Antinucleosome antibodies as a marker of active proliferative lupus nephritis.

BACKGROUND: Antinucleosome autoantibodies were previously described to be a marker of active lupus nephritis. However, the true prevalence of antinucleosome antibodies at the time of active proliferative lupus nephritis has not been well established. Therefore, the aim of this study is to define the prevalence and diagnostic value of autoantibodies against nucleosomes as a marker for active proliferative lupus nephritis. STUDY DESIGN: Prospective multicenter diagnostic test study. SETTING & PARTICIPANTS: 35 adult patients with systemic lupus erythematosus (SLE) at the time of the renal biopsy showing active class III or IV lupus nephritis compared with 59 control patients with SLE. INDEX TEST: Levels of antinucleosome antibodies and anti-double-stranded DNA (anti-dsDNA) antibodies. REFERENCE TEST: Kidney biopsy findings of class III or IV lupus nephritis at the time of sampling in a study population versus clinically inactive or no nephritis in a control population. RESULTS: Increased concentrations of antinucleosome antibodies were found in 31 of 35 patients (89%) with active proliferative lupus nephritis compared with 47 of 59 control patients (80%) with SLE. No significant difference between the 2 groups with regard to number of positive patients (P = 0.2) or antibody concentrations (P = 0.2) could be found. The area under the receiver operating characteristic curve as a marker of the accuracy of the test in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.581 (95% confidence interval, 0.47 to 0.70; P = 0.2). Increased concentrations of anti-dsDNA antibodies were found in 33 of 35 patients (94.3%) with active proliferative lupus nephritis compared with 49 of 58 control patients (84.5%) with SLE (P = 0.2). In patients with proliferative lupus nephritis, significantly higher titers of anti-dsDNA antibodies were detected compared with control patients with SLE (P < 0.001). The area under the receiver operating characteristic curve in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.710 (95% confidence interval, 0.60 to 0.82; P < 0.001). CONCLUSIONS: Antinucleosome antibodies have a high prevalence in patients with severe lupus nephritis. However, our data suggest that determining antinucleosome antibodies is of limited help in the distinction of patients with active proliferative lupus nephritis from patients with SLE without active renal disease.

Assessment of particulate exposure and surface characteristics in association with urinary levels of 8-hydroxy-2'-deoxyguanosine, considered as marker of oxidative stress

Epidemiological studies have demonstrated that exposure to fine particles is associated to adverse health effects, including cancer, respiratory and cardiovascular diseases. However, mechanisms by which particles induce health effects remain unclear. According to one of the most investigated hypotheses, particles cause adverse effects through the production of reactive oxygen species (ROS), which are very hazardous compounds able to attack directly biological structures, including the DNA strand or the lipid bilayer of the cells. If the defense mechanisms, constituted of antioxidants, are not able to counter ROS, then these compounds will cause in the body a range of oxidation reactions called "oxidative stress". The aim of the present research project was to better understand mechanisms by which exposure to fine particles induces oxidative stress. The first point of this project was to check whether exposure to high levels of fine particles is directly linked to oxidative stress, and whether this oxidative stress is accompanied by the activation of the defense mechanisms (antioxidants). The second point was to study the role played by the particle surface characteristics in the oxidative stress process. For that purpose, a study was conducted in bus depots with the participation of 40 mechanics. First, occupational exposure to particles (PM4) and to other pollutants (NOx, O3) was measured over a two-day period. Then, urine samples of mechanics were collected in order to measure levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and antioxidants. 8OHdG is a molecule formed by the oxidation of DNA and allowing to assess the oxidative stress status of the mechanics. Finally, particles were collected on filters, and functional groups located on the particle surface were analyzed in the laboratory using a Knudsen flow reactor. This technique allows not only to quantify functional groups on the particle surface, but also to measure the reaction kinetics. Results obtained during the field campaign in bus depots showed that mechanics were exposed to rather low levels of PM4 (20-85 μg/m3) and of pollutants (NOx: 100-1000 ppb; O3: <15 ppb). However, despite this low exposure, urinary levels of the oxidative stress biomarker (8OHdG) increased significantly for non-smoking workers over a two-day period of shift. This oxidative stress was accompanied by an increase of antioxidants, indicating the activation of defense mechanisms. On the other hand, the analysis of functional groups on the particle surface showed important differences, depending on the workplace, the date and the activities of workers. The particle surface contained simultaneously antagonistic functional groups which did not undergo internal reactions (such as acids and bases), and was usually characterized by a high density of carbonyl functions and a low density of acidic sites. Reaction kinetics measured using the Knudsen flow reactor pointed out fast reactions of oxidizable groups and slow reactions of acidic sites. Several exposure parameters were significantly correlated with the increase of the oxidative stress status: the presence of acidic sites, carbonyl functions and oxidizable groups on the particle surface; reaction kinetics of functional groups on the particle surface; particulate iron and copper concentrations; and NOx concentration.

How to Get Your Bearings - How to Get A Job: A Guide for Women who are Unemployed, Underemployed, or Underpaid

A guide for women who are preparing to enter the workforce. Produced by the Iowa Commission on the Status of Women.

Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy.

OBJECTIVE: To determine changes of cerebrospinal fluid (CSF) biomarkers of patients on monotherapy with lopinavir/ritonavir. DESIGN: The Monotherapy Switzerland/Thailand study (MOST) trial compared monotherapy with ritonavir-boosted lopinavir with continued therapy. The trial was prematurely stopped due to virological failure in six patients on monotherapy. It, thus, offers a unique opportunity to assess brain markers in the early stage of HIV virological escape. METHODS: : Sixty-five CSF samples (34 on continued therapy and 31 on monotherapy) from 49 HIV-positive patients enrolled in MOST. Using enzyme-linked immunosorbent assay, we determined the CSF concentration of S100B (astrocytosis), neopterin (inflammation), total Tau (tTau), phosphorylated Tau (pTau), and amyloid-β 1-42 (Aβ), the latter three indicating neuronal damage. Controls were CSF samples of 29 HIV-negative patients with Alzheimer dementia. RESULTS: In the CSF of monotherapy, concentrations of S100B and neopterin were significantly higher than in continued therapy (P = 0.006 and P = 0.013, respectively) and Alzheimer dementia patients (P < 0.0001 and P = 0.0005, respectively). In Alzheimer dementia, concentration of Aβ was lower than in monotherapy (P = 0.005) and continued therapy (P = 0.016) and concentrations of tTau were higher than in monotherapy (P = 0.019) and continued therapy (P = 0.001). There was no difference in pTau among the three groups. After removal of the 16 CSF with detectable viral load in the blood and/or CSF, only S100B remained significantly higher in monotherapy than in the two other groups. CONCLUSION: Despite full viral load-suppression in blood and CSF, antiretroviral monotherapy with lopinavir/ritonavir can raise CSF levels of S100B, suggesting astrocytic damage.

Pancreatic stone protein as a novel marker for neonatal sepsis.

PURPOSE: Early-onset sepsis (EOS) is one of the main causes for the admission of newborns to the neonatal intensive care unit. However, traditional infection markers are poor diagnostic markers of EOS. Pancreatic stone protein (PSP) is a promising sepsis marker in adults. The aim of this study was to investigate whether determining PSP improves the diagnosis of EOS in comparison with other infection markers. METHODS: This was a prospective multicentre study involving 137 infants with a gestational age of >34 weeks who were admitted with suspected EOS. PSP, procalcitonin (PCT), soluble human triggering receptor expressed on myeloid cells-1 (sTREM-1), macrophage migration inhibitory factor (MIF) and C-reactive protein (CRP) were measured at admission. Receiver-operating characteristic (ROC) curve analysis was performed. RESULTS: The level of PSP in infected infants was significantly higher than that in uninfected ones (median 11.3 vs. 7.5 ng/ml, respectively; p = 0.001). The ROC area under the curve was 0.69 [95 % confidence interval (CI) 0.59-0.80; p < 0.001] for PSP, 0.77 (95 % CI 0.66-0.87; p < 0.001) for PCT, 0.66 (95 % CI 0.55-0.77; p = 0.006) for CRP, 0.62 (0.51-0.73; p = 0.055) for sTREM-1 and 0.54 (0.41-0.67; p = 0.54) for MIF. PSP independently of PCT predicted EOS (p < 0.001), and the use of both markers concomitantly significantly increased the ability to diagnose EOS. A bioscore combining PSP (>9 ng/ml) and PCT (>2 ng/ml) was the best predictor of EOS (0.83; 95 % CI 0.74-0.93; p < 0.001) and resulted in a negative predictive value of 100 % and a positive predictive value of 71 %. CONCLUSIONS: In this prospective study, the diagnostic performance of PSP and PCT was superior to that of traditional markers and a combination bioscore improved the diagnosis of sepsis. Our findings suggest that PSP is a valuable biomarker in combination with PCT in EOS.

S. Gregorius, Moralia in Job. S. Gregorius, Moralia in Job.

Augustins.

The Effect of occupational sex-composition on earnings: job-specialisation, sex-role attitudes and the division of domestic-labour in Spain

Important theoretical controversies remain unresolved in the literatire on occupational sex-segregation and the gender wage-gap. A useful way of summarising these controversies is viewing them as a debate between - cultural -socialisation. The paper discusses these theories in detail and carries out a preliminary test of the relative explanatory performance of some of their most consequential predictions. This is done by drawing on the Spanish sample of the second wave of the European Social Survey, ESS. The empirical analysis of ESS data illustrates the notable analytical pay-offs that can stem from using rich individual-level indicators, but also exemplifies the statistical llimitations generated by small sample size and high rates of non-response. Empirical results should, therefore, be taken as preliminary. They seem to suggest that the effect of occupational sex-segregation on wages could be explicable by workers' sex-role attitutes, their relative input in domestic production and the job-specific human capital requirements of their jobs. Of these three factors, job-specialisation seeems clearly the most important one.

Not the right job but a secure one : over-education and temporary employment in France, Italy and Spain

Resorting to four waves of the European Community Household Panel, this research explores the association between temporary employment and the likelihood of being over-educated. Such an association has been largely ignored by the literature explaining over-education, more inclined to attribute such a mismatch to the system of education. Selecting three similarly standarised and stratified systems of education (France, Italy and Spain) and controlling for many other variables likely to affect over-education, like gender, age, tenure, job change, firm size or sector, the paper demonstrates that such an association between temporary employment and over-education exists. Being a stepping stone towards a more stable and adjusted position in the labour market, holding a temporary employment may be associated to a higher likelihood of being over-educated. Such an association is more likely in Italy and France. Yet, the opposite sign prevails where permanent employment becomes such a valuable asset as to make individuals trade human capital by employment security. This is the case of Spain.

Finding a suitable job: the effect of the institutional context on self-perceived over-education

The current research compares the perception of over-education in four different European countries, resorting to European Household Panel Data. The results confirm that the type of educational system accounts for some of the cross-national differences in self-perceived over-education. In qualificational spaces, like Denmark, where vocational training receives more importance, self-perceived over-education is not associated as much with educational attainment as in the so-called’ organisational spaces’, like Spain, France and Italy. Yet, the results confirm that, controlling for the system of education, the traits and regulation of the labour market also have an effect on over-education. Thus, in Spain, where temporary employment has soared in recent decades, this type of contract is clearly associated with the perception of over-education, to a much higher extent than in Italy or France. Temporary contracts in Spain may not work as a steppig stone for attaining a job suitable to the training received by the individual, as they may in the case of France or Italy. In sum, not only institutions offering skills and human capital, but labour market regulation as well, have a clear impact on the incidence of over-education.

Evaluation of adding a second marker to overcome Staphylococcus aureus spa typing homoplasies.

The utility of sequencing a second highly variable locus in addition to the spa gene (e.g., double-locus sequence typing [DLST]) was investigated to overcome limitations of a Staphylococcus aureus single-locus typing method. Although adding a second locus seemed to increase discriminatory power, it was not sufficient to definitively infer evolutionary relationships within a single multilocus sequence type (ST-5).

Tartrate-Resistant Acid Phosphatase 5b: a Serum Marker of Bone Resorption

Bone is a physiologically dynamic tissue being constantly regenerated throughout life as a consequence of bone turnover by bone-resorbing osteoclasts and bone-forming osteoblasts. In certain bone diseases, such as osteoporosis, the imbalance in bone turnover leads to bone loss and increased fracture risk. Measurement of bone mineral density (BMD) predicts the risk of fracture, but also biochemical markers of bone metabolism have been suggested to be suitable for prediction of fractures and monitoring the efficacy of antiresorptive treatment. Tartrate-resistant acid phosphatase 5b (TRACP 5b) is an enzyme released from osteoclasts into the circulation, from where it can be detected kinetically or immunologically. Conventional assays for serum total TRACP were spectrophotometric and suffered from interference by other acid phosphatases and non-osteoclastic TRACP 5a isoform. Our aim was to develop novel immunoassays for osteoclastic TRACP 5b. Serum TRACP 5b levels were elevated in individuals with high bone turnover, such as children, postmenopausal women, patients with osteoporosis, Paget’s disease and breast cancer patients with bone metastases. As expected, hormone replacement therapy (HRT) in postmenopausal women decreased the levels of serum TRACP 5b. Surprisingly, the highest TRACP 5b levels were observed in individuals with rare autosomal dominant osteopetrosis type II (ADO2), which is characterized by high BMD and fracture risk with simultaneously elevated levels of deficient osteoclasts. In ADO2 patients, elevated levels of serum TRACP 5b were associated with high fracture frequency. It is likely that serum TRACP 5b reflects the number of inactive osteoclasts in ADO2. Similar results supporting the hypothesis that TRACP 5b would reflect the number of osteoclasts instead of their activity were observed with cultured osteoclasts and in animal models. Novel TRACP 5b immunoassays may prove to be of value either as independent or combinatory tools with other bone metabolic markers and BMD measurements in clinical practice and bone research.

Downsizing, Job Insecurity, and Firm Reputation

This paper studies how firms make layoff decisions in the presence of adverse shocks. In this uncertain environment, workers' expectations about their job security affect their on-the-job performance. This productivity effect on job insecurity forces firms to strike a balance between laying off redundant workers and maintaining survivors' commitment when deciding on the amount and timing of downsizing. This framework offers an explanation of conservative employment practices (such as zero or reduced layoffs) based on firms having private information about their future profits. High retention rates and wages can signal that the firm has a bright future, boosting workers' confidence. Moreover, the model provides clear predictions about when waves of downsizing will occur as opposed to one-time massive cuts.

Arginase as a marker of disease severity in human leishmaniasis

The leishmaniases are a group of diseases transmitted by the bite of Leishmania infected female phlebotomine sand flies. The diseases occur in different forms: localized, diffuse and muco-cutaneous leishmaniasis, and visceral leishmaniasis (VL). Inside macrophages, the main host cells of the obligate intracellular Leishmania parasites, nitric oxide synthase and arginase can regulate parasite killing or growth. In experimental leishmaniasis, we previously reported that non-healing disease is associated with higher arginase activity at site of pathology, correlating with local suppression of T cell function. To test whether these data translate to human leishmaniasis, the following study was initiated: I first tested the hypothesis that local suppression of T cell responses observed in persistent CL is associated with arginase induced L-arginine depletion. The results showed that arginase activity is increased at site of pathology compared to peripheral blood mononuclear cells (PBMCs) of LCL patients and intact skin of healthy controls. The phenotype of arginase expressing cells was identified in both compartments as CD15+ CD14|0W low-density granulocytes (LDGs). Finally, high arginase activity at site of pathology observed in cutaneous lesions of patients coincides with downregulation of CD3Ç, CD4 and CD8 molecules in CD4+ and CD8+ T cells at site of pathology. We concluded that increased arginase levels in lesions of LCL patients might contribute to CL pathogenesis by impairing T cell effector function at site of pathology. Next, it was tested whether arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell function through depletion of L- arginine. The results showed that higher level of arginase activity in the PBMC coincides with active phase of VL. Cells expressing arginase in PBMCs were also found to be LDGs. Importantly, increased arginase activity and frequency of degranulated neutrophils coincided with lower plasma L-arginine levels. Furthermore, downregulation of CD3Ç, in T cells correlated with low plasma arginine levels. VL/HIV co-infection is a frequently reported leishmaniasis complication in Ethiopia associated with poor prognosis, with up to 40% mortality rate and high relapse rate. Arginase activity was significantly increased in PBMCs and plasma of VL patients co-infected with HIV than in those having VL alone. Similarly, cells expressing arginase in PBMCs were found to be LDGs. In summary, the results presented here show that increased arginase activity is a marker of disease severity in human leishmaniasis with and without HIV; further, these results suggest that arginase mediated L-arginine depletion may inhibit T cell function and contribute to impaired control of infection. - Les leishmanioses sont un groupe de maladies transmises par la piqûre de mouches des sables femelles, appelées phlébotomes, ayant été infectées par Leishmania. Les maladies se manifestent sous différentes formes: la leishmaniose cutanée localisée, la leishmaniose diffuse et mucocutanée et la leishmaniose viscérale (LV). A l'intérieur des macrophages, les principales cellules hôtes des parasites, l'oxyde nitrique synthase et l'arginase, peuvent contrôler, soit la mort du parasite, soit sa croissance. Pour la leishmaniose expérimentale, nous avons déjà rapporté que le développement de lesions qui ne guérissent pas est associé à une activité plus grande d'arginase au site d'infection, en corrélation avec la suppression locale de la fonction des cellules T. Pour vérifier si ces données pouvaient s'appliquer à la leishmaniose humaine, j'ai d'abord vérifié l'hypothèse selon laquelle la suppression locale des réponses des cellules T observée dans la CL persistante, est associée à la la diminution de L- arginine induite par l'arginase. Les résultats ont montré que l'activité arginase est augmentée au site d'infection, par rapport aux cellules mononucléées du sang périphérique (CMSP) de patients LCL et à la peau intacte des contrôles sains. Le phénotype de cellules exprimant l'arginase a été identifié dans les deux compartiments comme des granulocytes CD15+ et CD 14" de basse densité (LDG). Enfin, l'activité arginase élevée au site de la pathologie, observée dans les lésions cutanées de patients, coïncide avec la reduction dde l'expression des molécules CD3Ç, CD4 et CD8 dans les cellules T CD4+ et CD8+ au site de pathologie . Nous avons conclu que l'augmentation des niveaux d'arginase dans les lésions de patients LCL pourrait contribuer à la pathogenèse de la CL, en altérant la fonction effectrice des celllules T au site de la pathologie. Ensuite, nous avons vérifié si l'arginase, une enzyme associée à l'immunosuppression, était plus élevée chez les patients atteints de VL et si elle contribuait à la mauvaise fonction des cellules T par la depletion en L-arginine. Les résultats ont montré qu'un niveau plus élevé de l'activité arginase dans les PBMC correspond à la phase active de la VL. Les cellules exprimant l'arginase dans les CMSP se sont révélées à être de type LDG . Il est important de souligner que l'augmentation de l'activité arginase et la fréquence des neutrophiles dégranulés a coïncidé avec des niveaux inférieurs de L-arginine plasmatique. En outre, la suppression de CD3Ç dans les cellules T correlle avec de faibles niveaux d'arginine plasmatique . Il a été fréquement rapporté que la co-infection VL/VIH est une complication de la leishmaniose en Ethiopie, associée à un mauvais prognostic, un taux de mortalité pouvant atteindre 40% et un pourcentage élevé de rechutes. L'activité de l'arginase a beaucoup plus augmentée dans les CMSP et le plasma de patients atteints de VL et co-infectés par le VIH, que chez ceux seulement attaints de VL. De même, les cellules exprimant l'arginase dans les CMSP sont aussi des LDG. En résumé, les résultats présentés ici montrent que l'augmentation de l'activité de l'arginase est un marqueur de gravité de la la leishmaniose humaine, avec ou sans VIH ; en outre, ces résultats suggèrent que la déplétion de L-arginine par l'arginase pourrait inhiber la fonction des cellules T et contribuer à un contrôle réduit de l'infection. - Les Leishmanioses sont des maladies parasitaires transmises par la piqûre d'une mouche des sables femelle (phlébotome) infectée par Leishmania. La maladie se manifeste sous différentes formes cliniques : la leishmaniose viscérale, une maladie progressive mortelle en l'absence de traitement, la leishmaniose muco-cutanée (MCL), la leishmaniose cutanée diffuse (LCD ) maladie mutilante, qui peut être de longue durée et la leishmaniose cutanée localisée maladie dont on guérit mais laissant une cicatrice inesthétique à vie. La maladie est largement répandue, elle affecte les populations les plus pauvres dans 98 pays et 350 millions de personnes à risque. Globalement on estime à 500.000 les nouveaux cas de la forme viscérale et 1-1.5 million ceux de la leishmaniose cutanée. La leishmaniose est fortement endémique en Ethiopie et se manifeste dans les formes viscérale et cutanée. Le parasite Leishmania infecte et se multiplie dans les cellules du système immunitaire, principalement les macrophages. Les macrophages sont capables de tuer le parasite Leishmania s'ils reçoivent des instructions correctes de la part d'autres cellules du système immunitaire, les lymphocytes. Les macrophages expriment deux enzymes importants, appelés oxide nitrique synthase inductible (iNOS ) et l'arginase, qui sont respectivement associés à la promotion de la mort du parasite et la multiplication. L'enzyme iNOS présent dans les macrophages métabolise l'arginine afin de générer de l'oxyde d'azote (NO) , une molécule effectrice nécessaire pour tuer le parasite . Au contraire, lorsque les macrophages sont activés d'une certaine manière conduisant à l'augmention de la régulation de l'arginase, ils métabolisent l'arginine en polyamines qui favorisent la croissance du parasite. Au cours du développement de la leishmaniose, les lymphocytes ne parviennent pas à transmettre aux macrophages les signaux nécessaires pour tuer le parasite. Les mécanismes cellulaires qui sont la cause de ce défaut, ne sont pas bien compris. En utilisant des modèles animaux, nous avons montré la régulation à la hausse de l'arginase au site de la pathologie, qui s'est traduit par l'altération de la fonction effectrice des lymphoctes. Nous avons initié des études de leishmaniose humaine en Ethiopie afin d'identifier le rôle de l'arginase dans la sévérité de la maladie. Nos résultats montrent, que l'arginase est fortement augmentée dans la lésion des patients CL, et dans le sang des patients VL et ceux co-infectés par VL / VIH. Le niveau d' arginase régulée à la hausse coincide avec l'expression inférieure d'une molécule de signalisation dans les lymphocytes, qui est essentielle à leur bon fonctionnement. En VL actif, l'augmentation d'arginase se traduit par la diminution de l'arginine qui est indispensable à la synthèse de NO et au bon fonctionnement des lymphocytes. Ainsi, l'incapacité des lymphocytes à envoyer des signaux adéquats aux macrophages pourrait être due à la suppression de l'arginine.

De novo characterization of the Timema cristinae transcriptome facilitates marker discovery and inference of genetic divergence.

Adaptation to different ecological environments can promote speciation. Although numerous examples of such 'ecological speciation' now exist, the genomic basis of the process, and the role of gene flow in it, remains less understood. This is, at least in part, because systems that are well characterized in terms of their ecology often lack genomic resources. In this study, we characterize the transcriptome of Timema cristinae stick insects, a system that has been researched intensively in terms of ecological speciation, but for which genomic resources have not been previously developed. Specifically, we obtained >1 million 454 sequencing reads that assembled into 84,937 contigs representing approximately 18,282 unique genes and tens of thousands of potential molecular markers. Second, as an illustration of their utility, we used these genomic resources to assess multilocus genetic divergence within both an ecotype pair and a species pair of Timema stick insects. The results suggest variable levels of genetic divergence and gene flow among taxon pairs and genes and illustrate a first step towards future genomic work in Timema.