone, provided minimal but equal protection against infection. In this model, the combination of E-CRP and clarithromycin drastically reduced bacteremia and increased survival of mice when compared to the protective effects of either E-CRP or clarithromycin alone. E-CRP was more effective in reducing bacteremia in mice treated with clarithromycin than in untreated mice. Also, there was 90% reduction in antibiotic dosing by including E-CRP in the antibiotic-treatment for maximal protection of infected mice. These findings provide an example of cooperation between the innate immune system and molecules that prevent multiplication of bacteria, and that should be exploited to develop novel combination therapies for infections against multidrug-resistant pneumococci. The reduction in antibiotic dosing by including E-CRP in the combination therapy might also resolve the problem of developing antibiotic resistance.

Correlation between MMP-2 gene polymorphism and cataract susceptibility.

OBJECTIVE: To investigate the correlation between matrix metalloproteinase-2 (MMP-2) gene polymorphism and cataract. PATIENTS AND METHODS: 104 cataract patients and 100 healthy subjects were enrolled and assigned to the observation group and control group, respectively. General clinical data of the enrolled subjects were collected. The inflammatory factors were detected, and the rs243865 polymorphism of MMP-2 gene was detected using the TaqMan-MGB probe. RESULTS: The levels of interleukin-6 (IL-6), IL-1ß, C-reactive protein (CRP), and tumor necrosis factor-1α (TNF-1α) in the observation group were higher than those in the control group (p<0.05). There were significant differences in the genotype and allele distribution frequency between the two groups (p<0.05). In the genetic model analysis, the additive model was remarkably different between the two groups (p<0.05). However, the recessive model and dominant model were not different between the two groups (p>0.05). CONCLUSIONS: Cataract is correlated with inflammatory factors, and the rs243865 polymorphism of MMP-2 gene has a correlation with the incidence of cataract.

IMMUNEPOTENT CRP induces cell cycle arrest and caspase-independent regulated cell death in HeLa cells through reactive oxygen species production.

BACKGROUND: Regulated cell death (RCD) is a mechanism by which the cell activates its own machinery to self-destruct. RCD is important for the maintenance of tissue homeostasis and its deregulation is involved in diseases such as cervical cancer. IMMUNEPOTENT CRP (I-CRP) is a dialyzable bovine leukocyte extract that contains transfer factors and acts as an immunomodulator, and can be cytotoxic to cancer cell lines and reduce tumor burden in vivo. Although I-CRP has shown to improve or modulate immune response in inflammation, infectious diseases and cancer, its widespread use has been limited by the absence of conclusive data on the molecular mechanism of its action. METHODS: In this study we analyzed the mechanism by which I-CRP induces cytotoxicity in HeLa cells. We assessed cell viability, cell death, cell cycle, nuclear morphology and DNA integrity, caspase dependence and activity, mitochondrial membrane potential, and reactive oxygen species production. RESULTS: I-CRP diminishes cell viability in HeLa cells through a RCD pathway and induces cell cycle arrest in the G2/M phase. We show that the I-CRP induces caspase activation but cell death induction is independent of caspases, as observed by the use of a pan-caspase inhibitor, which blocked caspase activity but not cell death. Moreover, we show that I-CRP induces DNA alterations, loss of mitochondrial membrane potential, and production of reactive-oxygen species. Finally, pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, prevented both ROS generation and cell death induced by I-CRP. CONCLUSIONS: Our data indicate that I-CRP treatment induced cell cycle arrest in G2/M phase, mitochondrial damage, and ROS-mediated caspase-independent cell death in HeLa cells. This work opens the way to the elucidation of a more detailed cell death pathway that could potentially work in conjunction with caspase-dependent cell death induced by classical chemotherapies.

Involvement of pentraxin-3 in anti-neutrophil cytoplasmic antibody production induced by aluminum salt adjuvant.

OBJECTIVES: Pentraxin 3 (PTX3) is a multifunctional soluble factor. PTX3 can be involved in the regulation of vasculitis and is expressed in the cytoplasm of neutrophils. As anti-neutrophil cytoplasmic antibody (ANCA) is recognised as a cause of vasculitis, we aimed to discover the role of PTX3 in ANCA production in vivo. METHODS: To this end, we used aluminum salt (alum), which induces neutrophil extracellular traps, as an adjuvant for producing anti-myeloperoxidase-ANCA (MPO-ANCA). Specifically, we intraperitoneally injected alum and recombinant MPO (rMPO) into MPO-deficient mice and then measured the concentration of anti-MPO IgG in their blood. To show the involvement of extracellular PTX3 in this model, we assessed PTX3 protein content and host double-stranded DNA levels in the mice's peritoneal fluid after alum injection. In addition, we simultaneously administered recombinant PTX3, rMPO and alum to MPO-deficient mice to assess the function of PTX3 in producing anti-MPO IgG in vivo. RESULTS: Anti-MPO IgG was produced by the alum + rMPO immunisation model in MPO-deficient but not wildtype mice. Injection of alum induced extracellular PTX3 as well as double-stranded DNA and dead cells in MPO-deficient mice. Simultaneous injection of recombinant PTX3 with rMPO and alum attenuated the production of anti-MPO IgG in MPO-deficient mice. CONCLUSIONS: Our current findings provide evidence that PTX3 attenuates the production of murine MPO-ANCA.

Biomarcadores de infección bacteriana grave: ¿ayudan en la práctica clínica? / Biomarkers of severe bacterial infection: do they help in clinical practice?

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Valoración del uso de la procalcitonina en el lactante febril hospitalizado / Assessing the use of procalcitonin in the hospitalised young febrile infant

INTRODUCCIÓN: El uso de la procalcitonina (PCT) se ha generalizado en la evaluación del lactante febril en urgencias. Este trabajo pretende evaluar si la introducción de la PCT ha cambiado el manejo del lactante febril hospitalizado y el coste/efectividad de dicho marcador. PACIENTES Y MÉTODOS: Estudio retrospectivo comparando 2 periodos: enero-diciembre de 2009 (sin PCT) y enero-diciembre de 2011 (uso rutinario de PCT). Se incluyó a los pacientes de 7 a 90 días de vida con fiebre ingresados en un hospital universitario y con analítica realizada. Se compararon porcentajes de infección bacteriana, uso de antibióticos, estancia hospitalaria y coste analítico. Se evaluó la PCT, la proteína-C reactiva (PCR), recuento leucocitario, score de Rochester y el lab-score propuesto por Galetto-Lacour para el diagnóstico de infección bacteriana. RESULTADOS: Se incluyó a 109 pacientes en el periodo 1 y 111 en el periodo 2 (de los cuales en 87 se dispuso de valor de PCT). La prevalencia de infección bacteriana, uso de antibióticos, repetición de analíticas y estancia hospitalaria fue similar en los 2 periodos. El coste analítico fue significativamente superior en el segundo periodo. La sensibilidad, especificidad, valor predictivo positivo y valor predictivo negativo de la PCR (punto de corte 1mg/dl) fue 70,6; 58,1; 52,6 y 75% y de la PCT (punto de corte 0,5ng/ml) 41,7; 78,4; 57,7 y 65,6%. CONCLUSIONES: El uso de la PCT no parece haber tenido un impacto significativo en el manejo del paciente hospitalizado

INTRODUCTION: The use of procalcitonin (PCT) in the evaluation of the febrile infant in the emergency care unit has been widespread. The aim of this study is to assess whether the introduction of PCT has changed the management of hospitalised febrile infants and the cost/effectiveness of this marker. MATERIALS AND METHODS: A retrospective study was performed comparing 2 periods: January-December 2009 (without PCT) and January-December 2011 (routine use of PCT). Infants aged 7 to 90 days with fever who were admitted to a university hospital and had a blood test performed were included in the study. Bacterial infection rate, antibiotic use, hospitalisation days, and analytical costs were compared. Evaluations were made using PCT, C-reactive protein (CRP), white cell count, Rochester score, and the lab-score proposed by Galetto-Lacour for the diagnosis of bacterial infection. RESULTS: A total of 109 patients were included in period 1, and 111 in period 2 (87 of which had a PCT value). The prevalence of bacterial infection, use of antibiotics, number of blood tests, and days of hospital admission was similar in both periods. The blood test cost was significantly higher in the second period. Sensitivity, specificity, positive predictive value and negative predictive value were 70.6, 58.1, 52.6 and 75%, respectively for the CRP (cut-off 1mg/dL) and 41.7; 78.4; 57.7, and 65.6% for the PCT (cut-off value 0.5ng/ml). CONCLUSIONS: The use of PCT does not seem to have a significant impact on the management of the hospitalised febrile infant

¿Cómo disminuir la mortalidad de la fístula anastomótica en cirugía colorrectal? / How can we decrease mortality due to anastomotic fistula in colorectal surgery?

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Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental neurological disease.

Pentraxin-3 (PTX3), an acute-phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2-mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti-inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3-deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation.

Antibacterial effect of porcine PTX3 against Streptococcus suis type 2 infection.

Pentraxin 3 (PTX3), a soluble pattern recognition receptor, plays an important role in innate immunity and has been implicated to be a candidate resistance gene against Streptococcus suis 2 infection. To discover the antibacterial effect of porcine PTX3 against S. suis 2, the 42-kDa PTX3 protein was expressed by Chinese hamster ovary cells (CHO), and an additional eukaryotic expression vector pVAX-ptx3 was constructed. The expressed porcine PTX3 mediated a range of antibacterial activities including increasing phagocytic capacity of primary porcine alveolar macrophages (PAM) against S. suis 2 and inhibiting adhesion of S. suis 2 to human epidermoid cancer cells (Hep-2). In mouse model, pre-intramuscular injecting with pVAX-ptx3 reduced mortality and reduced bacteria loads in blood, spleen, lung and brain compared with that of control group during 2-12 h following intraperitoneal injection (i.p.) with S. suis 2. Meanwhile, the expressions of IL-6 and IL-8 in blood were increased in pVAX-ptx3 group, whereas no obvious changes about IL-10. In piglet model, bacteria load in blood of pVAX-ptx3 group was significantly lower than that of control group after i.p. with S. suis 2, correspondingly, expression of IL-6 and IL-8 were significantly increased in pVAX-ptx3 group. In contrast, white blood cell (WBC) and neutrophil cell (NEU) count of peripheral blood in pVAX-ptx3 group were lower than that of control group. These studies described a novel antibacterial role for porcine PTX3 against S. suis 2 both in vitro and in vivo and suggested that porcine PTX3 may be a potential biological agent against S. suis 2 in pig and be used for the clinical prevention and treatment of streptococcosis caused by S. suis 2.

C-reactive protein inhibits expression of N-cadherin and ZEB-1 in murine colon adenocarcinoma.

Epithelial-to-mesenchymal transition (EMT) is thought to play a key role in cancer cell invasion and metastasis. We previously demonstrated that cancer cell migration is inhibited by C-reactive protein (CRP), which is widely used as a biomarker of inflammation, though its functions are not fully understood. In the present study, we evaluated the effect of CRP on cancer cell migration and expression of mesenchymal and epithelial markers of EMT and of related transcription factors. MCA-38 murine colon adenocarcinoma cells were subcutaneously inoculated into the backs of C57BL/6 mice, which also received 1 µg of recombinant mouse CRP or vehicle (phosphate-buffered saline) subcutaneously every 3 days for 4 weeks. Thereafter, the mice were sacrificed for evaluation using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. There was no statistical difference in tumor size between the control and CRP groups, but CRP dose-dependently inhibited MCA-38 cell migration. PCR analysis confirmed that CRP suppresses expression of N-cadherin (p < 0.01), a mesenchymal marker of EMT, and ZEB-1, an EMT-related transcription factor (p < 0.01). These findings suggest that CRP inhibits EMT in a MCA-38 tumor-bearing mouse model. CRP may thus be a potentially useful tool for preventing cancer progression through suppression of EMT.

Recognition of Neisseria meningitidis by the long pentraxin PTX3 and its role as an endogenous adjuvant.

Long pentraxin 3 (PTX3) is a non-redundant component of the humoral arm of innate immunity. The present study was designed to investigate the interaction of PTX3 with Neisseria meningitidis. PTX3 bound acapsular meningococcus, Neisseria-derived outer membrane vesicles (OMV) and 3 selected meningococcal antigens (GNA0667, GNA1030 and GNA2091). PTX3-recognized microbial moieties are conserved structures which fulfil essential microbial functions. Ptx3-deficient mice had a lower antibody response in vaccination protocols with OMV and co-administration of PTX3 increased the antibody response, particularly in Ptx3-deficient mice. Administration of PTX3 reduced the bacterial load in infant rats challenged with Neisseria meningitidis. These results suggest that PTX3 recognizes a set of conserved structures from Neisseria meningitidis and acts as an amplifier/endogenous adjuvant of responses to this bacterium.

C-reactive protein specifically enhances platelet-activating factor-induced inflammatory activity in vivo.

Platelet-activating factor (PAF) is a potent lipid mediator that is implicated in numerous inflammatory diseases. C-reactive protein (CRP) is an acute-phase plasma protein that increases rapidly and dramatically in response to inflammation. In this study, we investigated the effect of the interaction between CRP and PAF on inflammatory responses in vivo. From binding analysis using a time-resolved fluorometric assay, CRP bound to PAF and its precursor/metabolite lyso-PAF in a concentration-dependent manner. In addition, CRP bound to several phospholipids containing lysophosphatidylcholine, which bears structural resemblance to PAF and lyso-PAF, sphingosylphosphorylcholine, and lysophosphatidylethanolamine more readily than to lysophosphatidic acid and lysophosphatidylserine. In in vivo experiments using a rat model of hind paw oedema, CRP increased PAF-induced rat paw oedema in a dose-dependent manner, without causing the oedema itself, but it did not increase histamine and serotonin-induced paw oedema. Furthermore, the receptor for CRP, lectin-like oxidized low-density lipoprotein receptor 1 was not involved in the increase in PAF-induced inflammatory responses caused by CRP. These results indicate that CRP can specifically enhance PAF-induced inflammatory activity through binding to PAF and lyso-PAF. Therefore, CRP may accelerate the pathogenesis of numerous inflammatory diseases caused by PAF.