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Recently envisaged high-temperature superconductor (HTS) applications rely on their radio-frequency properties in very high magnetic fields. As an example, coating of surfaces facing particle beams with HTS for reducing the beam coupling impedance is being considered for the next generation of hadron colliders, such as the FCC-hh at CERN, where HTS would be exposed to the high-frequency wakefields generated by the particle bunches and to the strong field (>16 T) of the steering magnets. Other considered applications are radio-frequency cavities for axion detection as well as capture cavities for muon colliders. In these applications, it is important to keep under control the level of the nonlinear effects, always present using superconductors. In this frame, we developed a simple model for the calculation of the radio-frequency behavior of HTS exposed to a strong external magnetic field, which takes into account the nonlinearity of the pinning potential of the Abrikosov vortices. In particular, we calculate the surface resistance as a function of the impressed radio-frequency current and the harmonic content of the electric field produced by vortex oscillation as a function of the nonlinearity level of the assumed potential. The calculations are compared with recent experimental data on YBCO tapes’ nonlinear behavior.

Within the healthcare landscape, clinical nutrition is pivotal. However, knowledge gaps in nutritional expertise remain among professionals. This study assesses the efficacy of active teaching methodologies among Master's students.

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Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus.

Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone.

The unprecedented success of image reconstruction approaches based on deep neural networks has revolutionised both the processing and the analysis paradigms in several applied disciplines. In the field of digital humanities, the task of digital reconstruction of ancient frescoes is particularly challenging due to the scarce amount of available training data caused by ageing, wear, tear and retouching over time. To overcome these difficulties, we consider the Deep Image Prior (DIP) inpainting approach which computes appropriate reconstructions by relying on the progressive updating of an untrained convolutional neural network so as to match the reliable piece of information in the image at hand while promoting regularisation elsewhere. In comparison with state-of-the-art approaches (based on variational/PDEs and patch-based methods), DIP-based inpainting reduces artefacts and better adapts to contextual/non-local information, thus providing a valuable and effective tool for art historians. As a case study, we apply such approach to reconstruct missing image contents in a dataset of highly damaged digital images of medieval paintings located into several chapels in the Mediterranean Alpine Arc and provide a detailed description on how visible and invisible (e.g., infrared) information can be integrated for identifying and reconstructing damaged image regions.

Background: Iron deficiency anemia (IDA) is relatively common in the third trimester of pregnancy, but causal associations with low birth weight and compromised neonatal iron status are difficult to establish in human populations. Objective: The objective was to determine the effects of diet-induced IDA on intrauterine growth and neonatal iron status in an appropriate animal model for third-trimester IDA in women. Design: Hematologic and iron-status measures, pregnancy outcomes, and fetal and neonatal evaluations were compared between pregnant rhesus monkeys (n = 14) fed a diet containing 10 [micro]g Fe/g diet from the time of pregnancy detection (gestation days 28-30) and controls (n = 24) fed 100 [micro]g Fe/g diet. Results: By the third trimester, 79% of the iron-deprived dams and 29% of the control monkeys had a hemoglobin concentration < 11 g/dL There were also significant group differences in hematocrit, mean corpuscular volume, transferrin saturation, serum ferritin, and serum iron. At birth, the newborns of monkeys iron-deprived during pregnancy had significantly lower hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin values and a lower ratio of erythroid to total colony-forming units in bone marrow than did the control newborns. Pregnancy weight gain did not differ significantly between the iron-deprived and control dams, and the fetuses and newborns of the iron-deprived dams were not growth retarded relative to the controls. Gestation length, the number of stillbirths, and neonatal neurobehavioral test scores did not differ significantly by diet group. Conclusion: These data indicate that an inadequate intake of iron from the diet during pregnancy in rhesus monkeys can lead to compromised hematologic status of the neonate without indications of growth retardation or impaired neurologic function at birth. KEY WORDS Iron deficiency, pregnancy, rhesus monkeys, intrauterine growth retardation, anemia

Sarcoidosis is a systemic inflammatory disease of unknown etiology. The pathogenesis rests on an aberrant T cell response to unidentified antigens in individuals predisposed by genetic and environmental factors. Increased expression of polarized macrophages and disequilibrium between effector and regulator T cells contribute to the formation of noncaseating granulomas, that are frequently found in affected organs. The main kidney abnormalities in sarcoidosis are granulomatous interstitial nephritis (GIN) and hypercalcemia-related disorders. The clinical diagnosis is difficult. The outcome is variable, ranging from spontaneous remission to end-stage kidney disease (ESKD). Early diagnosis and prompt treatment with corticosteroids can improve the prognosis. Hypercalcemia may be responsible for acute kidney injury (AKI) caused by vasoconstriction of afferent arterioles. Complications of persistent hypercalcemia include nephrocalcinosis and renal stones. In patients with ESKD, dialysis and transplantation can offer results comparable to those observed in patients with other causes of kidney failure. Based on a review of the literature, we present an overview of the etiopathogenesis, the renal manifestations of sarcoidosis and their complications, management and prognosis.

Purpose: To evaluate the post- coronavirus disease-19 (COVID-19) outcome of thyroid function in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyrotoxicosis. Methods: This was a single-center prospective study involving 29 patients (11 females, 18 males; median age 64 years, range: 43–85) with thyrotoxicosis diagnosed after hospitalization for COVID-19 and then followed-up for a median period of 90 days (range: 30–120) after hospital discharge. At follow-up, patients were evaluated for serum thyrotropin (TSH), free-thyroxine (FT4), free-triiodiothyronine (FT3), TSH receptor antibodies (TRAb), thyroglobulin antibodies (TgAb), thyroperoxidase antibodies (TPOAb) and ultrasonographic thyroid structure. Results: After recovery of COVID-19, serum TSH values significantly increased (P&lt; 0.001) and FT4 values significantly decreased (P= 0.001), without significant change in serum FT3 (P= 0.572). At follow-up, 28 subjects (96.6%) became euthyroid whereas overt hypothyroidism developed in one case. At the ultrasound evaluation of thyroid gland, hypoecogenicity was found in 10 patients (34.5%) and in these cases serum TSH values tended to be higher than those without thyroid hypoecogenity (P= 0.066). All subjects resulted to be negative for TgAb, TPOAb and TRAb. Conclusion: In a short-term follow-up, thyroid function spontaneously normalized in most subjects with SARS-CoV-2-related thyrotoxicosis. However, thyroid hypoecogenicity was found in a remarkable number of them and future longer-term studies are needed to clarify whether this ultrasonographic alteration may predispose to develop late-onset thyroid dysfunction.

Staphylococcus aureuscolonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominisA9 (ShA9), a bacterium isolated from healthy human skin, as a topical therapy for AD. ShA9 killed S. aureuson the skin of mice and inhibited expression of a toxin from S. aureus(psmα) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical ShA9 or vehicle on the forearm skin of 54 adults with S. aureus-positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving ShA9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with ShA9 but a significant decrease in S. aureusand increased ShA9 DNA were seen and met secondary endpoints. Some S. aureusstrains on participants were not directly killed by ShA9, but expression of mRNA for psmα was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureusdirectly killed by ShA9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.

ABSTRACTIn a sub-study of a clinical trial (NCT01737710) investigating the immunogenicity of trivalent inactivated influenza vaccine (IIV3) administered intradermally or intramuscularly to individuals with atopic dermatitis (AD), we assessed T cell and antigen-presenting cell (APC) responses to influenza B in AD and Non-AD controls. The comparison of IFN-γ ELISpot in 58 AD and 31 Non-AD showed lower responses in AD pre-vaccination. Pre-vaccination, AD also had lower Th2 responses and less inflammatory cytokine production by APC measured by flow cytometry and cytokine levels in culture supernatants. AD also had lower Th1 and Th2 responses to nonspecific anti-CD3/anti-CD28-stimulation, but these were not significantly correlated with the influenza-specific responses, suggesting a primary role for the APC in the decreased influenza-specific T cell responses. Multivariate modeling of influenza-specific responses pre-vaccination with influenza-specific antibody titers and IFN-γ ELISpot as outcome measures identified several T cell and APC subsets that negatively or positively predicted protective responses to the vaccine. However, none of the functional differences between AD and Non-AD had high predictive value on adaptive responses to influenza vaccine, which was in agreement with the overall similar responses to the vaccine in the parent clinical trial.

African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus.

Although pets are found in more than 50% of US homes, the effect of pet allergen exposure on asthma morbidity in the US population is not well documented.

The last 50 years have seen an impressive development of mathematical methods for the analysis and processing of digital images, mostly in the context of photography, biomedical imaging and various forms of engineering. The arts have been mostly overlooked in this process, apart from a few exceptional works in the last 10 years. With the rapid emergence of digitisation in the arts, however, the arts domain is becoming increasingly receptive to digital image processing methods and the importance of paying attention to this therefore increases. In this paper we discuss a range of mathematical methods for digital image restoration and digital visualisation for illuminated manuscripts. The latter provide an interesting opportunity for digital manipulation because they traditionally remain physically untouched. At the same time they also serve as an example for the possibilities mathematics and digital restoration offer as a generic and objective toolkit for the arts.

Conventional data analysis of flow cytometry‐based basophil activation testing requires repetitive, labor‐intensive analysis that hampers efforts to standardize testing for clinical applications. Using an open‐source platform, we developed and implemented a programmatic approach to the analysis of the basophil activation test (BAT) by flow cytometry. Using the BÜHLMANN FlowCAST® assay, peripheral blood from peanut allergic patients undergoing oral immunotherapy was incubated with peanut allergens (Arah1, Arah2, Arah6, whole peanut extract) and stained with fluorescent antibodies to CCR3 and CD63 for the development of a data‐driven programmatic analysis using Bioconductor and R. Basophil identification using clustering and classification was validated using manually gated comparisons in an experimental subset. Reproducibility of CD63 upregulation set on unstimulated or anti‐FcERI stimulated basophils was compared. BAT analysis of 294 experiments was successful in 91.5% using the above approach, with a total of 7,166 individual basophil activation tests from 269 experiments. We estimate this represents a net saving of 1340 min of labor by a skilled operator. Medium‐based gating correlated to respective manual gating more closely than anti‐FcERI based gating (R= 0.96 vs. R= 0.84, P< 0.001). Only 2% of the basophil activation results were significantly different from manual gating. Quality measures of the experiments and other measures of basophil activation were also provided by the analysis. We present a novel data‐driven flow cytometric platform for the analysis of clinical basophil activation testing, providing a high throughput objective approach to basophil activation analysis. © 2017 International Clinical Cytometry Society

Giant adrenal cysts represent very rare clinical cases that are normally incidentally discovered and occur extremely rarely among pediatric patients. This case reports a patient who presented with generalized intestinal complaints and GI bleeding. Ultrasound and MRI were performed and identified a giant right retroperitoneal cyst (9.2 cm × 10.5 cm x 11.7 cm). The patient underwent laparoscopic surgery with complete removal of the cyst from the right adrenal gland. Pathologic evaluation confirmed a benign adrenal cyst.

The Learning Early About Peanut Allergy (LEAP) study team developed a protocol-specific algorithm using dietary history, peanut-specific IgE, and skin prick test (SPT) to determine peanut allergy status if the oral food challenge (OFC) could not be administered or did not provide a determinant result.

The machine recognition of user trajectories and activities is fundamental to devise context-aware applications for support and monitoring in daily life. So far, tracking and activity recognition were mostly considered as orthogonal problems, which limits the richness of possible context inference. In this work, we introduce the novel unified computational and representational framework S-SMART that simultaneously models the environment state (semantic mapping), localizes the user within this map (tracking), and recognizes interactions with the environment (activity recognition). Thus, S-SMART identifies which activities the user executes where (e.g., turning a handlenext to a window), and reflects the outcome of these actions by updating the world model (e.g., the window is now open). This in turn conditions the future possibility of executing actions at specific places (e.g., closing the windowis likely to be the next action at this location). S-SMART works in a self-contained manner and iteratively builds the semantic map from wearable sensors only. This enables the seamless deployment to new environments.We characterize S-SMART in an experimental dataset with people performing hand actions as part of their usual routines at home and in office buildings. The framework combines dead reckoning from a foot-worn motion sensor with template-matching-based action recognition, identifying objects in the environment (windows, doors, water taps, phones, etc.) and tracking their state (open/closed, etc.). In real-life recordings with up to 23 action classes, S-SMART consistently outperforms independent systems for positioning and activity recognition, and constructs accurate semantic maps. This environment representation enables novel applications that build upon information about the arrangement and state of the user’s surroundings. For example, it may be possible to remind elderly people of a window that they left open before leaving the house, or of a plant they did not water yet, using solely wearable sensors.

Investigations have suggested degradation of native hyaluronan (HA) into small oligosaccharides as being involved in the development and progression of inflammatory diseases, particularly rheumatoid arthritis (RA). Inflammatory responses occur by modulating the TLR4 and 2, and the CD44 natural HA receptor. As reported recently, the adenosine A2 receptor (A2AR) plays an important anti-inflammatory role in arthritis. TLR4, TLR2 and CD44 stimulation activate NF-κB, which stimulates the production of pro-inflammatory cytokines and other mediators. In contrast, A2AR stimulation inhibits NF-κB activation. The aim of this study was to investigate the effect of combined treatment of HA inhibitor Pep-1 and a selective A2AR agonist (CV-1808) in collagen-induced arthritis (CIA) in mice. Arthritis was induced via intradermal injection of bovine collagen-II. Mice were treated with Pep-1 plus CV-1808 intraperitoneally daily for 20 d. CIA increased TLR4, TLR2, CD44 and A2AR mRNA expression and the related proteins in the joint cartilage of arthritic mice, where significantly increased concentrations were of TNF-α, IL-1-β, IL-17, matrix metalloprotease-13 and inducible nitric oxide synthase. Pep-1 with CV-1808 treatment significantly reduced CIA damage and all the up-regulated biochemical parameters. These reductions were supported by microscopic analysis and synovial fluid HA levels.

Most approaches to recognize human activities rely on pattern recognition techniques that are trained once at design time, and then remain unchanged during usage. This reflects the assumption that the mapping between sensor signal patterns and activity classes is known at design-time. This cannot be guaranteed in mobile and pervasive computing, where unpredictable changes can often occur in open-ended environments. Run-time adaptation can address these issues. We introduce and formalize a data processing architecture extending current approaches that allows for a wide range of realizations of adaptive activity recognition systems. The adaptiveactivity recognition chain (adARC) includes self-monitoring, adaptation strategies and external feedback as components of the now closed-loop recognition system. We show an adARC capable of unsupervised self-adaptation to run-time changing class distributions. It improves activity recognition accuracy when sensors suffer from on-body displacement. We show an adARC capable of adaptation to changing sensor setups. It allows for scalability by enabling a recognition systems to autonomously exploit newly introduced sensors. We discuss other adaptive recognition systems within the adARC architecture. The results outline that this architecture frames a useful solution space for the real-world deployment of adaptive activity recognition systems. It allows to present and compare recognition systems in a coherent and modular manner. We discuss the challenges and new research directions resulting from this new perspective on adaptive activity recognition.

4-mer hyaluronan (HA) oligosaccharides stimulate pro-inflammatory effects in different cell types by interacting with both the toll-like receptor-4 (TLR-4) and -2 (TLR-2). This interaction induces the activation of the transforming growth factor activated kinase-1 (TAK-1) that activates the nuclear factor kappaB (NF-kB) either directly and/or through the activation of p38-mitogen-activated protein kinase (p38-MAPK). This in turn induces the transcription of proinflammatory mediators that prime inflammation. Our aim was to investigate the involvement of TAK-1 and p38-MAPK in 4-mer HA oligosaccharide-induced inflammatory response in mouse synovial fibroblasts obtained from normal DBA/J1 mice (NSF) and from mice subjected to collagen-induced arthritis (CIA). Treatment of NSF and rheumatoid arthritis synovial fibroblasts (RASF) with 4-mer HA showed a marked up-regulation of TLR-4, TLR-2, TAK-1 and p38-MAPK mRNA expression and of the related proteins, as well as NF-kB activation. High levels were also detected of TNF-α, IL- 1β, MMP-13 and iNOS. Treatment of NSF and RASF, previously stimulated with 4-mer HA oligosaccharides, with TAK- 1 and/or p38-MAPK specific inhibitors significantly reduced all the parameters, although the inhibitory effect of p38- MAPK was less effective than that of TAK-1. The addition of CD44 antibody to both NSF and RASF showed that CD44 was not involved in 4-mer HA-induced inflammation.

Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.

Designing human activity recognition systems, an integral part of any ambient assisted living environment, is an active area of research in the ubiquitous computing, wearable sensing, and computer vision communities. Yet most of the systems ignore human body motion and arm motion action primitives to recognize high-level human activities and are limited to object usage action primitives. Consequently, there is little understanding of the significance of these action primitives on the performance of activity recognition systems. In this paper, we comparatively assess the role of the object usage action primitives, body motion action primitives, and arms motion action primitives to recognize human activities of daily living. Our experiments show that the body motion action primitives and arms motion action primitives are vital to recognize the human activities that do not involve much interaction with the objects and the environment.

Hyaluronan (HA) oligosaccharides stimulate pro-inflammatory responses in different cell types by modulating both cluster determinant 44 (CD44) and TLR4. The activation of these receptors is also mediated by collagen-induced arthritis (CIA) that, via two different pathways, culminates in the liberation of NF-κB. This then stimulates the production of pro-inflammatory cytokines, including IL-18 and IL-33, that are greatly involved in rheumatoid arthritis. The aim of this study was to investigate the effects of 6-mer HA oligosaccharides on mouse synovial fibroblasts obtained from normal DBA/J1 mice or mice subjected to CIA. Compared with normal synovial fibroblasts (NSF), rheumatoid arthritis synovial fibroblasts (RASF) showed no up-regulation of CD44 and TLR4 mRNA expression and the related proteins, as well as no activation of NF-κB. Very low levels of both mRNA and related proteins were also detected for IL-18 and IL-33. Treatment of NSF and RASF with 6-mer HA oligosaccharides significantly increased all the parameters in both fibroblast groups, although to a greater extent in RASF. The addition of hyaluronan binding protein to both NSF and RASF inhibited HA activity and was able to reduce the effects of 6-mer HA oligosaccharides and the consequent inflammatory response.

Hydroxyurea has enhanced the treatment for children with sickle cell anemia. The objectives of this study were to compare perioperative transfusions and outcomes for children taking hydroxyurea versus those not taking hydroxyurea. We retrospectively reviewed perioperative management and outcomes for 51 children with sickle cell anemia (HbSS genotype) who underwent surgery in our center between January 2003 and April 2008. Of the 51 patients, 30 (59) were taking hydroxyurea and 21 (41) were not taking hydroxyurea. Eight of 30 (27) in the hydroxyurea group were not transfused preoperatively, 12 of 30 (40) received a single transfusion and 10 of 30 (33) received serial transfusions, compared with 1 of 21 (5) children in the nonhydroxyurea group who was not transfused, 2 of 21 (10) who received a single transfusion and 18 of 21 (85) who received serial transfusions or pheresis (P=0.004; for comparison across groups). One patient not taking hydroxyurea developed a delayed hyperhemolytic transfusion reaction, and 2 children taking hydroxyurea developed acute chest syndrome. Overall, children taking hydroxyurea had substantially fewer transfusions compared with children not taking hydroxyurea. Both groups of children had a low complication rate. Further research should be done to optimize perioperative management of children taking hydroxyurea.

Hydroxyurea is a safe and efficacious medication for children with sickle cell disease (SCD). Our objective was to compare health-related quality of life (HRQL) between children taking hydroxyurea and those not taking hydroxyurea. We conducted a retrospective cohort study of children with SCD who had completed the PedsQL 4.0 at Duke University Medical Center or the Midwest Sickle Cell Center. Our primary outcome was HRQL in children receiving hydroxyurea therapy compared with those not receiving hydroxyurea. One hundred and ninety-one children with SCD were included in the study. Children in the hydroxyurea group had higher self-reported Total PedsQL median scores than children in the no hydroxyurea group (P=0.04). Child self-reported physical functioning scores were significantly higher for children in the hydroxyurea group (P=0.01). In conclusion, children with SCD who received hydroxyurea therapy reported better overall HRQL and better physical HRQL than children who did not receive this therapy despite disease severity. Further research assessing the impact of hydroxyurea therapy on HRQL, such as prospective assessment over time, would aid in our understanding of the effectiveness of hydroxyurea for individual children. Ultimately, this may aid in decreasing the barriers to the use of hydroxyurea.

Hyaluronan is a biological polysaccharide that may exist in different degrees of polymerization. Several investigations reported that low molecular mass hyaluronan may have pro-inflammatory activity, while high molecular mass hyaluronan can exert beneficial effects. Starting from these data, the aim of this study was to investigate the effect of hyaluronan of different molecular mass in mouse articular chondrocyte cultures stimulated with lipopolysaccharide (LPS). Inflammation was induced in chondrocytes by acute treatment with 2.0 µg/ml LPS. High levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ and iNOS gene expression and their related proteins were found in chondrocytes 24 h after treatment with LPS. High concentrations of NO, NF-κB activation, IκBα phosphorylation and apoptosis, evaluated by the increase in caspase-3 expression and its related protein amount were also produced by LPS stimulation. In contrast, LPS reduced aggrecan and collagen type II (Col2A) expression and their protein production. The treatment of chondrocytes with hyaluronan of different molecular mass produced the following effects: (i) low molecular mass hyaluronan exerted a slight inflammatory effect in untreated chondrocytes, while in LPS-treated chondrocytes it enhanced cytokine production and decreased aggrecan and Col2A compared with cells treated with LPS alone; (ii) no effect was exerted on LPS-induced apoptosis and NO production; (iii) medium molecular mass hyaluronan did not exert any inflammatory/anti-inflammatory activity in LPS-untreated/treated cells and failed to reduce apoptosis; and (iv) high molecular mass hyaluronan had no inflammatory effect in LPS-untreated cells while it was able to reduce all the detrimental effects stimulated by LPS treatment. These data confirm the multifactorial role played by hyaluronan and suggest, in particular, that hyaluronan may modulate inflammation during pathologies by its different degrees of polymerization.

Cytokines such as tumour necrosis factor-α (TNFα), interferon-γ (IFNγ), and transforming growth factor-β (TGF1β) modulate hyaluronan synthase (HAS) gene expression and protein activity. The aim of this research is to evaluate the response of HASgene expression and the related protein synthesis in fibroblasts after treatment with TNFα, IFNγ and TGF1β and to assess the potential protective effect of increased hyaluronan (HA) synthesis during oxidative stress. In this study, gene expression, protein synthesis, hyaluronan content, cell death, lactate dehydrogenase (LDH) activity, membrane lipid peroxidation and endogenous antioxidant depletion are determined for HAS1, HAS2 and HAS3. Messenger RNA (mRNA) expression and protein formation of the three HASgenes is modulated using different cytokines and various doses and correlated with increased HA synthesis. Protection of fibroblasts from injury induced by exposure to reactive oxygen species was significantly increased by TGF1β and was associated with increased gene expression and protein formation of HAS1 and HAS2 enzymes synthesising high-molecular-weight HA. It is proposed that specific HAS enzyme activity and HA molecular weight specificity is involved in the protective mechanism.

Introduction There have been several cases reporting a significant increase in chondroitin sulphate plasma levels in patients with different types of disease, such as systemic lupus erythematosus, rheumatoid arthritis, and liver disease. At present, the precise role of chondroitin sulphate molecules in blood is unclear. Previous investigations have shown that the addition of purified human plasma glycosaminoglycans (GAGs), containing a high percentage of chondroitin-4-sulphate (C4S) was able to inhibit lipid peroxidation and to protect cells from reactive oxygen species damage, suggesting antioxidant activity. Starting from these reports, the aim of this study was to evaluate the effectiveness of GAG structures purified from normal human plasma in reducing inflammation using a model of lipopolysaccharide (LPS)-induced increase of pro-inflammatory cytokines in mouse articular chondrocyte cultures.Results Chondrocyte stimulation with LPS (50 μg/ml) for 24 h enhanced gene expression of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin 6 (IL-6), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS) and increases in their related protein levels, as well as NF-κB activation, IκBα phosphorylation and apoptosis evaluated by the increase in caspase-3 expression and its related protein amount. LPS treatment also generated a high amount of nitric oxide (NO). The addition of different doses of purified human GAGs to LPSstimulated chondrocytes reduced inflammatory cytokines and iNOS both at mRNA and protein levels, blocked NF-κB activation and cytoplasmic IκBα phosphorylation, limited cell death by inhibiting apoptosis, and reduced NO concentrations.Conclusions These results further support the hypothesis that plasma GAGs may function as immunomodulators and their increased release and degradation could be a biological response acting to modulate inflammation during disease.

Histoplasmosis, a granulomatous disease caused by Histoplasma capsulatum, is endemic in Venezuela. We conducted the current study to appraise retrospectively the demographic data, clinical features, diagnostic methods, and treatment of patients with histoplasmosis from January 2000 to December 2005.

Most biological molecules exhibit more than one function. In particular, many molecules have the ability to directly/ indirectly scavenge free radicals and thus act in living organisms as antioxidant. During oxidative stress, the increase of these molecules levels seems to be a biological response that in synergism with the other antioxidant defence systems may protect cells from oxidation. Among these structures, chondroitin sulphate is a biomolecule which has increasingly focused the interest of many research groups due to its antioxidant activity. This review briefly summarises the action of chondroitin sulphate in reducing molecular damage caused by free radicals and associated oxygen reactants.

Abstract: Several reports have shown that a number of cytokines such as tumor necrosis-α (TNF-α), interferon-γ (IFN-γ), and interleukin-β (IL-1β) are capable to induce hyaluronan sinthases (HASs) mRNA expression in different cell culture types. The obvious consequence of this stimulation is a marked increment in hyaluronan (HA) production. It has been also reported that oxidative stress, by itself, may increase HA levels. The aim of this study was to evaluate how TNF-α, IFN-γ,IL−1β, and exposition to oxidative stress may modulate HAS activities in normal human skin fibroblasts. Moreover, the effects on HAS mRNA expression of the concomitant treatment with cytokines and oxidants, and the HA concentrations after treatments, were studied. TNF-α, IFN-γ, and IL-1β were added to normal or/and exposed to FeSO4 plus ascorbate fibroblast cultures and HAS1, HAS2 and HAS3 mRNA content, by PCR-real time, was assayed 3,h later. HA levels were also evaluated after 24,h incubation. The treatment of fibroblasts with cytokines up-regulated HASs gene expression and increased HA production. IL-1β induced HAS mRNA expression and HA production more efficiently than TNF-α and IFN-γ. The exposition of the fibroblasts with the oxidant system markedly increased HAS activities while slightly HA production. The concomitant treatment of cells with the cytokines and the oxidant was able to further enhance, in a dose dependent way, with synergistic effect on HAS mRNA expression. On the contrary HA levels resulted unaffected by the concomitant treatment, and resemble those obtained with the exposure to FeSO4 plus ascorbate only. This lack in HA production could be due to the deleterious action of free radicals on the HA synthesis.

Serum prolactin may reflect CNS dopaminergic function. Because iron deficiency (ID) alters brain dopamine in rats, serum prolactin levels were previously investigated in infants with varied iron status. High serum prolactin levels correlated with behaviors typical of chronic ID. The objective of this study was to determine the effect of infant iron status on serum prolactin levels after a stressor in early adolescence. One hundred fifty-nine of 191 children enrolled in infancy (chronic ID, n = 46; good iron comparison group, n = 113) had serum prolactin measurements after catheter placement at 11–14 y of age. Serum prolactin levels were compared by sex, pubertal status and infant iron status and the pattern of change over time was compared by infant iron status controlling for pubertal stage and background factors. Males and less mature adolescents had lower serum prolactin concentrations than females and more mature adolescents. Controlling for these factors, the serum prolactin response pattern differed significantly by infant iron status. Serum prolactin declined earlier for the chronic ID group. In conclusion, an altered serum prolactin response pattern was observed 10 y after chronic ID in infancy and may suggest a long-lasting effect of ID on the regulation of prolactin.

The main role of superoxide dismutases (SODs) is to eliminate reactive oxygen species in cells and tissues. Extracellular SOD (EC-SOD/SOD3) is a major superoxide scavenger and it is located on cell surfaces and primarily in extracellular matrix, and binds heparan sulfates by its carboxyterminal portion. Human EC-SOD gene is located on chromosome 4 and comprises three exons and two introns. The SOD3 coding sequence is entirely located within exon 3 and has missense polymorphisms. The Arg213Gly mutation affects the function of the carboxyterminus and correlates with several diseases. In this work, we explored genetic variants within EC-SOD gene of subjects living in southern Italy. Four new variations were detected: one was silent mutation, while three were missense variations that give rise to amino acid substitutions at position 131 (F>C), 160 (V>L) and 202 (R>L) in the mature product. The Arg213Gly variant was not found. The missense mutations in the DNA of assayed 2400 chromosomes had frequencies of 5.34% for the F131C variation, 0.25% for the V160L variation and 0.84% for the R202L variation. The effect of these alterations on the metabolic activity and diseases remains to be further explained.

Objectives To compare the antiviral efficacy of a salvage therapy combining lopinavir and amprenavir with 200 mg/d or 400 mg/d ritonavir, together with nucleoside reverse transcriptase inhibitors, over a 26-week period in HIV-infected patients in whom multiple anti-retroviral regimens had failed.Design Phase IIb, randomized, open-label, multicentre trial. Patients were eligible if they had <500 CD4+ cells/mm3and >4 log10copies/ml HIV-RNA after treatment with at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor.Results At baseline (n=37), the median CD4+ cell count was 207/mm3and the median plasma HIV-1 RNA level was 4.7 log10copies/ml; the median number of PI mutations was seven and the median decrease in phenotypic susceptibility to lopinavir and amprenavir was 9.7 and 2.6, respectively. The mean number of antiretrovirals received prior to randomization was 7.7. The fall in the median HIV-1 RNA level at week 26 was -1.4 log10copies/ml in the 200 mg/d ritonavir group and -2.5 log10copies/ml in the 400 mg/d group (P=0.02). Viral load fell below 50 copies/ml in 32% and 61% of patients, respectively (P=0.07). After adjustment for the ritonavir dose, a smaller number of PI mutations was the only baseline characteristic associated with a better virological response at week 26. Amprenavir concentrations were significantly lower in presence of lopinavir. The lopinavir inhibitory quotient at week 6 correlated weakly with the change in the HIV-RNA level at week 26.Conclusion Combination of amprenavir, lopinavir and 400 mg/d ritonavir shows significant virological efficacy without increased toxicity in HIV-infected patients in whom multiple antiretroviral regimens have failed.

Several reports have described a loss of endogenous antioxidants and molecular oxidative damage during acute pancreatitis. Since hyaluronic acid and chondroitin-4-sulfate possess antioxidant properties, the effect of the administration of these glycosaminoglycans in a cerulein-induced acute pancreatitis in rats was investigated. Cerulein administration produced pancreatic edema and a marked increase in serum lipase and amylase activity; induced a severe depletion of reduced glutathione, catalase, and superoxide dismutase levels; primed lipid peroxidation; and promoted neutrophil intervention. Intraperitoneal pretreatment of rats with hyaluronic acid or chondroitin-4-sulfate or with both compounds ameliorated pancreatic cell conditions; restored the endogenous antioxidants reduced glutathione, catalase and superoxide dismutase; limited cell membrane peroxidation; and reduced neutrophil activation. Our data confirm the antioxidant activity of these 2 glycosaminoglycans.

PON gene family includes at least three members termed PON1, PON2 and PON3, and it is mapped on human chromosome 7q21-q22. PON1 and PON3 gene products are constituents of high density lipoprotein (HDL) and have many enzymatic properties and antioxidant activity. PONs are proposed to participate in the prevention of low density lipoprotein (LDL) oxidation. PON1 and PON2 genes have missense polymorphisms, but, to date, no missense variants are reported in PON3 gene. In this work we explored the existence of genetic variants within the PON3 coding sequences. Five point mutations were identified by direct sequencing of genomic DNA derived from 250 randomly selected DNA samples of 1143 blood donors living in southern Italy. Three were silent mutations, while two were missense mutations that give rise to amino acid substitutions at positions 311 ( S > T ) and 324 ( G > D ). The missense variations in the DNA of the 1143 samples had frequencies of 0.22% (5 out of 2286 alleles) for the S311T mutation, and 0.57% (13 out of 2286 alleles) for the G324D mutation. The effect of these variants on the metabolic activity of paraoxonase 3 remains to be further evaluated.

A new method for the analysis of the dispersion behaviour of a transparent medium is presented: the refractive index n is obtained as a function of the wavelength λ: n &equal; n(λ). The procedure is based on the analysis of the hybrid bi-dimensional fringe pattern obtained at the exit plane of a spectrometer which performs the spectral analysis of a white-light interferogram. The phase of the signal depends both on a spatial coordinate and on the chromatic variable wavenumber σ &equal; λ⁻¹. Taking advantage of the dispersion behaviour of the sample, the phase of the signal can be forced to become stationary at certain points of this hybrid plane. The line which joins the stationary phase points stores the parameters of a series expansion of the refractive index as a function of wavenumber. These parameters are experimentally obtained through an appropriate numerical fitting procedure.

Recurring chromosomal abnormalities are detected in most patients with acute myeloid leukemia (AML). They may be associated with a distinct AML FAB subtype or may identify distinct clinicobiological entities within the same FAB subtype. Therefore, cytogenetic investigation has a pivotal role in AML diagnosis. In addition, it is one of the most valuable prognostic determinants of the disease, as recently demonstrated. The development of new molecular techniques, such as reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization, has allowed perfect definition of the chromosome regions containing genes with a crucial role in normal hemopoiesis and leukemia. Understanding the action of such genes provides new insights into AML pathogenesis and has led us to envisage new therapeutic options.