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In the safety risk assessment of genetically modified (GM) crops, it is imperative to evaluate potential unintended effects derived from genetic manipulation. Here, we analyzed the differential proteomic signatures and compositional equivalence of two GM insect- and herbicide-resistant maize cultivars (named here as GM1 and GM2), extensively cultivated and commercialized in Brazil, and their respective conventional counterparts (CON1 and CON2). Complementary 2-DE-based and bottom-up shotgun proteomic analysis were used. All cultivars presented similar chemical compositions between the GMs and CONs, with values expected for Zea maysspecies. A total of 22 and 21 differentially expressed proteins (DEPs) were identified in the 2-DE proteomic analysis for the GM1 vs. CON1 and GM2 vs. CON2 comparisons, respectively. In same order, 11 and 16 DEPs were identified in the bottom-up shotgun proteomic. DEPs were related to various biological processes including metabolism, energy, storage, defense, and cell stress. Vicilin-like embryo storage protein, tubulin, ADP-glucose pyrophosphorylase endosperm large subunit, globulin-1, and cytosolic 3-phosphoglycerate kinase, were consistently identified using both proteomic approaches. Of particular interest, vicilin-like embryo, identified as a natural allergen in maize, was down-regulated in the GM1 event compared to CON1. Our findings provide insights into potential unintended effects revealed through proteomic methodologies, utilizing both gel-based and gel-free techniques to identify alterations in protein abundance influenced by transgenic modification.

ABSTRACTThe objective was to evaluate different levels of crambe cake (CC) protein (0, 250, 500, 750 and 1000 g/kg DM) as a replacement for soybean meal protein in diets for lambs and their effect on performance, carcass traits and meat quality. Forty not castrated crossbred male lambs, weighing 20 ± 3.45 kg, were settled in a completely randomized design with eight replicates per treatment. Final body weight (BW), dry matter intake per kg BW (DMI), DMI over metabolic weight and average daily gain showed linear decreasing effect (p < 0.05), meanwhile, feed efficiency presented a quadratic effect for replacement levels. There was a quadratic effect with replacement levels of CC protein for hot carcass weight; cold carcass weight; cooling loss index; muscle fat thickness; leg perimeter; leg depth and carcass finishing. Hot carcass yield, carcass length; shoulder clods weight, rib weight and the leg weight showed a linear decrease within BW. Bones and muscle weight of shoulder clods showed a decreasing linear effect. Replacing up to 500 g/kg DM of protein of soybean meal protein for CC protein does not affect performance, carcass traits and meat quality.

Unit commitment has been at the center of power system operations for over 50 years. Yet, this problem cannot be considered solved due to its size and complexity. Today, operators rely on off-the-shelf optimization solvers to tackle it, and often resort to simplifications to make the problem tractable and solvable in reasonable times. Nonetheless, despite the simplifications and advancements in commercial optimization solvers, solving the unit commitment in a timely manner is still a challenge. In this work, we propose a parallel dual dynamic integer programming approach for solving this problem. Different from what can be currently found in the literature, our parallel approach is applied to a deterministic problem and thus requires induced parallelization. Our strategy is assessed on 20 cases of a hydrothermal system with over 7,000 buses and it is able to solve all instances to a 0.1% gap in less than two hours with speed-ups up to 9.2 compared to a sequential strategy. We also apply our strategy to a purely thermal, large-scale academic system with 9,241 buses, 16,049 transmission lines and 1,445 generating units, for which our strategy returns a 0.1% solution in less than 30 min.

Psychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. The integration of multimodal biological data could reveal different subtypes of psychosis onset to target for the personalization of care. In this study, we tested the existence of subgroups of patients affected by first-episode psychosis (FEP) with a possible immunopathogenic basis. To do this, we designed a data-driven unsupervised machine learning model to cluster a sample of 127 FEP patients and 117 healthy controls (HC), based on the peripheral blood expression levels of 12 psychosis-related immune gene transcripts. To validate the model, we applied a resampling strategy based on the half-splitting of the total sample with random allocation of the cases. Further, we performed a post-hoc univariate analysis to verify the clinical, cognitive, and structural brain correlates of the subgroups identified. The model identified and validated two distinct clusters: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A and CXCR3); 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). None of the subgroups was related to specific symptoms dimensions or longitudinal diagnosis of affective vs non-affective psychosis. FEP patients included in the balanced immune subgroup showed a thinning of the left supramarginal and superiorfrontal cortex (FDR-adjusted p-values< 0.05). Our results demonstrated the existence of a FEP patients’ subgroup identified by a multivariate pattern of immunomarkers involved in inflammatory activation. This evidence may pave the way to sample stratification in clinical studies aiming to develop diagnostic tools and therapies targeting specific immunopathogenic pathways of psychosis.

We consider a class of multistage stochastic linear programs in which at each stage a coherent risk measure of future costs is to be minimized. A general computational approach based [...]

OVERVIEW: This article presents a case study on MINATEC, a regional innovation cluster in Grenoble, France, encompassing several entities: applied and basic research institutes, a university, and incubation and technology transfer facilities. MINATEC was created to foster development in the field of micro- and nanotechnologies. It is organized in a systemic way intended to make the most of interactions among its institutions to create synergistic relations. Established in 2006, MINATEC operates under an organizational model that connects basic and applied research, higher education, and support for start-ups and technology transfer. These features make MINATEC a relevant case study for both public and private innovation managers. KEYWORDS: Microtechnologies, Nanotechnologies, Clustering, Education, Technology transfer, The geographic clustering of research centers, R&D facilities, institutions for higher education, and enterprise incubators fruitfully promotes flows of knowledge, money, and collaboration while also fostering the growth of the [...]

Managing power production for hydro-dominated electrical energy systems in the long-term horizon is a challenging task that requires a trade-off between costs and electricity shortage risks. Because of the inflow uncertainty, this trade-off can be assessed by an operating policy that determines how much water should be used to generate power at the beginning of each time-step and how much should be stored for the future. The long-term generation scheduling (LTGS) is often solved by system operators using multistage stochastic optimization and stochastic dual dynamic programming (SDDP) approaches. Although the literature related to the LTGS problem is vast, several practical aspects used in SDDP are not demonstrated clearly, which can prevent the interest of young researchers and hinder the advances and new applications usually employed by senior professionals in industry and universities. Thus, this paper provides a tutorial on (but not limited to) (i) the application of SDDP for solving the LTGS problem, including water inflow inter-stage dependence, (ii) assessment of the impacts of hydropower function in the policy and (iii) inclusion of a risk measure to obtain a more reliable operation in unfavorable (dry) inflow scenarios. We present the main ideas behind each aspect's inclusion in the SDDP algorithm, using simple (but comprehensive) numerical examples. The overview is intended to understand these main characteristics, presenting them as powerful tools to investigate the LTGS problem in detail, searching for a good or even (near) optimal operating policy.

The real-time optimal load dispatch (OLD) problem in a hydropower plant aims to determine the generation level of each generating unit (GU) in the most efficient way and a few seconds. Due to the hydro production function (HPF), it is a nonlinear programming (NLP) problem that can be efficiently handled via mixed-integer linear programming (MILP). However, solving the real-time OLD of the Santo Antônio Hydro Plant (SAHP) is particularly challenging, both in terms of modeling and execution time, due to the following issues: (1) there are 50 GUs with different hydraulic efficiency curves; (2) the gross head is dependent of the GU dam location; and (3) significant (and potentially dangerous) losses in the trash racks produced by the Madeira River debris. In this scenario, this paper presents a recommendation system for the real-time OLD of the SAHP based on MILP. In real-time, the system employs gross head and trash rack losses measures to model and solve a MILP problem that obtains the GUs power level to be used by the hydro plant operator. We compare the system solution with the strategy currently used by the plant operator and with the equal dispatch between the identical GUs. The results emphasize the improvement in plant productivity. In the 2019 year, for example, the OLD real-time recommendation system presents a 9852.63 MWh increasing in power energy generation.

Taking oral fluconazole early in pregnancy does not appear to cause fetal anomalies. Short-term, low doses of fluconazole are prescribed to treat vaginal yeast infections. Researchers compared outcomes between 226 pregnant women who called a teratogen hotline because they had taken fluconazole and 452 women who called asking about exposure to harmless substances. Four percent of both groups had infants with anomalies. However, women exposed to fluconazole were five times more likely to have an abortion, suggesting fear may have led them to terminate the pregnancy. Prolonged, high doses cannot be assumed to be equally harmless.

Diabetes is an independent risk factor in the development of atherosclerosis, although the pathophysiological processes underlying this association are poorly understood. The oxidation of low-density lipoprotein (LDL) is considered a [...]

The aim of this 3-month, double-blind, double-dummy, parallel group study was to compare the antihypertensive efficacy and acceptability of perindopril (4-8 mg/day) in 54 patients (30 males, 24 females, 25-68 years of age) and captopril (50-100 mg/day) in 54 patients (39 males, 15 females, 29-66 years of age) in the treatment of essential hypertension. In a subgroup of 38 patients a complete echocardiographic study was performed. The two groups had similar (ANOVA) blood pressure (BP), heart rate (HR), body mass index, and duration of hypertension. Supine and standing BP was significantly reduced by both drugs, without differences between them. Owing to poor control of BP, hydrochlorothiazide (25 mg/day) was added to 27% of patients on perindopril and to 41% of patients on captopril (p

Confluent and reticulated papillomatosis of Gougerot and Carteaud is a rare dermatosis with onset during puberty, more prevalent in females than in males. The pathogenesis is unknown, but some theories suggest either a keratinization or endocrine disorder. The lesions are verrucous, brownish, hyperkeratotic papules or spots that coalesce in a confluent and/or reticulated pattern. This report presents a case with extensive cutaneous involvement associated with acanthosis nigricans and good response to treatment with methotrexate.

Using digitized M-mode echocardiography, the left ventricular (LV) response to acute increase in blood pressure after regression of myocardial hypertrophy due to an effective antihypertensive treatment was evaluated. Fifteen hypertensive patients with basal LV hypertrophy (LV mass > 230 g, and normal LV diastolic diameter) and normal LV mass after 3 to 4 months of treatment with angiotensin-converting enzyme inhibitors were selected for study. Subjects performed a cold pressor test before and after therapy. LV systolic function was normal in all subjects. LV diastolic function (impaired at basal evaluation in 13 subjects) improved after therapy in all subjects, with normalization in 10. Before treatment, the cold pressor test induced significant increases in blood pressure and heart rate without changes in LV parameters. After regression of hypertrophy, the cold pressor test induced increases in hemodynamic parameters comparable to those of the basal test, and LV parameters remained unchanged. Our results indicate that regression of myorcardial hypertrophy induced by angiotensin-converting enzyme inhibitors does not impair the ability of the left ventricle to face acute increases in afterload. The improvements in LV diastolic function (found at rest after reversal of hypertrophy) persists during the cold pressor test, which confirms that it is primarily due to LV mass reduction and is not simply a consequence of decrease in afterload induced by treatment. (Am J Cardiol 1992;69:1439-1441)

We performed an end-to-end process, ranging from design, fabrication, and characterization of integrated polymeric optical devices under a mass production technology. Inverted rib waveguides formed by SU-8 photoresist deposited on top of full wafers, with trenches in silica, were used as a platform to implement such optical devices. Narrowband spectral filters based on microracetrack resonators and diplexers based on directional couplers, both with high extinction ratios, are demonstrated. Full wafers of those devices were processed in a complementary metal-oxide-semiconductor foundry’s 150 mm-facility. We believe the results are promising for applications ranging from telecommunication components to sensing devices.

Extracellular vesicles (EVs) play a major role in cell-to-cell communication in physiological and pathological conditions, and their manipulation may represent a promising therapeutic strategy. Microglia, the parenchymal mononuclear phagocytes of the brain, modulate neighboring cells also through the release of EVs. The production of custom EVs filled with desired molecules, possibly targeted to make their uptake cell specific, and their administration in biological fluids may represent a valid approach for drug delivery. We engineered a murine microglia cell line, BV-2, to release EVs overexpressing the endogenous “eat me” signal Lactadherin (Mfg-e8) on the surface to target phagocytes and containing the anti-inflammatory cytokine IL-4. A single injection of 107IL-4+Mfg-e8+EVs into the cisterna magna modulated established neuroinflammation and significantly reduced clinical signs in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Injected IL-4+Mfg-e8+EVs target mainly phagocytes (i.e., macrophages and microglia) surrounding liquoral spaces, and their cargo promote the upregulation of anti-inflammatory markers chitinase 3-like 3 (ym1) and arginase-1 (arg1), significantly reducing tissue damage. Engineered EVs may represent a biological drug delivery tool able to deliver multiple functional molecules simultaneously to treat neuroinflammatory diseases.

In multi-robot systems, it is commonly used collaborative approaches to solve complex tasks faster and efficiently. In most of those approaches, the decisions are made centralized or require global information about the objective or the robots, limiting many real implementations. The present work is based on a decentralized solution for the Rendezvousproblem, by using only local information about the robots and asymmetrical information about the meeting point. As the primary contribution, we propose a sequential convex programming approach to overcome the non-convexities when physical spaces are taken into account in the optimization problem, which provides the robots with the collision avoidance capability during their movement to the target point. Experiments are also performed to show the effectiveness of the proposed approach.

Supplemental Digital Content is available in the text.

Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients’ quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)–mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs. Transplantation of mouse and human HSPCs transduced with an IL-1RA–encoding LV ensured stable IL-1RA production while maintaining the clonogenic and differentiation capacities of HSPCs in vivo. We examined the efficacy of cell-mediated IL-1RA delivery in three models of IL-1–dependent inflammation, for which treatment hindered neutrophil recruitment in an inducible model of gout, prevented systemic and multi-tissue inflammation in a genetic model of cryopyrin-associated periodic syndromes, and reduced disease severity in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Our findings demonstrate HSPC-mediated IL-1RA delivery as a potential therapeutic modality that can be exploited to suppress tissue and organ inflammation in diverse immune-related diseases involving IL-1–driven inflammation.

what are the right policy tools to help people cut down on so-called 'junk foods'? This question has led to some vigorous political clashes and brought about a new wave [...]

•CSF BACE1 levels are associated with depression and worse visual-spatial memory performance in RR-MS patients.•Higher levels of BACE1 correlate with worse prognosis and disease course of RR-MS patients.•BACE1 influences a group of neuroinflammatory mediators in RR-MS.•BACE1 is involved in mitochondrial dysfunction and oxidative stress mechanisms at the basis of MS pathophysiology.•BACE1 CSF levels correlate with neurodegenerative biomarkers including p-Tau and Aβ 1-42/1-40 ratio, a biomarker of Aβ pathology burden.

Microvesicles released by activated macrophages, and detected in biological fluids, may constitute a valuable biomarker to identify myeloid cell activation phenotype during disease. MVs are known vehicles of horizontal communication among cells, currently under scrutiny as powerful biomarkers in several pathological processes. The potential advantage of MVs relies on the assumption that their content reflects processes ongoing in pathologically relevant cell types. We have described that MVs of myeloid origin in the CSF are a marker of microglia/macrophage activation. Myeloid cells have different activation types, resulting in diverse functional phenotypes. Knowledge on the activation type of myeloid cells during disease would be of paramount importance for the understanding of ongoing pathogenic processes. We show here that macrophages activated in vitro in different ways all release increased amounts of MVs compared with NS cells. Moreover, we show that macrophage‐derived MVs contain a repertoire of mRNAs that is not the result of casual sampling from the parental cells, as it is characterized by distinct mRNA enrichments and species. Nevertheless, mRNA content of MVs clearly allows identification in vivo of the activated phenotype of the cell of origin, indicating carryover of functional macrophage traits. We propose that detection of mRNAs in myeloid MVs permits identification of myeloid cell activation type during disease, allowing for further stratification of pathological processes.

Stochastic programming deals with a class of optimization models and algorithms in which some of the data may be subject to significant uncertainty. Such models are appropriate when data evolve over time and decisions need to be made before observing the entire data stream. Mathematically, this uncertainty is modeled by means of including random variables in the optimization model; however, such strategy demands a different methodological approach in relation to those usually found in deterministic optimization problems. This tutorial focuses on the main methodological aspects of stochastic programming. The long-term hydrothermal scheduling problem is used to present the ideas didactically. Two reasons justify the choice: (i) this problem is inherently stochastic because the generation decisions on hydrothermal systems are directly influenced by the reservoirs’ water availability, which is associated with future inflows uncertainty; (ii) the problem has great practical relevancy as a decision computational model to use the energy resources in an electrical energy system efficiently. Thus, in general terms, this tutorial aims to motivate the use of this important and fascinating methodological tool that is stochastic optimization.

The purpose of this paper is to measure and analyse the rate of scientific and technological advance of some emerging nanotechnological research fields in biomedicine to detect path-breaking technological trajectories. The approach, based on exponential models of growth, shows the current evolutionary trends of nano-research that may underpin future patterns of technological innovation in biomedicine and nanomedicine. In particular, results show that biosensors, quantum dots, carbon nanotubes and nanomicelles have innovative applications in diagnostics and targeted therapies for cancers that have been generating a revolution in clinical practice. The present study also detects two main determinants that have been supporting continuous diffusion of nano-technology in biomedicine: convergence of genetics, genomics and nanotechnology and multiplicity of learning processes in clinical research/practice. These drivers have been paving groundbreaking pathways in biomedicine that can lead to longer, better and healthier living of societies in not-too-distant future.

This study aimed to evaluate the effect of application of microbial transglutaminase (MTGase) in breadmaking, through the development of ideal formulation, with combinations of additives and enzyme, and the evaluation of the effect of the enzyme on proteins. To verify the enzyme effects, three formulations were tested: Base formulation, characterized by the absence of enzyme and emulsifying agents (bread Zero); Control formulation, comprised by the presence of emulsifying agents and ascorbic acid (bread Control), and the formulation prepared with the Base formulation and enzyme (bread MTGase). Protein fractions of gliadins, glutenin and waste extraction were obtained from samples of flour, dough and bread. The gliadins and glutenin were analyzed by RP-HPLC (reversed phase high performance liquid chromatography). The best formulation was obtained using a experimental design, with variations in the concentrations of emulsifying agents, ascorbic acid and enzyme. The results were evaluated by response surface methodology, which values are 0.6% of transglutaminase, 0.2% of emulsifying agent and 70ppm of ascorbic acid. The analysis of gliadins fractions showed about 3% protein, dry basis, and glutenins fractions were between 2 and 5% protein. The results indicated that the enzyme modified chemical and functional properties of glutenins fraction, improving dough strength and bread volume. Results of total nitrogen content, and chromatographic profiles of the protein fractions suggest that while glutenins proteins were modified by enzyme, gliadins proteins were not affected.

The experience of noninvasive positive pressure ventilation (NPPV) in the pediatric setting is limited. The aim of the present study is to retrospectively evaluate the effectiveness of NPPV in pediatric immunocompromised patient admitted in our PICU (Pediatric Intensive Care Unit) for acute respiratory failure.

AbstractObjective: Treatment with interferon (IFN) of patients affected by chronic hepatitis C (CH-C) may produce alterations in thyroid function, such as hypothyroidism, Graves’-like hyperthyroidism and destructive thyrotoxicosis (DT). IFN-induced DT is characterized by suppressed serum TSH levels, normal or elevated FT4 and FT3 concentrations, with the presence or absence of thyroid peroxidase antibodies and antithyroglobulin antibodies, the absence of thyroid receptor antibodies and radioactive iodine uptake suppressed or &lt;5%. Design: IFN-induced DT is a mild clinical disease, because thyroid-destructive processes last for a short time and involve a small portion of the gland. At present, the therapeutic approach in DT suggests IFN withdrawal and 1–2 months of methylprednisolone treatment. Methods: In consideration of possible untoward side effects of steroid treatment in patients with CH-C, we studied two groups of patients with CH-C who developed DT after treatments with various preparations of recombinant IFN (with or without ribavirin). Patients sequentially entered the study during a 4-year period, at the time of DT diagnosis, when IFN therapy was discontinued. The first 12 subjects (group A) were treated with 8–16 mg/day methylprednisolone for 30–40 days after IFN withdrawal; in the following 15 patients (group B), IFN withdrawal was not followed by any additional treatment. All patients underwent clinical and laboratory controls of thyroid function at 1, 2, 3 and 6 months after DT diagnosis. Results: The results showed restoration of euthyroidism in both group A and group B patients at 6 months after DT diagnosis, regardless of steroid treatment. Conclusions: The simple withdrawal of IFN therapy in patients with CH-C, who had developed DT, appears to be effective in the treatment of the thyroid disease. This therapeutic approach should be preferred in order to avoid possible undesired side effects of steroid therapy in patients with CH-C.Copyright © 2005 S. Karger AG, Basel

Introduction:Impairment in growth hormone (GH) secretion has been reported to occur in primary hyperparathyroidism (PHP) with strikingly elevated (>150 pg/ml) plasma PTH and free Ca levels. Patients with these characteristics are relatively few, whereas the great majority of patients with biochemically diagnosed PHP are asymptomatic and show borderline or slightly elevated plasma PTH and Ca levels. We wondered whether also patients in these latter conditions show a defective GH secretory pattern. Methods:In order to answer this question, 8 female subjects (mean age ± SE: 44 ± 1.3 years) were selected at the time of a checkup examination from a larger population of persons in fairly good clinical condition. Inclusion criteria were plasma PTH values slightly above the normal range (up to 50% higher than the maximum limit) with free Ca levels in the upper normal range or slightly higher (experimental group). Normal values in our laboratory are ionized calcium: 1.22–1.42 mmol/ml and plasma PTH: 12–72 pg/ml. A group of 15 age-matched healthy women with plasma PTH and Ca levels in the middle normal range and significantly lower than values found in the experimental group was also selected and used as control. Experimental and control groups were tested with arginine [0.5 mg/kg body weight (BW)] infused intravenously over 30 min and arginine plus GH-releasing hormone (GHRH; 1 µg/kg BW in an intravenous bolus injection). The GH responses to these challenging stimulations were compared between groups. Results:Basal serum GH values were similar in all subjects. Both arginine and arginine plus GHRH induced a significant GH rise in both groups; however, the GH responses were significantly lower in the experimental than in the control group. Mean GH peak was 27.7 and 14.6 times higher than baseline after arginine and 57.5 and 26.6 times higher than baseline after arginine plus GHRH in the control and experimental group, respectively. No significant correlation was observed between PTH or Ca levels and the GH responses to challenging stimuli in any group. Conclusion:These data show that impairment in GH secretion is associated with slightly elevated levels of PTH in the presence of serum Ca values in the upper normal range. GH responses to stimulations were reduced by about 50% in our hyperparathyroid subjects. A long-time duration of this relatively small decline of GH secretory activity may be supposed to contribute to age-related catabolic processes in a large number of patients with mild primary hyperparathyroidism.

OBJECTIVE: Nerve growth factor (NGF) has antiproliferative and differentiating effects in neuroendocrine tumors. In cell lines derived from small cell lung cancer (SCLC), NGF treatment stimulates NGF receptor expression, activates NGF secretion, inhibits proliferation and abrogates invasion. Since these effects are lost upon NGF withdrawal, it is relevant to identify other differentiation factors that may co-operate with the NGF system to control SCLC growth and differentiation. DESIGN: Retinoic acid (RA), which has been shown to inhibit cell transformation and proliferation, modulates the expression of NGF receptors and the sensitivity to NGF in different cell models. In the present study, we have investigated whether NGF and RA may interact to control the proliferation of SCLC cell lines. METHODS: SCLC cells were exposed to 50 ng/ml NGF or 1 microM all-trans RA for different times. Cell proliferation was measured by the [(3)H]thymidine incorporation test and NGF receptor expression was evaluated by immunofluorescence. RESULTS: We found that RA increased the expression of both trkA and p75 NGF receptors in NCI-N-592 and GLC8 cell lines and prevented the loss of both NGF production and NGF receptor expression occurring when NGF treatment was discontinued. As a result, RA, which did not inhibit the proliferation of untreated cells, abolished NGF withdrawal-related increase in cell proliferation both in vitro and in vivo, thus making permanent the antiproliferative effects of NGF. CONCLUSIONS: These data suggest that combined treatments with NGF and RA or mimicking drugs may represent a strategy to be further investigated for the treatment of SCLC.

We have investigated the distribution of NMDA and neurotrophin receptor systems and their reciprocal interactions in post-synaptic densities (PSD) purified from spinal cord. NMDA receptor subunits, trkA and trkB, but not trkC, were present in spinal cord PSD. The incubation of PSD with BDNF and NGF induced the phosphorylation of NR2A and B subunits. This phosphorylation was counteracted by antibodies directed against the catalytic domain of trkA and trkB receptors and by genistein. These results suggest the existence of a previously unexplored cross-talk between neurotrophins and NMDA receptors in rat spinal cord neurons.

Objectives. The purpose of this study was to investigate lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] phenotypes in relation to age of onset of coronary heart disease (CHD).

The European Network of the Teratology Information Services (ENTIS) collected and evaluated data on 423 pregnancies exposed during the first 9 weeks of gestation to a “high” dose of vitamin A (10,000 IU per day or more). Data were collected prospectively; 394 women (93.1%) were followed by telephone interview up to the first few weeks after the expected date of delivery, using standardized procedures. The presence of major structural malformations, excluding chromosomal and genetic diseases, was evaluated in 311 infants exposed to a median daily dose of vitamin A of 50,000 IU per day (range, 10,000–300,000 IU per day; interquartile range, 25,000–60,000 IU per day). Three infants with a major malformation were reported: pulmonary stenosis, stenotic anus with fistula, and bilateral inguinal hernia. No congenital malformations were reported among 120 infants exposed to more than 50,000 IU per day of vitamin A. When the birth prevalence rate of major malformations in the study group was compared with two internal control groups of infants exposed to: 1) “high” vitamin A exposure later in pregnancy, and 2) nonteratogenic agent exposures, the rate ratio was, respectively, 0.28 (CI 95% interval, 0.06, 1.23) and 0.50 (CI 95% interval, 0.14, 1.76). The studied sample did not provide evidence for an increased risk of major malformations, associated with “high” vitamin A intake during the organogenetic period, higher than 2.76 above the control reference risk of 1.91% (power 80%, alpha 0.10). Teratology 59:7–11, 1999. © 1999 Wiley-Liss, Inc.

ObjectiveTo investigate the correlation between ultrasonographically evaluated intima-media thickness (IMT) of common carotid artery (CCA) and cardiovascular risk factors for subjects with newly detected, uncomplicated and untreated primary hypertension.MethodsThe study population consisted of 200 subjects (123 men and 77 women, aged 46±7.5 years). Blood pressure was measured in the clinical setting and by 24 h noninvasive ambulatory monitoring. Fasting levels of blood glucose, plasma lipids and lipoproteins, fibrinogen and plasminogen activator inhibitor (PAI)-1 were measured. Ultrasound examination included measurement of far-wall intima-media complex of CCA and morphologic evaluation of occurrence of plaques in carotid and femoral bifurcations.ResultsThe prevalence of greater than normal IMT (mean IMT ≥ 0.80 mm) was 22%. Significant univariate correlations to the dichotomy between normal and greater than normal mean IMT were detected for age, smoking, level of LDL cholesterol, level of PAI-1 and total ultrasonographic score. Multivariate logistic regression analysis confirmed the associations between greater than normal mean IMT and plasma concentrations of LDL cholesterol and PAI-1 as well as total ultrasonographic score.ConclusionGreater than normal IMT of CCA was more strictly related to other cardiovascular risk factors than it was to blood pressure and was strongly associated with the occurrence of atherosclerotic plaques in carotid and femoral arteries. The role of PAI-1 in intima-media thickening that is emerging suggests that fibrinolytic balance is an important determinant of vessel-wall homeostasis in hypertensive patients.

The common bean, Phaseolus vulgaris, contains a family of defense proteins that comprises phytohemagglutinin (PHA), arcelin, and a-amylase inhibitor (aAI). Here we report eight new derived amino acid sequences of genes in this family obtained with either the polymerase chain reaction using genomic DNA, or by screening cDNA libraries made with RNA from developing beans. These new sequences are: two aAI sequences and arcelin-4 obtained from a wild accession of P. vulgaris that is resistant to the Mexican bean weevil (Zabrotes subfasciatus) and the bean weevil (Acanthoscelides obtectus); an aAI sequence from the related species P. acutifolius (tepary bean); a PHA and an arcelin-like sequence from P. acutifolius; an aAI-like sequence from P. maculatus; and a PHA sequence from an arcelin-5 type P. vulgaris. A dendrogram of 16 sequences shows that they fall into the three identified groups: phytohemagglutinins, arcelins and aAIs. A comparison of these derived amino acid sequences indicates that one of the four amino acid residues that is conserved in all legume lectins and is required for carbohydrate binding is absent from all the arcelins; two of the four conserved residues needed for carbohydrate binding are missing from all the aAIs. Proteolytic processing at an Asn-Ser site is required for the activation of aAI, and this site is present in all aAI-like sequences; this processing site is also found at the same position in certain arcelins, which are not proteolytically processed. The presence of this site is therefore not sufficient for processing to occur.

Various cholesterol oxides generated during the oxidation of low-density lipoproteins have been reported to exert cytotoxic effects in cultured endothelial cells and to decrease their barrier function. The cytoskeleton, and in particular the actin microfilament meshwork, is one of the preferential targets in oxidative stress-and thiol-depleting agent-induced cell injury. The alterations occurring in the microfilament network were investigated using the endothelial cell line 73/73 treated with increasing concentrations (0.5–10 μg/ml) of cholestane-3β,5α,6β-triol, CH, 5-cholesten-3β-ol-7one, KC, and 25-OH-cholesterol, COH, for up to 6 h. The distribution of microfilaments was visualized using immunofluorescence and laser scanner confocal microscopy. All cholesterol oxides caused a progressive disruption of actin microfilaments that was characterized by the disappearance of the stress fibers within the cell body and, in selected cells, by a complete marginalization and clustering of the filaments to one edge of the cell. In addition, COH promoted F-actin fragmentation, as revealed by the presence of scattered fragments of F-actin in various cell regions. The redistribution of actin microfilaments was associated with a similar redistribution of α-actinin, an actin-binding protein involved in bundle formation and in the anchorage of actin filaments to the adhesion plaques. Concomitantly, cholesterol oxides promoted a loss of vinculin, another actin-binding protein, from the focal adhesion plaques located under the cell body and their marginalization and thinning. These alterations preceded cell detachment and cell death by apoptosis as revealed by the subsequent leakage of cytosolic enzymes and nuclear fragmentation. These results suggest that cytoskeletal (microfilament) alterations caused by cholesterol oxides may be one of the cytopathological events involved in the detachment of endothelial cells from the inner vascular surface promoted by cholesterol oxides.

Besides hypertension, several cardiovascular risk factors can play a role in the development of coronary heart disease (CHD) in hypertensive patients. Lipoprotein(a) [Lp(a)] is an important and independent cardiovascular risk factor, but its role in the development of CHD in hypertensives has not been studied.

1. Although the high-frequency fluctuations in R—R interval (respiratory sinus arrhythmia) observed in heart transplant recipients are not a reliable marker of reinnervation because of a previously shown direct mechanical effect of breathing, the presence of a non-respiration-related low-frequency oscillation reflects rhythms generated outside the heart, and thus could be neurally mediated. 2. To evaluate the presence of reinnervation, the spontaneous variability in R—R interval was investigated, supine and after passive tilting, in 23 heart transplant recipients (age 43 years, range 23–64 years) and in 25 normotensive control subjects by autoregressive spectral analysis of low- and high-frequency spontaneous fluctuations in R—R interval and respiration. The response of R—R interval to amyl nitrite inhalation was also evaluated in five heart transplant recipients and eight control subjects. 3. Detectable low-frequency oscillations, unrelated to respiration, were present in 13/23 heart transplant recipients, particularly in those who were transplanted at least 20 months earlier (11/14). The natural logarithm of the power of low-frequency fluctuations was markedly lower than in control subjects (0.75 ± 0.21 versus 5.62 ± 0.20 ms2, P < 0.001). The low-frequency but not the high-frequency fluctuations correlated with time since transplantation (r = 0.44, P < 0.05). The subjects with low-frequency fluctuations showed a sudden decrease in R—R interval with amyl nitrite linearly related to the decrease in mean blood pressure (r ≧ 0.94). The slopes obtained in these heart transplant recipients were comparable (although of lower values) with those obtained in control subjects. The subjects with no low-frequency fluctuations showed no change in R—R interval despite a similar reduction in blood pressure. 4. Twenty months after transplantation signs of functional (reflex) reinnervation can be found in most heart transplant recipients.

Among the different targets of the cytodamaging effects of cholesterol oxides in endothelial cells, cytoskeleton is one of the most relevant, due to the large variety of biological events controlled by this subcellular structure. The modifications of the intermediate filament network caused by three cholesterol oxides (cholestane-3β,5α,6β-triol, CH, 7-keto-cholesterol, KC, and 25-OH-cholesterol, COH) was investigated in the endothelial cell line 73/73 using immunofluorescence and laser scanner confocal microscopy. All three cholesterol oxides promoted a redistribution of vimentin filaments that took place well before cell detachment and the occurrence of any detectable sign of cell death. CH-induced alterations were characterized by the polarization of vimentin to the edges of the cell and a concomitant destruction of its interaction with the nucleus. In KC-treated cells, vimentin filaments appeared cross-linked and formed a sort of circular network ring between the nucleus and the cell periphery. COH promoted the aggregation of vimentin filaments in thick and irregular bundles that delimited apparently empty regions. All these changes occurred independently of gross modifications in microtubule organization, which was generally retained except for the appearance of immunoreactive tubulin spots throughout the cytoplasm. These results indicate that the organization of the intermediate-size filament protein vimentin is markedly affected by cholesterol oxides. The different rearrangements caused by CH, KC, and COH may derive from different pathobiochemical processes triggered by these compounds.

Using digitized M-mode echocardiograms, we evaluated left ventricular (LV) anatomy and function at rest and during handgrip in 24 normotensive young adults with both parents hypertensive (HP+), each matched for age, sex, body weight, and body surface area with one normotensive adult with both parents normotensive (HP-). LV parameters were within the normal range in all HP+ and HP-. At rest, HP+ as compared to HP- had higher systolic and diastolic blood pressure (BP), septal and posterior wall thickness, and LV mass; LV diastolic diameter and end-systolic wall stress were similar in the two groups. Modified midwall fractional shortening, peak shortening rate of LV diameter and peak thickening rate of LV posterior wall, indices of LV systolic function, and peak lengthening rate of LV diameter and peak thinning rate of LV posterior wall, indices of ventricular relaxation, were significantly higher in HP+. Handgrip induced significant (P < .001) and percent-comparable increases of systolic and diastolic BP, heart rate, and cardiac output in HP+ and HP-; peak shortening and lengthening rates of LV diameter and peak thickening and thinning rates of LV posterior wall increased significantly in HP-, whereas in HP+ the value of the four parameters, higher at rest as compared to HP-, did not show any further increase. In conclusion, normotensive young adults with high genetic risk for hypertension have higher BP and thicker and overactive LV as compared to subjects with normotensive parents. Handgrip stimulates LV function in offspring of normotensives, but not the already hyperkinetic LV of hypertensive offspring.

The medium‐term (16 weeks) effects of the combination of captopril and hydrochlorothiazide (HCTZ) on some metabolic indexes, particularly on plasma lipoproteins, were evaluated in 20 mild to moderate hypertensive outpatients.

Il presente studio prende in esame il CAPM e ne illustra i principali approcci teorici più recenti; soprattutto in questi ultimi anni, infatti, l'argomento ha attirato l'attenzione degli studiosi in campo finanziario e si presenta ancora molto interessante per i possibili sviluppi futuri. Senza esaurire l'argomento, che comporterebbe una trattazione molto ampia e una molteplicità di modelli a questo collegati, è parso utile ripercorrere l'iter logico e cronologico di questa teoria al fine di osservare come da un modello relativamente semplice sia stata a poco a poco enucleata tutta una serie di importanti problemi collaterali. This paper reviews the theoretical literature on the CAPM, considering the most important and recent approaches. Actually this model has been studied and developed very much in the financial field and further applications can be obtained in the future. The logical and historical development of the CAPM has been here the perspective to observe this theory, without exhausting the literature in this field, so the main aim is to present the relevant importance of the actual theory and some important problems which come from that.