The Natural History of Patients With Pre-Existing and De Novo Inflammatory Bowel Disease After Solid Organ Transplantation: EITOS Study of GETECCU.

BACKGROUND: Limited data are available on the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). We describe the natural history of pre-existing IBD and de novo IBD after SOT. METHODS: This was a retrospective, multicenter study that included patients with pre-existing IBD at the time of SOT and patients with de novo IBD after SOT. The primary outcome was IBD progression, defined by escalation of medical treatment, surgical therapy, or hospitalization due to refractory IBD. Risk factors were identified using multivariate Cox proportional hazard analysis. RESULTS: A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) were included. Most patients with pre-existing IBD (92.5%) were in remission before SOT. During follow-up, 32% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 (interquartile range, 1.3-4.6) years. In the de novo cohort, 55% of patients had disease progression with a median time to flare of 1.9 (interquartile range, 0.8-3.9) years after diagnosis. In the pre-existing IBD cohort, active IBD at the time of SOT (hazard ratio, 1.80; 95% confidence interval, 1.14-2.84; P = .012) and the presence of extraintestinal manifestations (hazard ratio, 3.10; 95% confidence interval, 1.47-6.54; P = .003) were predictive factors for IBD progression. CONCLUSIONS: One-third of patients with pre-existing IBD and about half of patients with de novo IBD have disease progression after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for IBD progression.

C4BP(ß-)-mediated immunomodulation attenuates inflammation in DSS-induced murine colitis and in myeloid cells from IBD patients.

The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(ß-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(ß-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(ß-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(ß-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(ß-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to "reprogram" myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD.

Value of total tumor load as a clinical and pathological factor in the prognosis of breast cancer patients receiving neoadjuvant treatment. Comparison of three populations with three different surgical approaches: NEOVATTL Pro 3 Study.

PURPOSE: This study aimed to compare the prognosis in terms of disease-free survival (DFS) in three populations of women with breast cancer (BC) treated with neoadjuvant systemic treatment (NAST) in which axillary lymph node dissection (ALND) was performed based on different total tumor load (TTL) thresholds in the sentinel nodes. METHODS: This was an observational, retrospective study carried out in three Spanish centers. Data from patients with infiltrating BC who underwent BC surgery after NAST and intraoperative sentinel lymph node biopsy (SLNB) performed by One Step Nucleic acid Amplification (OSNA) technique during 2017 and 2018 were analyzed. ALND was performed according to the protocol of each center, based on three different TTL cut-offs (TTL > 250, TTL > 5000, and TTL > 15,000 CK19-mRNA copies/µL for centers 1, 2, and 3, respectively). RESULTS: A total of 157 BC patients were included in the study. No significant differences in DFS were observed between centers (Hazard ratio [HR] center 2 vs 1: 0.77; p = 0.707; HR center 3 vs 1: 0.83; p = 0.799). Patients with ALND had a shorter DFS (HR 2.43; p = 0.136), albeit not statistically significant. Patients with a triple negative subtype had a worse prognosis than those with other molecular subtypes (HR 2.82; p = 0.056). CONCLUSION: No significant differences in DFS were observed between three centers with different surgical approaches to ALND based on different TTL cut-offs in patients with BC after NAST. These results suggest that restricting ALND to those patients with TTL ≥ 15,000 copies/µL is a reliable approximation, avoiding unnecessary morbidities caused by ALND.

Nurse-Led Interventions in Chronic Obstructive Pulmonary Disease Patients: A Systematic Review and Meta-Analysis.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, causing 3.32 million deaths in 2019. COPD management has increasingly become a major component of general and hospital practice and has led to a different model of care. Nurse-led interventions have shown beneficial effects on COPD patient satisfaction and clinical outcomes. This systematic review was conducted to identify and assess nurse-led interventions in COPD patients in terms of mental, physical, and clinical status. The review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The relevance of each manuscript was assessed according to the inclusion criteria, and we retrieved full texts, as required, to reach our conclusions. Data extraction was performed independently by two reviewers, and the risk of bias was assessed using the Cochrane Risk of Bias tool. Forty-eight articles were included in the analysis, which focused on the management of COPD patients by hospital, respiratory and primary nursing care. Nursing management was shown to be highly effective in improving quality of life, emotional state, and pulmonary and physical capacity in COPD patients. In comparison, hospital and respiratory nurses carried out interventions with higher levels of effectiveness than community nurses.

The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity.

C4b-binding protein (C4BP) is a well-known regulator of the complement system that holds additional and important activities unrelated to complement inhibition. Recently, we have described a novel immunomodulatory activity in the minor C4BP(ß-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the ß-chain to the C4BP α-chain oligomer interferes with this immunomodulatory activity of C4BP. Moreover, an oligomeric form including only the complement control protein 6 (CCP6) domain of the C4BP α-chain (PRP6-HO7) is sufficient to "reprogram" monocyte-derived DCs (Mo-DCs) from a pro-inflammatory and immunogenic phenotype to an anti-inflammatory and tolerogenic state. PRP6-HO7 lacks complement regulatory activity but retains full immunomodulatory activity over inflammatory Mo-DCs induced by TLRs, characterized by downregulation of relevant surface markers such as CD83, HLA-DR, co-stimulatory molecules such as CD86, CD80 and CD40, and pro-inflammatory cytokines such as IL-12 and TNF-α. Furthermore, PRP6-HO7-treated Mo-DCs shows increased endocytosis, significantly reduced CCR7 expression and CCL21-mediated chemotaxis, and prevents T cell alloproliferation. Finally, PRP6-HO7 shows also full immunomodulatory activity over Mo-DCs isolated from lupus nephritis patients with active disease, even without further pro-inflammatory stimulation. Therefore PRP6-HO7, retaining the immunomodulatory activity of C4BP(ß-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases.

WhatsApp-Based Focus Groups Among Mexican-Origin Women in Zika Risk Area: Feasibility, Acceptability, and Data Quality.

BACKGROUND: Despite unprecedented advances in worldwide access to the internet via smartphones, barriers to engaging hard-to-reach populations remain in many methods of health research. A potential avenue for conducting qualitative research is via participatory web-based media, including the free, popular social platform WhatsApp. However, despite the clear advantages of engaging with participants over a well-established web-based platform, logistical challenges remain. OBJECTIVE: This study aims to report evidence on the feasibility and acceptability of WhatsApp as a method to conduct focus groups. METHODS: A pilot focus group was conducted with Spanish-speaking women near the US-Mexico border. The content focus was knowledge and perceived risks for exposure to the Zika virus during pregnancy. RESULTS: Evidence was obtained regarding WhatsApp as a low-cost, logistically feasible methodology that resulted in rich qualitative data from a population that is often reticent to engage in traditional research. A total of 5 participants participated in a focus group, of whom all 5 consistently contributed to the focus group chat in WhatsApp, which was conducted over 3 consecutive days. CONCLUSIONS: The findings are noteworthy at a time when face-to-face focus groups, the gold standard, are risky or precluded by safe COVID-19 guidelines. Other implications include more applications and evaluations of WhatsApp for delivering one-on-one or group health education interventions on sensitive topics. This paper outlines the key steps and considerations for the replication or adaptation of methods.

Noncanonical immunomodulatory activity of complement regulator C4BP(ß-) limits the development of lupus nephritis.

Lupus nephritis is a chronic autoimmune-inflammatory condition that can lead to end-stage kidney disease. Presently available immunosuppressive treatments for lupus nephritis are suboptimal and can induce significant side effects. Recently, we characterized a novel immunomodulatory activity of the minor isoform of the classical pathway complement inhibitor, C4BP(ß-). We show here that C4BP(ß-) treatment prevented the development of proteinuria and albuminuria, decreased significantly the formation of anti-dsDNA antibodies and, locally, mitigated renal glomerular IgG and C3 deposition and generation of apoptotic cells. There was a consequent histological improvement and increased survival in lupus-prone mice. The therapeutic efficacy of C4BP(ß-) was analogous to that of the broad-acting immunosuppressant cyclophosphamide. Remarkably, a comparative transcriptional profiling analysis revealed that the kidney gene expression signature resulting from C4BP(ß-) treatment turned out to be 10 times smaller than that induced by cyclophosphamide treatment. C4BP(ß-) immunomodulation induced significant downregulation of transcripts relevant to lupus nephritis indicating immunopathogenic cell infiltration, including activated T cells (Lat), B cells (Cd19, Ms4a1, Tnfrsf13c), inflammatory phagocytes (Irf7) and neutrophils (Prtn3, S100a8, S100a9). Furthermore, cytokine profiling and immunohistochemistry confirmed that C4BP(ß-), through systemic and local CXCL13 downregulation, was able to prevent ectopic lymphoid structures neogenesis in aged mice with lupus nephritis. Thus, due to its anti-inflammatory and immunomodulatory activities and high specificity, C4BP(ß-) could be considered for further clinical development in patients with systemic lupus erythematosus.

Complement components as promoters of immunological tolerance in dendritic cells.

Complement and dendritic cells (DCs) share many functional features that drive the outcome of immune-inflammatory processes. Both have a sentinel function, acting as danger sensors specialized for a rapid, comprehensive and selective action against potential threats without damaging the healthy host cells. But while complement has been considered as a "master alarm" system poised for direct pathogen killing, DCs are regarded as "master regulators" or orchestrators of a vast range of effector immune cells for an effective immune response against threatening insults. The original definition of the complement system, coined to denote its auxiliary function to enhance or assist in the role of antibodies or phagocytes to clear microbes or damaged cells, envisaged an important crosstalk between the complement and the mononuclear phagocyte systems. More recent studies have shown that, depending on the microenvironmental conditions, several complement effectors are competent to influence the differentiation and/or function of different DC subsets toward immunogenicity or tolerance. In this review we will infer about the capability of complement activators and inhibitors to "condition" a tolerogenic and anti-inflammatory immune response by direct interaction with DC surface receptors, and about the implications of this knowledge to devise new complement-based therapeutic approaches for autoimmune pathologies.

Association between low levels of serum miR-638 and atherosclerotic plaque vulnerability in patients with high-grade carotid stenosis.

OBJECTIVE: Carotid artery atherosclerosis is a major cause of ischemic stroke. However, reliable criteria to identify patients with high-risk carotid plaques beyond the severity of stenosis are still lacking. Circulating microRNAs (miRNAs) are being postulated as biomarkers for a variety of vascular immune-inflammatory diseases. The authors investigated whether cell-free circulating miR-638, highly expressed in vascular smooth muscle cells and implicated in proliferative vascular diseases, is associated with vulnerable atherosclerotic plaques in high-risk patients with advanced carotid artery stenosis undergoing carotid endarterectomy (CEA). METHODS: The authors conducted a prospective study in 22 consecutive symptomatic patients with high-grade carotid stenosis undergoing CEA and 36 age- and sex-matched patients without ischemic stroke history or carotid atherosclerosis (control group). In addition, they reviewed data from a historical group of 9 CEA patients who underwent long-term follow-up after revascularization. Total RNA was isolated from all serum samples, and relative miR-638 expression levels were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and compared among groups. A correlation analysis of serum miR-638 levels with vascular risk factors and treatments, and with plaque features, was performed. The ability of serum miR-638 to discriminate between the non-CEA control group and the different CEA groups was assessed by receiver operating characteristic evaluation. A logistic regression model was employed to examine the association between stratified CEA patients and serum miR-638 levels. RESULTS: Serum levels of miR-638 were significantly lower in symptomatic CEA patients (p = 0.009) and particularly in the subgroup of CEA patients who had experienced stroke (p = 0.0006) than in non-CEA controls. Discrimination of high-risk plaques was accurate (area under the curve [AUC] 0.66 for symptomatic CEA patients in general and 0.76 for those who had experienced stroke). When only patients with high cardiovascular risk were considered, the diagnostic value of serum miR-638 from symptomatic CEA patients and CEA patients who had experienced stroke improved (AUC 0.79 and 0.85). Moreover, serum miR-638 was negatively correlated with the occurrence of stroke, smoker status, presence of bilateral pathology, coronary artery disease, and cholesterol treatment; and with the high-risk fibroatheroma plaques extracted from CEA patients. Multivariate logistic regression analysis demonstrated that serum miR-638 was an independent predictor of plaque instability. Furthermore, serum miR-638 appeared to attain good discrimination for atherosclerotic stenosis in CEA patients based on analysis of blood samples obtained in the historical group before and 5 years after intervention (p = 0.04) (AUC = 0.79). CONCLUSIONS: According to this preliminary proof-of-concept study, serum miR-638 might constitute a promising noninvasive biomarker associated with plaque vulnerability and ischemic stroke, particularly in individuals with elevated cardiovascular risk.

Exploring the Immunomodulatory Moonlighting Activities of Acute Phase Proteins for Tolerogenic Dendritic Cell Generation.

The acute phase response is generated by an overwhelming immune-inflammatory process against infection or tissue damage, and represents the initial response of the organism in an attempt to return to homeostasis. It is mediated by acute phase proteins (APPs), an assortment of highly conserved plasma reactants of seemingly different functions that, however, share a common protective role from injury. Recent studies have suggested a crosstalk between several APPs and the mononuclear phagocyte system (MPS) in the resolution of inflammation, to restore tissue integrity and function. In fact, monocyte-derived dendritic cells (Mo-DCs), an integral component of the MPS, play a fundamental role both in the regulation of antigen-specific adaptive responses and in the development of immunologic memory and tolerance, particularly in inflammatory settings. Due to their high plasticity, Mo-DCs can be modeled in vitro toward a tolerogenic phenotype for the treatment of aberrant immune-inflammatory conditions such as autoimmune diseases and allotransplantation, with the phenotypic outcome of these cells depending on the immunomodulatory agent employed. Yet, recent immunotherapy trials have emphasized the drawbacks and challenges facing tolerogenic Mo-DC generation for clinical use, such as reduced therapeutic efficacy and limited in vivo stability of the tolerogenic activity. In this review, we will underline the potential relevance and advantages of APPs for tolerogenic DC production with respect to currently employed immunomodulatory/immunosuppressant compounds. A further understanding of the mechanisms of action underlying the moonlighting immunomodulatory activities exhibited by several APPs over DCs could lead to more efficacious, safe, and stable protocols for precision tolerogenic immunotherapy.

Cultura de seguridad del paciente percibida en una muestra de enfermeros en hospitales de Corrientes Capital 2017 / Culture of patient safety perceived in a sample of nurses in hospitals of Corrientes Capital 2017

Objetivo: Describir la cultura de seguridad del paciente referida por el personal de enfermeríaDiseño: estudio descriptivo y transversal. Lugar: Hospitales públicos de la ciudad de Corrientes, 2017.Participantes: personal de enfermería, para la recolección de los datos se utilizó el cuestionario de versión española del cuestionario Hospital Survey on Patient Safety Culture. Resultados: se observó en cuanto a la percepción que poseen sobre la cultura de la seguridad del paciente, el 45,84% percibe que es positiva, el 93,01 % manifestó como positiva la notificación de errores.Las acciones para promover la seguridad por parte de la supervisión el 59,64% percibieron que existe cultura en este aspecto, el 80% de las repuestas fueron positivas para la percepción sobre la cultura del aprendizaje organizacional y la mejora continua.En la dimensión, trabajo en equipo el 84 ,6% percibió que existe cultura en este aspecto y el 70,7% que existe comunicación abierta en la organización.El 85,1% percibe que existe un Feedback y comunicación del error, el 61,5% manifestó que existe una cultura de respuesta no punitiva.El 53,9% percibe que hay cultura en la dotación de personal, y el 63,9% de las respuestas fue positiva en relación a la gerencia.El 63,9% percibe que trabaja en equipos multidisciplinario, y el 60,9% percibe una cultura de seguridad en la transferencia y el traspaso del paciente a los servicios.Conclusión: El personal de enfermería percibe como baja la cultura de la seguridad en los Hospitales. Existen varias dimensiones de la cultura por mejorar

Summary:Objective: To describe the safety culture of the patient referred by the nursing staffDesign: descriptive and cross-sectional study.Place: Public hospitals of the city of Corrientes, 2017.Participants: nurses, the questionnaire for the Spanish version of the Survey on Patient Safety Culture questionnaire was used to collect data.Results: it was observed in the perception that they have on the safety culture of the patient, 45.84% perceive that it is positive, 93.01% showed as positive the notification of errors.The actions to promote safety by supervision 59.64% perceived that there is culture in this regard, 80% of the responses were positive for the perception about the culture of organizational learning and continuous improvement.In the dimension, teamwork 84, 6% perceived that there is culture in this aspect and 70.7% that there is open communication in the organization.85.1% perceive that there is a feedback and communication of the error, 61.5% stated that there is a culture of non-punitive response.53.9% perceived that there was culture in staffing, and 63.9% of the responses were positive in relation to management.63.9% perceive that they work in multidisciplinary teams, and 60.9% perceive a safety culture in the transfer and transfer of the patient to the services.Conclusion: Nurses perceive the culture of safety in Hospitals as low. There are several dimensions of culture to be improved

Resumo:Para descrever a cultura de segurança do paciente encaminhados por enfermeirosDesenho: estudo descritivo.Local: Hospitais públicos na cidade de Corrientes, 2017.Foi utilizado enfermeiros, para coleta de dados questionário versão espanhola do Inquérito aos Hospitais da Cultura de Segurança do Paciente: Participantes.Resultados: Observou-se na percepção que têm sobre a cultura de segurança do paciente, 45,84% percebem é positivo, a 93,01% relataram o relatório de erros como positivo.Ações para promover a segurança, monitorando a 59,64% perceberam que a cultura existe nesta área, 80% das respostas foram positivas para a percepção de cultura organizacional de aprendizagem e melhoria contínua.Em dimensão, trabalho em 84, 6% sentiram que a cultura existe nesta área e 70,7% que não há uma comunicação aberta dentro da organização.85,1% perceber que existe um feedback de erro e comunicação, 61,5% referido que existe uma cultura de resposta não punitiva.53,9% percebem que não há cultura em termos de pessoal, e 63,9% das respostas foram positivas em relação à gestão.63,9% percebem a trabalhar em equipas multidisciplinares, e 60,9% percebem uma cultura de segurança na transferência e entrega de serviços paciente.Conclusão: Os enfermeiros percebida baixa cultura de segurança em hospitais. Existem várias dimensões de cultura para melhorar

The Complement Inhibitor Factor H Generates an Anti-Inflammatory and Tolerogenic State in Monocyte-Derived Dendritic Cells.

The activation of the complement system is a key initiating step in the protective innate immune-inflammatory response against injury, although it may also cause harm if left unchecked. The structurally related soluble complement inhibitors C4b-binding protein (C4BP) and factor H (FH) exert a tight regulation of the classical/lectin and alternative pathways of complement activation, respectively, attenuating the activity of the C3/C5 convertases and, consequently, avoiding serious damage to host tissues. We recently reported that the acute-phase C4BP isoform C4BP lacking the ß-chain plays a pivotal role in the modulation of the adaptive immune responses. In this study, we demonstrate that FH acts in the early stages of monocyte to dendritic cell (DC) differentiation and is able to promote a distinctive tolerogenic and anti-inflammatory profile on monocyte-derived DCs (MoDCs) challenged by a proinflammatory stimulus. Accordingly, FH-treated and LPS-matured MoDCs are characterized by altered cytoarchitecture, resembling immature MoDCs, lower expression of the maturation marker CD83 and the costimulatory molecules CD40, CD80, and CD86, decreased production of key proinflammatory Th1-cytokines (IL-12, TNF-α, IFN-γ, IL-6, and IL-8), and preferential production of immunomodulatory mediators (IL-10 and TGF-ß). Moreover, FH-treated MoDCs show low Ag uptake and, when challenged with LPS, display reduced CCR7 expression and chemotactic migration, impaired CD4(+) T cell alloproliferation, inhibition of IFN-γ secretion by the allostimulated T cells, and, conversely, induction of CD4(+)CD127(low/negative)CD25(high)Foxp3(+) regulatory T cells. Thus, this novel noncanonical role of FH as an immunological brake able to directly affect the function of MoDCs in an inflammatory environment may exhibit therapeutic potential in hypersensitivity, transplantation, and autoimmunity.

IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation.

BACKGROUND: The role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non-redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM-CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation. RESULTS: Here, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell-specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes. CONCLUSIONS: Our study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation.

Usefulness of circulating microRNAs for the prediction of early preeclampsia at first-trimester of pregnancy.

To assess the usefulness of circulating microRNAs (miRNAs) as non-invasive molecular biomarkers for early prediction of preeclampsia, a differential miRNA profiling analysis was performed in first-trimester pooled sera from 31 early preeclampsia patients, requiring delivery before 34 weeks of gestation, and 44 uncomplicated pregnancies using microfluidic arrays. Among a total of 754 miRNAs analyzed, the presence of 63 miRNAs (8%) was consistently documented in the sera from preeclampsia and control samples. Nevertheless, only 15 amplified miRNAs (2%) seemed to be differentially, although modestly, represented (fold change range: 0.4-1.4). After stem loop RT-qPCR from individual samples, the statistical analysis confirmed that none of the most consistent and differentially represented miRNAs (3 overrepresented and 4 underrepresented) were differentially abundant in serum from preeclamptic pregnancies compared with serum from normal pregnancies. Therefore, maternal serum miRNA assessment at first-trimester of pregnancy does not appear to have any predictive value for early preeclampsia.

The α7ß0 isoform of the complement regulator C4b-binding protein induces a semimature, anti-inflammatory state in dendritic cells.

The classical pathway complement regulator C4b-binding protein (C4BP) is composed of two polypeptides (α- and ß-chains), which form three plasma oligomers with different subunit compositions (α7ß1, α7ß0, and α6ß1). We show in this article that the C4BP α7ß0 isoform (hereafter called C4BP[ß(-)] [C4BP lacking the ß-chain]), overexpressed under acute-phase conditions, induces a semimature, tolerogenic state on human monocyte-derived dendritic cells (DCs) activated by a proinflammatory stimulus. C4BP isoforms containing ß-chain (α7ß1 and α6ß1; C4BP[ß(+)]) neither interfered with the normal maturation of DCs nor competed with C4BP(ß(-)) activity on these cells. Immature DCs (iDCs) treated with C4BP(ß(-)) retained high endocytic activity, but, upon LPS treatment, they did not upregulate surface expression of CD83, CD80, and CD86. Transcriptional profiling of these semimature DCs revealed that treatment with C4BP(ß(-)) prevented the induction of IDO and BIC-1, whereas TGF-ß1 expression was maintained to the level of iDCs. C4BP(ß(-))-treated DCs were also unable to release proinflammatory Th1 cytokines (IL-12, TNF-α, IFN-γ, IL-6, IL-8) and, conversely, increased IL-10 secretion. They prevented surface CCR7 overexpression and, accordingly, displayed reduced chemotaxis, being morphologically indistinguishable from iDCs. Moreover, C4BP(ß(-))-treated DCs failed to enhance allogeneic T cell proliferation, impairing IFN-γ production in these cells and, conversely, promoting CD4(+)CD127(low/neg)CD25(high)Foxp3(+) T cells. Deletion mutant analysis revealed that the complement control protein-6 domain of the α-chain is necessary for the tolerogenic activity of C4BP(ß(-)). Our data demonstrate a novel anti-inflammatory and immunomodulatory function of the complement regulator C4BP, suggesting a relevant role of the acute-phase C4BP(ß(-)) isoform in a number of pathophysiological conditions and potential applications in autoimmunity and transplantation.

Early atherosclerotic plaques show evidence of infection by Chlamydia pneumoniae.

Chlamydia pneumoniae (Cpn) could play an important role in the development of atherosclerosis. Cpn interferes with HIF-1alpha regulation in infected host cells during intracellular replication in hypoxia. We obtained carotid artery specimens with low (n=38), high (n=25) levels of stenosis and 10 middle cerebral arteries. Fifty eight percent of the carotids with low levels of stenosis showed evidence of the viable organism. Ninety one percent of the positive results were derived from pre-atheromatous lesions. Only 12 percent of plaques removed at endarterectomy showed the presence of Cpn DNA. All middle cerebral arteries failed to show evidence of live Chlamydia. Ninety one percent of sera from 22 endarterectomy patients failed to show the presence of Cpn antibodies. Immunohistology of carotid arteries with low levels of stenosis was used to confirm the presence of HIF-1alpha in infected specimens and showed a correlation between the over-expression of HIF-1alpha and Cpn in the plaque (p less than 0.05). Cpn might play an important role in activation and development of the initial stages of atherosclerotic lesions.

Evaluation of care for at-risk newborns from the perspective of a public health policy.

The aim was to evaluate the care for at-risk newborns under follow-up in their first year of life by the Growing Happily Program, developed in a city in inner São Paulo state. It is a population-based epidemiological health program evaluation study, which was based on the national guidelines of the Agenda of Commitments to Children and Child Mortality Reduction for data analysis. Results showed the program's institutional vulnerability, caused by problems related to its structure and process, with implications for its outcomes. Considering the adaptation of the criteria adopted by the Program for defining at-risk newborns, as well as the proposed interventions and strategies, in consonance with the Agenda of Commitments, the need for managers to make it a priority is appointed, by effectively including it in public health care policies to be developed in cities, in order to reverse the institutional vulnerability identified.

Evaluation of care for at-risk newborns from the perspective of a public health policy / Avaliação da atenção ao recém-nascido de risco, na perspectiva de uma política pública de saúde / Evaluación de la atención al recién nacido con riesgo bajo la perspectiva de una política pública de salud

The aim was to evaluate the care for at-risk newborns under follow-up in their first year of life by the Growing Happily Program, developed in a city in inner São Paulo state. It is a population-based epidemiological health program evaluation study, which was based on the national guidelines of the Agenda of Commitments to Children and Child Mortality Reduction for data analysis. Results showed the program's institutional vulnerability, caused by problems related to its structure and process, with implications for its outcomes. Considering the adaptation of the criteria adopted by the Program for defining at-risk newborns, as well as the proposed interventions and strategies, in consonance with the Agenda of Commitments, the need for managers to make it a priority is appointed, by effectively including it in public health care policies to be developed in cities, in order to reverse the institutional vulnerability identified.

Objetivou-se avaliar a atenção à saúde de recém-nascidos de risco, acompanhados no primeiro ano de vida pelo Programa Crescer Feliz, desenvolvido em município do interior paulista. Trata-se de estudo epidemiológico populacional, do tipo avaliação de programa de saúde, que se baseou, para análise dos dados, nas diretrizes nacionais da Agenda de Compromissos da Criança. Os resultados evidenciaram a vulnerabilidade institucional do programa, decorrente de problemas relacionados à estrutura e processo, com implicações nos resultados. Considerando a adequação dos critérios adotados pelo programa, para definição dos recém-nascidos de risco e das intervenções e estratégias propostas, que se mostram em consonância com a Agenda de Compromissos, aponta-se a necessidade dos gestores priorizá-lo, inserindo-o, efetivamente, na política pública de saúde a ser desenvolvida no âmbito do município, para reversão da vulnerabilidade institucional identificada.

Se objetivó evaluar la atención a la salud de recién nacidos con riesgo acompañados en el primer año de vida por el Programa Crecer Feliz, desarrollado en un municipio del interior del estado de Sao Paulo. Se trata de un estudio epidemiológico poblacional del tipo evaluación de programa de salud que se basó, para el análisis de los datos, en las directrices nacionales de la Agenda de Compromisos del Niño. Los resultados evidenciaron la vulnerabilidad institucional del programa, proveniente de problemas relacionados a la estructura y proceso, con implicaciones en los resultados. Considerando la adecuación de los criterios adoptados por el programa para definición de los recién nacidos con riesgo y de las intervenciones y estrategias propuestas, que se muestran en consonancia con la Agenda de Compromisos, se apunta la necesidad de los administradores de priorizarlo, introduciéndolo efectivamente en la política pública de salud a ser desarrollada en el ámbito del municipio, para reversión de la vulnerabilidad institucional identificada.

Modified C-reactive protein is expressed by stroke neovessels and is a potent activator of angiogenesis in vitro.

Native C-reactive protein (nCRP) is a pentameric oligo-protein and an acute phase reactant whose serum expression is increased in patients with inflammatory disease. We have identified by immunohistochemistry, significant expression of a tissue-binding insoluble modified version or monomeric form of CRP (mCRP) associated with angiogenic microvessels in peri-infarcted regions of patients studied with acute ischaemic stroke. mCRP, but not nCRP was expressed in the cytoplasm and nucleus of damaged neurons. mCRP co-localized with CD105, a marker of angiogenesis in regions of revascularisation. In vitro investigations demonstrated that mCRP was preferentially expressed in human brain microvessel endothelial cells following oxygen-glucose deprivation and mCRP (but not column purified nCRP) associated with the endothelial cell surface, and was angiogenic to vascular endothelial cells, stimulating migration and tube formation in matrigel more strongly than fibroblast growth factor-2. The mechanism of signal transduction was not through the CD16 receptor. Western blotting showed that mCRP stimulated phosphorylation of the key down-stream mitogenic signalling protein ERK1/2. Pharmacological inhibition of ERK1/2 phosphorylation blocked the angiogenic effects of mCRP. We propose that mCRP may contribute to the neovascularization process and because of its abundant presence, be important in modulating angiogenesis in both acute stroke and later during neuro-recovery.