Antibodies Against Human BLyS and APRIL Attenuate EAE Development in Marmoset Monkeys

B lymphocyte stimulator (BLyS, also indicated as BAFF (B-cell activating factor) and CD257), and A Proliferation Inducing Ligand (APRIL, CD256) are two members of the TNF superfamily with a central role in B cell survival. Antibodies against these factors have potential therapeutic relevance in autoimmune inflammatory disorders with a proven pathogenic contribution of B cells, such as multiple sclerosis (MS). In the current study we performed a multi-parameter efficacy comparison of monoclonal antibodies against human anti-BLyS and anti-APRIL in a common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE). A MS-like disease was induced by immunization with recombinant human myelin/oligodendrocyte glycoprotein (rhMOG) in complete Freund's adjuvant. The results show that the anti-BLyS and anti-APRIL antibody cause significant depletion of circulating CD20+ B cells, but a small subset of CD20 + CD40highB cells was not depleted. Induction of CD20+ B cell depletion from lymph nodes was only observed in the anti-BLyS treated monkeys. Both antibodies had a significant inhibitory effect on disease development, but all monkeys developed clinically evident EAE. Anti-BLyS treated monkeys were sacrificed with the same clinical signs as saline-treated monkeys, but nevertheless displayed significantly reduced spinal cord demyelination. This effect was not observed in the anti-APRIL treated monkeys. The two antibodies had a different effect on T cell subset activation and the profiles of ex vivo released cytokines. In conclusion, treatment with anti-BLyS and anti-APRIL delays the development of neurological disease in a relevant preclinical model of MS. The two mAbs achieve this effect via different mechanisms

Municipal mortality due to thyroid cancer in Spain

BACKGROUND: Thyroid cancer is a tumor with a low but growing incidence in Spain. This study sought to depict its spatial municipal mortality pattern, using the classic model proposed by Besag, York and Mollié. METHODS: It was possible to compile and ascertain the posterior distribution of relative risk on the basis of a single Bayesian spatial model covering all of Spain's 8077 municipal areas. Maps were plotted depicting standardized mortality ratios, smoothed relative risk (RR) estimates, and the posterior probability that RR > 1. RESULTS: From 1989 to 1998 a total of 2,538 thyroid cancer deaths were registered in 1,041 municipalities. The highest relative risks were mostly situated in the Canary Islands, the province of Lugo, the east of La Coruña (Corunna) and western areas of Asturias and Orense. CONCLUSION: The observed mortality pattern coincides with areas in Spain where goiter has been declared endemic. The higher frequency in these same areas of undifferentiated, more aggressive carcinomas could be reflected in the mortality figures. Other unknown genetic or environmental factors could also play a role in the etiology of this tumor

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Numerical approximation of viscous contact problems applied to glacial sliding

Viscous contact problems describe the time evolution of fluid flows in contact with a surface from which they can detach and reattach. These problems are of particular importance in glaciology, where they arise in the study of grounding lines and subglacial cavities. In this work, we propose a novel numerical method for solving viscous contact problems based on a mixed formulation with Lagrange multipliers of a variational inequality involving the Stokes equations. The advection equation for evolving the geometry of the domain occupied by the fluid is then solved via a specially-built upwinding scheme, leading to a robust and accurate algorithm for viscous contact problems. We first verify the method by comparing the numerical results to analytical results obtained by a linearised method. Then we use this numerical scheme to reconstruct friction laws for glacial sliding with cavitation. Finally, we compute the evolution of cavities from a steady state under oscillating water pressures. The results depend strongly on the location of the initial steady state along the friction law. In particular, we find that if the steady state is located on the downsloping or rate-weakening part of the friction law, then the cavity evolves towards the upsloping section, indicating that the downsloping part is unstable

Apolipoprotein-E modulates the cytotoxic effect of beta-amyloid on rat brain endothelium in an isoform-dependent specific manner

Several studies support the hypothesis that apolipoprotein-E (ApoE) acts as a pathological chaperone protein that promotes the beta-plated sheet conformation of beta-amyloid (Abeta) peptides into amyloid fibers. In vitro evidence is also available that ApoE inhibits the neurotoxic effect of Abeta in an allele-specific manner (E2 >/= E3 > E4). We have recently shown that Abeta peptides exert a time- and concentration-dependent toxic effect on rat neuromicrovascular endothelial cells (NECs), and this study aimed to ascertain whether ApoE isoforms are able to modulate this effect. ApoE2 and ApoE4 decreased and increased, respectively, the cytotoxic effect of Abeta(1-40) and Abeta(1-42) on NECs, as evaluated by their survival and viability rates. The toxic effect of both Abeta peptides and ApoE4 was associated with the rise in the necrosis rate of NECs within a 24-h incubation period. Moreover, ApoE2 prevented and ApoE4 magnified the inhibitory effect of Abeta on the capability of NECs cultured on Matrigel to form a capillary-like network. The opposite effects of ApoE isoforms could be due to their different interactions with the C-terminal domain of Abeta. ApoE2, at variance with ApoE4, is thought to form sodium dodecyl sulphate-stable complexes with Abeta and, as a consequence, it could block the interactions of the non-fibrillar Abeta peptide with the plasma membrane, Abeta peptide aggregation and the ensuing cytotoxicity. Collectively, our findings confirm the view that ApoE plays a relevant role in the pathogenesis of Alzheimer's disease

Identification and localization of adrenomedullin-storing cardiac mast cells

Adrenomedullin (AM), a potent vasodilatory hypotensive peptide, is expressed in the heart, where it is known to play a protective action. Light-microscopy immunocytochemistry (ICC) demonstrated the presence of AM immunoreactivity not only in the coronary-vessel wall and ventricular myocytes of the human and rat heart, but also in sparse voluminous cells located in the perivascular space. These cells displayed the same location of toluidine blue-positive mast cells, and electron microscopy ICC showed AM-immunogold staining over the granules of rat cardiac mast cells. The incubation of rat left ventricle fragments with the mast-cell histamine releaser compound 48/80 evidenced groups of AM-positive cells undergoing degranulation and caused an increase of approximately 50% in the AM concentration in the incubation medium. Collectively, our findings provide evidence that at least a subset of cardiac mast cells are able to synthesize and store AM, and upon stimulation to release it near coronary arterioles and venules