Serum immunoglobulins in children perinatally exposed to human immunodeficiency virus

OBJECTIVE: Hypergammaglobulinemia is an early manifestation of perinatal HIV infection. Our objective was to analyze the differences in serum immunoglobulin levels between infected and seroreverting children and their association with clinical outcome. METHODS: We carried out a historical prospective study with 107 infected and 90 seroreverting children. We compared the IgA, IgG, and IgM levels between infected and seroreverting patients within the first 18 months of life; IgA, IgG, and IgM as surrogate markers of infection; and IgA, IgG, and IgM levels within the first 5 years in infected children, according to clinical outcome. The Mann-Whitney test was used for comparison between groups. Surrogate markers were assessed according to sensitivity, specificity, positive and negative predictive values, and Youden's index. RESULTS: Infected children, when compared to seroreverters, showed significantly higher levels of IgM between the 1st and 5th trimesters; IgA and IgG between the 2nd and 6th trimesters (P less than or equal to 0.05). Levels of IgA greater than or equal to 90 mg/dl in the 2nd trimester and IgG greater than or equal to 1,700 mg/dl or 1,200 mg/dl in the 2nd and 3rd trimesters were associated with HIV infection, with Youden's indexes of 0.97, 0.92, and 0.93, respectively. Infected children in the B and C categories, compared to those in the N and A, showed higher levels of IgM between the 2nd and 4th years, and IgA between the 3rd and 5th year (P > 0.05). CONCLUSIONS: The temporal progression of IgA, IgG, and IgM levels showed an early and intense stimulation to the synthesis of immunoglobulin in infected children. Clinical and epidemiological indicators showed that such levels may be surrogate markers of infection. Higher IgM and IgA levels between the 2nd and 5th years in more severely infected children suggest a dysfunction in immune regulation secondary to persistent antigenic stimulation.OBJETIVO: a hipergamaglobulinemia é uma manifestação precoce da infecção perinatal por HIV. O objetivo foi analisar as diferenças nos níveis séricos de imunoglobulinas entre crianças infectadas e sororreversoras, e sua associação com a evolução clínica. MÉTODOS: Em um estudo prospectivo histórico, avaliaram-se 107 crianças infectadas e 90 sororreversoras. Compararam-se: IgA, IgG e IgM entre infectados e sororreversores nos primeiros 18 meses de vida; IgA, IgG e IgM como marcadores indiretos de infecção; IgA, IgG e IgM nos 5 primeiros anos em infectados, de acordo com a evolução clínica. Utilizou-se o teste de Mann-Whitney para a comparação entre grupos. Na avaliação de marcadores indiretos, analisaram-se Sensibilidade, Especificidade, Valores Preditivos Positivo e Negativo, e índice J. RESULTADOS: Infectados, em relação a sororreversores, apresentaram níveis significativamente superiores de IgM, do 1o ao 5o trimestre; IgA e IgG, do 2o ao 6o trimestre (P 90 mg/dl no 2o trimestre e IgG > 1.700 mg/dl ou 1.200 mg/dl no 2o e 3o trimestres associaram-se à infecção por HIV com índices J de 0,97, 0,92 e 0,93, respectivamente. Crianças infectadas nas categorias B e C, comparadas àquelas nas categorias N e A, apresentaram níveis superiores de IgM, do 2o ao 4o ano e IgA, do 3o ao 5o ano (P £.0,05). CONCLUSÕES: A evolução temporal dos níveis de IgA, IgG e IgM demonstra um estímulo intenso e precoce à síntese de imunoglobulinas em infectados. Indicadores clínico-epidemiológicos demonstram que tais níveis podem ser marcadores indiretos de infecção. Níveis superiores de IgM e IgA do 2o ao 5o ano em crianças infectadas com maior gravidade sugerem disfunção na regulação imune secundária ao estímulo antigênico persistente.20921

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

The PLASMONX Project for advanced beam physics experiments

The Project PLASMONX is well progressing into its design phase and has entered as well its second phase of procurements for main components. The project foresees the installation at LNF of a Ti:Sa laser system (peak power > 170 TW), synchronized to the high brightness electron beam produced by the SPARC photo-injector. The advancement of the procurement of such a laser system is reported, as well as the construction plans of a new building at LNF to host a dedicated laboratory for high intensity photon beam experiments (High Intensity Laser Laboratory). Several experiments are foreseen using this complex facility, mainly in the high gradient plasma acceleration field and in the field of mono- chromatic ultra-fast X-ray pulse generation via Thomson back-scattering. Detailed numerical simulations have been carried out to study the generation of tightly focused electron bunches to collide with laser pulses in the Thomson source: results on the emitted spectra of X-rays are presented

Congenital Zika syndrome is associated with maternal protein malnutrition

Zika virus (ZIKV) infection during pregnancy is associated with a spectrum of developmental impairments known as congenital Zika syndrome (CZS). The prevalence of this syndrome varies across ZIKV endemic regions, suggesting that its occurrence could depend on cofactors. Here, we evaluate the relevance of protein malnutrition for the emergence of CZS. Epidemiological data from the ZIKV outbreak in the Americas suggest a relationship between undernutrition and cases of microcephaly. To experimentally examine this relationship, we use immunocompetent pregnant mice, which were subjected to protein malnutrition and infected with a Brazilian ZIKV strain. We found that the combination of protein restriction and ZIKV infection leads to severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size. RNA-seq analysis reveals gene expression deregulation required for brain development in infected low-protein progeny. These results suggest that maternal protein malnutrition increases susceptibility to CZS.Fil: Barbeito Andrés, Jimena. Universidade Federal do Rio de Janeiro; Brasil. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Pezzuto, Paula. Universidade Federal do Rio de Janeiro; BrasilFil: Higa, Luiza. Universidade Federal do Rio de Janeiro; BrasilFil: Dias, André Alves. Universidade Federal do Rio de Janeiro; BrasilFil: Vasconcelos, Janaina. Universidade Federal do Pará; BrasilFil: Santos, T. M. P.. Universidade Federal do Rio de Janeiro; BrasilFil: Ferreira, Jéssica. Universidade Federal do Rio de Janeiro; BrasilFil: Ferreira, R. O.. Universidade Federal do Rio de Janeiro; BrasilFil: Dutra, F. F.. Universidade Federal do Rio de Janeiro; BrasilFil: Rossi, A. D.. Universidade Federal do Rio de Janeiro; BrasilFil: Barbosa, R. V.. Universidade Federal Do Rio de Janeiro. Centro Nacional de Biologia Estrutural E Bioimagem.; BrasilFil: Amorim, C. K. N.. Evandro Chagas Institute; BrasilFil: de Souza, M. P. C.. Evandro Chagas Institute; BrasilFil: Chimelli, L.. Instituto Estadual do Cérebro Paulo Niemeyer ; BrasilFil: Aguiar, R. S.. Universidade Federal do Rio de Janeiro; BrasilFil: Gonzalez, Paula Natalia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Lara, F. A.. Oswaldo Cruz Institute; BrasilFil: Castro, M.C.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Molnár, Z.. University of Oxford; Reino UnidoFil: Lopes, R. T.. Universidade Federal do Rio de Janeiro; BrasilFil: Bozza, M. T.. Universidade Federal do Rio de Janeiro; BrasilFil: Vianez, J. L. S. G.. Evandro Chagas Institute; BrasilFil: Barbeito, Claudio Gustavo. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Cuervo, P.. Oswaldo Cruz Institute; BrasilFil: Bellio, M.. Universidade Federal do Rio de Janeiro; BrasilFil: Tanuri, A.. Universidade Federal do Rio de Janeiro; BrasilFil: Garcez, P. P.. Universidade Federal do Rio de Janeiro; Brasi

The serine protease domain of MASP-3: enzymatic properties and crystal structure in complex with ecotin.

International audienceMannan-binding lectin (MBL), ficolins and collectin-11 are known to associate with three homologous modular proteases, the MBL-Associated Serine Proteases (MASPs). The crystal structures of the catalytic domains of MASP-1 and MASP-2 have been solved, but the structure of the corresponding domain of MASP-3 remains unknown. A link between mutations in the MASP1/3 gene and the rare autosomal recessive 3MC (Mingarelli, Malpuech, Michels and Carnevale,) syndrome, characterized by various developmental disorders, was discovered recently, revealing an unexpected important role of MASP-3 in early developmental processes. To gain a first insight into the enzymatic and structural properties of MASP-3, a recombinant form of its serine protease (SP) domain was produced and characterized. The amidolytic activity of this domain on fluorescent peptidyl-aminomethylcoumarin substrates was shown to be considerably lower than that of other members of the C1r/C1s/MASP family. The E. coli protease inhibitor ecotin bound to the SP domains of MASP-3 and MASP-2, whereas no significant interaction was detected with MASP-1, C1r and C1s. A tetrameric complex comprising an ecotin dimer and two MASP-3 SP domains was isolated and its crystal structure was solved and refined to 3.2 Å. Analysis of the ecotin/MASP-3 interfaces allows a better understanding of the differential reactivity of the C1r/C1s/MASP protease family members towards ecotin, and comparison of the MASP-3 SP domain structure with those of other trypsin-like proteases yields novel hypotheses accounting for its zymogen-like properties in vitro

Improving the Characterization of Radiologically Isolated Syndrome Suggestive of Multiple Sclerosis

OBJECTIVE: To improve the characterization of asymptomatic subjects with brain magnetic resonance imaging (MRI) abnormalities highly suggestive of multiple sclerosis (MS), a condition named as "radiologically isolated syndrome" (RIS). METHODS: Quantitative MRI metrics such as brain volumes and magnetization transfer (MT) were assessed in 19 subjects previously classified as RIS, 20 demographically-matched relapsing-remitting MS (RRMS) patients and 20 healthy controls (HC). Specific measures were: white matter (WM) lesion volumes (LV), total and regional brain volumes, and MT ratio (MTr) in lesions, normal-appearing WM (NAWM) and cortex. RESULTS: LV was similar in RIS and RRMS, without differences in distribution and frequency at lesion mapping. Brain volumes were similarly lower in RRMS and RIS than in HC (p<0.001). Lesional-MTr was lower in RRMS than in RIS (p = 0.048); NAWM-MTr and cortical-MTr were similar in RIS and HC and lower (p<0.01) in RRMS. These values were particularly lower in RRMS than in RIS in the sensorimotor and memory networks. A multivariate logistic regression analysis showed that 13/19 RIS had ≥70% probability of being classified as RRMS on the basis of their brain volume and lesional-MTr values. CONCLUSIONS: Macroscopic brain damage was similar in RIS and RRMS. However, the subtle tissue damage detected by MTr was milder in RIS than in RRMS in clinically relevant brain regions, suggesting an explanation for the lack of clinical manifestations of subjects with RIS. This new approach could be useful for narrowing down the RIS individuals with a high risk of progression to MS

Severe and Persistent Depletion of Circulating Plasmacytoid Dendritic Cells in Patients with 2009 Pandemic H1N1 Infection

Background: Dysregulation of host immune responses plays a critical role in the pathogenesis of severe 2009 pandemic H1N1 infection. Whether H1N1 virus could escape innate immune defense in vivo remains to be investigated. The aim of this study was to evaluate the pattern of innate immune response during human 2009 H1N1 infection. We performed the enumeration of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) in blood from patients with H1N1 pneumonia shortly after the onset of symptoms and during follow-up at different intervals of time. The analysis of CD4 and CD8 count, CD38 T-cell activation marker and serum cytokine/chemokine plasma levels was also done. Methodology/Principal Findings: Blood samples were collected from 13 hospitalized patients with confirmed H1N1-related pneumonia at time of admission and at weeks 1, 4, and 16 of follow-up. 13 healthy donors were enrolled as controls. In the acute phase of the disease, H1N1-infected patients exhibited a significant depletion in both circulating pDC and mDC in conjunction with a decrease of CD4 and CD8 T cell count. In addition, we found plasmatic hyperproduction of IP-10 and RANTES, whereas increase in T-cell immune activation was found at all time points. When we assessed the changes in DC count over time, we observed a progressive normalization of mDC number. On the contrary, H1N1-infected patients did not achieve a complete recovery of pDC count as values remained lower than healthy controls even after 16 weeks of follow-up. Conclusions: H1N1 disease is associated with a profound depletion of DC subsets. The persistence of pDC deficit for several weeks after disease recovery could be due to H1N1 virus itself or to a preexisting impairment of innate immunity

CNF1 Improves Astrocytic Ability to Support Neuronal Growth and Differentiation In vitro

Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number. CNF1 removal, however, restored dendritic tree development and synapse formation, suggesting that the toxin can reversibly block neuronal differentiation. On differentiated neurons, CNF1 had a similar effacing effect on synapses. Therefore, a direct interaction with CNF1 is apparently deleterious for neurons. Since astrocytes play a pivotal role in neuronal differentiation and synaptic regulation, we wondered if the beneficial in vivo effect could be mediated by astrocytes. Primary astrocytes from embryonic cortex were treated with CNF1 for 48 hours and used as a substrate for growing hippocampal neurons. Such neurons showed an increased development of neurites, in respect to age-matched controls, with a wider dendritic tree and a richer content in synapses. In CNF1-exposed astrocytes, the production of interleukin 1β, known to reduce dendrite development and complexity in neuronal cultures, was decreased. These results demonstrate that astrocytes, under the influence of CNF1, increase their supporting activity on neuronal growth and differentiation, possibly related to the diminished levels of interleukin 1β. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London