The conveyor belt hypothesis for thymocyte migration: participation of adhesion and de-adhesion molecules

Thymocyte differentiation is the process by which bone marrow-derived precursors enter the thymus, proliferate, rearrange the genes and express the corresponding T cell receptors, and undergo positive and/or negative selection, ultimately yielding mature T cells that will represent the so-called T cell repertoire. This process occurs in the context of cell migration, whose cellular and molecular basis is still poorly understood. Kinetic studies favor the idea that these cells leave the organ in an ordered pattern, as if they were moving on a conveyor belt. We have recently proposed that extracellular matrix glycoproteins, such as fibronectin, laminin and type IV collagen, among others, produced by non-lymphoid cells both in the cortex and in the medulla, would constitute a macromolecular arrangement allowing differentiating thymocytes to migrate. Here we discuss the participation of both molecules with adhesive and de-adhesive properties in the intrathymic T cell migration. Functional experiments demonstrated that galectin-3, a soluble ß-galactoside-binding lectin secreted by thymic microenvironmental cells, is a likely candidate for de-adhesion proteins by decreasing thymocyte interaction with the thymic microenvironment.

Family ownership – a source of sustainable success in listed companies

Extant research on exchange-listed firms has acknowledged that the concentration of ownership and the identity of owners make a difference. In addition, studies indicate that firms with a dominant owner outperform firms with dispersed ownership. During the last few years, scholars have identified one group of owners, in particular, whose ownership stake in publicly listed firm is positively related to performance: the business family. While acknowledging that family firms represent a unique organizational form, scholars have identified various concepts and theories in order to understand how the family influences organizational processes and firm performance. Despite multitude of research, scholars have not been able to present clear results on how firm performance is actually impacted by the family. In other words, studies comparing the performance of listed family and other types of firms have remained descriptive in nature since they lack empirical data and confirmation from the family business representatives. What seems to be missing is a convincing theory that links the involvement and behavioral consequences. Accordingly, scholars have not yet come to a mutual understanding of what precisely constitutes a family business. The variety of different definitions and theories has made comparability of different results difficult for instance. These two issues have hampered the development of a rigorous theory of family business. The overall objective of this study is to describe and understand how the family as a dominant owner can enhance firm performance, and can act a source of sustainable success in listed companies. In more detail, in order to develop understanding of the unique factors that can act as competitive advantages for listed family firms, this study is based on a qualitative approach and aims at theory development, not theory verification. The data in this study consist of 16 thematic interviews with CEOs, members of the board, supervisory board chairs, and founders of Finnish listed-family firms. The study consists of two parts. The first part introduces the research topic, research paradigm, methods, and publications, and also discusses the overall outcomes and contributions of the publications. The second part consists of four publications that address the research questions from different viewpoints. The analyses of this study indicate that family ownership in listed companies represents a structure that differs from the traditional views of agency and stewardship, as well as from resource-based and stakeholder views. As opposed to these theories and shareholder capitalism which consider humans as individualistic, opportunistic, and self-serving, and assume that the behaviors of an investor are based on the incentives and motivations to maximize private profits, the family owners form a collective social unit that is motivated to act together toward their mutual purpose or benefit. In addition, socio-emotional and psychological elements of ownership define the family members as owners, rather than the legal and financial dimensions of ownership. That is, collective psychological ownership of family over the business (F-CPO) can be seen as a construct that comprehensively captures the fusion between the family and the business. Moreover, it captures the realized, rather than merely potential, family influence on and interaction with the business, and thereby brings more theoretical clarity of the nature of the fusion between the family and the business, and offers a solution to the problem of family business definition. This doctoral dissertation provides academics, policy-makers, family business practitioners, and the society at large with many implications considering family and business relationships.

Pentoxifylline decreases tumor necrosis factor and interleukin-1 during high tidal volume

Tumor necrosis factor-alpha (TNF-alpha) is one of the most important proinflammatory cytokines which plays a central role in host defense and in the acute inflammatory response related to tissue injury. The major source of TNF-alpha are immune cells such as neutrophils and macrophages. We tested the hypothesis that pentoxifylline, a methylxanthine derivative, down-regulates proinflammatory cytokine expression during acute lung injury in rats. Male Wistar rats weighing 250 to 450 g were anesthetized ip with 50 mg/kg sodium thiopental and randomly divided into three groups: group 1 (N = 7): tidal volume (V T) = 7 ml/kg, respiratory rate (RR) = 50 breaths/min and normal saline infusion; group 2 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and normal saline infusion; group 3 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and pentoxifylline infusion. The animals were ventilated with an inspired oxygen fraction of 1.0, a positive end-expiratory pressure of 3 cmH2O, and normal saline or pentoxifylline injected into the left femoral vein. The mRNA of TNF-alpha rapidly increased in the lung tissue within 180 min of ventilation with a higher V T with normal saline infusion. The concentrations of inflammatory mediators were decreased in plasma and bronchoalveolar lavage (BAL) in the presence of higher V T with pentoxifylline infusion (TNF-alpha: plasma, 102.2 ± 90.9 and BAL, 118.2 ± 82.1; IL-1ß: plasma, 45.2 ± 42.7 and BAL, 50.2 ± 34.9, P < 0.05). We conclude that TNF-alpha produced by neutrophil influx may function as an alert signal in host defense to induce production of other inflammatory mediators.

Allogeneic hematopoietic stem cell transplantation from an alternative stem cell source in Fanconi anemia patients: analysis of 47 patients from a single institution

We transplanted 47 patients with Fanconi anemia using an alternative source of hematopoietic cells. The patients were assigned to the following groups: group 1, unrelated bone marrow (N = 15); group 2, unrelated cord blood (N = 17), and group 3, related non-sibling bone marrow (N = 15). Twenty-four patients (51%) had complete engraftment, which was not influenced by gender (P = 0.87), age (P = 0.45), dose of cyclophosphamide (P = 0.80), nucleated cell dose infused (P = 0.60), or use of anti-T serotherapy (P = 0.20). Favorable factors for superior engraftment were full HLA compatibility (independent of the source of cells; P = 0.007) and use of a fludarabine-based conditioning regimen (P = 0.046). Unfavorable factors were > or = 25 transfusions pre-transplant (P = 0.011) and degree of HLA disparity (P = 0.007). Intensity of mucositis (P = 0.50) and use of androgen prior to transplant had no influence on survival (P = 0.80). Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD were diagnosed in 47 and 23% of available patients, respectively, and infections prevailed as the main cause of death, associated or not with GVHD. Eighteen patients are alive, the Kaplan-Meyer overall survival is 38% at ~8 years, and the best results were obtained with related non-sibling bone marrow patients. Three recommendations emerged from the present study: fludarabine as part of conditioning, transplant in patients with <25 transfusions and avoidance of HLA disparity. In addition, an extended family search (even when consanguinity is not present) seeking for a related non-sibling donor is highly recommended.

Water deprivation and the double- depletion hypothesis: common neural mechanisms underlie thirst and salt appetite

Water deprivation-induced thirst is explained by the double-depletion hypothesis, which predicts that dehydration of the two major body fluid compartments, the extracellular and intracellular compartments, activates signals that combine centrally to induce water intake. However, sodium appetite is also elicited by water deprivation. In this brief review, we stress the importance of the water-depletion and partial extracellular fluid-repletion protocol which permits the distinction between sodium appetite and thirst. Consistent enhancement or a de novo production of sodium intake induced by deactivation of inhibitory nuclei (e.g., lateral parabrachial nucleus) or hormones (oxytocin, atrial natriuretic peptide), in water-deprived, extracellular-dehydrated or, contrary to tradition, intracellular-dehydrated rats, suggests that sodium appetite and thirst share more mechanisms than previously thought. Water deprivation has physiological and health effects in humans that might be related to the salt craving shown by our species.

The husk fiber of Cocos nucifera L. (Palmae) is a source of anti-neoplastic activity

In the present study, we investigated the in vitro anti-tumoral activities of fractions from aqueous extracts of the husk fiber of the typical A and common varieties of Cocos nucifera (Palmae). Cytotoxicity against leukemia cells was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Cells (2 x 104/well) were incubated with 0, 5, 50 or 500 µg/mL high- or low-molecular weight fractions for 48 h, treated with MTT and absorbance was measured with an ELISA reader. The results showed that both varieties have almost similar antitumoral activity against the leukemia cell line K562 (60.1 ± 8.5 and 47.5 ± 11.9% for the typical A and common varieties, respectively). Separation of the crude extracts with Amicon membranes yielded fractions with molecular weights ranging in size from 1-3 kDa (fraction A) to 3-10 kDa (fraction B) and to more than 10 kDa (fraction C). Cells were treated with 500 µg/mL of these fractions and cytotoxicity was evaluated by MTT. Fractions ranging in molecular weight from 1-10 kDa had higher cytotoxicity. Interestingly, C. nucifera extracts were also active against Lucena 1, a multidrug-resistant leukemia cell line. Their cytotoxicity against this cell line was about 50% (51.9 ± 3.2 and 56.3 ± 2.9 for varieties typical A and common, respectively). Since the common C. nucifera variety is extensively cultured in Brazil and the husk fiber is its industrial by-product, the results obtained in the present study suggest that it might be a very inexpensive source of new antineoplastic and anti-multidrug resistant drugs that warrants further investigation.

Stress-induced neuroinflammation: mechanisms and new pharmacological targets

Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, long-lasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO) and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2), another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-D-aspartate (NMDA) glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB). In the case of inducible NO synthase (iNOS), release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas' disease?

Intense immune responses are observed during human or experimental infection with the digenetic protozoan parasite Trypanosoma cruzi. The reasons why such immune responses are unable to completely eliminate the parasites are unknown. The survival of the parasite leads to a parasite-host equilibrium found during the chronic phase of chagasic infection in most individuals. Parasite persistence is recognized as the most likely cause of the chagasic chronic pathologies. Therefore, a key question in Chagas' disease is to understand how this equilibrium is established and maintained for a long period. Understanding the basis for this equilibrium may lead to new approaches to interventions that could help millions of individuals at risk for infection or who are already infected with T. cruzi. Here, we propose that the phenomenon of immunodominance may be significant in terms of regulating the host-parasite equilibrium observed in Chagas' disease. T. cruzi infection restricts the repertoire of specific T cells generating, in some cases, an intense immunodominant phenotype and in others causing a dramatic interference in the response to distinct epitopes. This immune response is sufficiently strong to maintain the host alive during the acute phase carrying them to the chronic phase where transmission usually occurs. At the same time, immunodominance interferes with the development of a higher and broader immune response that could be able to completely eliminate the parasite. Based on this, we discuss how we can interfere with or take advantage of immunodominance in order to provide an immunotherapeutic alternative for chagasic individuals.

EEG spike source localization before and after surgery for temporal lobe epilepsy: a BOLD EEG-fMRI and independent component analysis study

Simultaneous measurements of EEG-functional magnetic resonance imaging (fMRI) combine the high temporal resolution of EEG with the distinctive spatial resolution of fMRI. The purpose of this EEG-fMRI study was to search for hemodynamic responses (blood oxygen level-dependent - BOLD responses) associated with interictal activity in a case of right mesial temporal lobe epilepsy before and after a successful selective amygdalohippocampectomy. Therefore, the study found the epileptogenic source by this noninvasive imaging technique and compared the results after removing the atrophied hippocampus. Additionally, the present study investigated the effectiveness of two different ways of localizing epileptiform spike sources, i.e., BOLD contrast and independent component analysis dipole model, by comparing their respective outcomes to the resected epileptogenic region. Our findings suggested a right hippocampus induction of the large interictal activity in the left hemisphere. Although almost a quarter of the dipoles were found near the right hippocampus region, dipole modeling resulted in a widespread distribution, making EEG analysis too weak to precisely determine by itself the source localization even by a sophisticated method of analysis such as independent component analysis. On the other hand, the combined EEG-fMRI technique made it possible to highlight the epileptogenic foci quite efficiently.

Implications of infectious diseases and the adrenal hypothesis for the etiology of childhood acute lymphoblastic leukemia

Acute leukemia is the most frequent cancer in children. Recently, a new hypothesis was proposed for the pathogenesis of childhood acute lymphoblastic leukemia (ALL). The so-called "adrenal hypothesis" emphasized the role of endogenous cortisol in the etiology of B-cell precursor ALL. The incidence peak of ALL in children between 3 to 5 years of age has been well documented and is consistent with this view. The adrenal hypothesis proposes that the risk of childhood B-cell precursor ALL is reduced when early childhood infections induce qualitative and quantitative changes in the hypothalamus-pituitary-adrenal axis. It suggests that the increased plasma cortisol levels would be sufficient to eliminate all clonal leukemic cells originating during fetal life. Because Brazil is a continental and tropical country, the exposure to infections is diversified with endemic viral and regionally non-viral infections, with some characteristics that support the recent adrenal hypothesis. Here we discuss this new hypothesis in terms of data from epidemiological studies and the possible implications of the diversity of infections occurring in Brazilian children.

The response of social anxiety disorder patients to threat scenarios differs from that of healthy controls

The objective of the present study was to evaluate the response of social anxiety disorder (SAD) patients to threat scenarios. First-choice responses to 12 scenarios describing conspecific threatening situations and mean scores of defensive direction and defensive intensity dimensions were compared between 87 SAD patients free of medication and 87 matched healthy controls (HC). A significant gender difference in the first-choice responses was identified for seven scenarios among HCs but only for two scenarios among SAD patients. A significantly higher proportion of SAD patients chose "freezing" in response to "Bush" and "Noise" scenarios, whereas the most frequent response by HCs to these scenarios was "check out". SAD males chose "run away" and "yell" more often than healthy men in response to the scenarios "Park" and "Elevator", respectively. There was a positive correlation between the severity of symptoms and both defensive direction and defensive intensity dimensions. Factorial analysis confirmed the gradient of defensive reactions derived from animal studies. SAD patients chose more urgent defensive responses to threat scenarios, seeming to perceive them as more dangerous than HCs and tending to move away from the source of threat. This is consistent with the hypothesis that the physiopathology of anxiety disorders involves brain structures responsible for defensive behaviors.

Oat hulls treated with alkaline hydrogen peroxide associated with extrusion as fiber source in cookies

Cookies were prepared with the replacement of 20% of wheat flour by chemically (alkaline hydrogen peroxide) and physically (extrusion) treated oat hulls, with the objective to investigate the possibility of use of this modified material. Cookies elaborated with the untreated hulls were used as control. Cookies were evaluated for their physical (spread ratio, specific volume and color) and sensory characteristics, and no difference was detected (p<0.05) among the cookies in relation to the physical properties. Triangule test, used to verify difference (p<0.05) among treated and untreated cookies, confirmed the efficiency of the treatment in sensory level. The acceptance level of cookies with treated fiber was evaluated by potential consumers of the product, obtaining 91% acceptance. The cookies presented 10.6 g of dietary fiber per 100 g of product.

Influence of carbon source and the fermentation process on levan production by Zymomonas mobilis analyzed by the surface response method

The aim of this study is to assess sugar cane juice and sucrose as substrates, the batch and fed batch processes and their interaction in the levan production using a complete factorial design. Zymomonas mobilis was cultivated in different sugar cane juice and sucrose concentrations in two fermentation processes at 25 °C for 20 h. A complete factorial design (2³) was used to analyze the effects of the type and concentration of the substrate, as well as the batch and fed batch processes. A complete second factorial design (2²) was used to observe the importance of sugar cane juice. The results indicated that the batch process improved the levan production reaching 40.14 g/L. The addition of sugar cane juice was not statistically significant for levan formation, however sugar cane juice stimulated biomass, sorbitol and ethanol production. The best medium for levan production was 150 g/L sucrose in batch.

Benefits of gas driven ground source heat pump systems

This thesis studies energy efficiencies and technical properties of gas driven ground source heat pumps and pump systems. The research focuses on two technologies: gas engine driven compressor heat pump and thermally driven gas absorption heat pump. System consist of a gas driven compressor or absorption ground source heat pump and a gas condensing boiler, which covers peak load. The reference system is a standard electrically powered compressor heat pump with electric heating elements for peak load. The systems are compared through primary energy ratios. Coefficient of performances of different heat pump technologies are also compared. At heat pump level, gas driven heat pumps are having lower coefficient of performances as compared with corresponding electric driven heat pump. However, gas heat pumps are competitive when primary energy ratios, where electricity production losses are counted in, are compared. Technically, gas heat pumps can potentially achieve a slightly higher temperatures with greater total energy efficiency as compared to the electric driven heat pump. The primary energy ratios of gas heat pump systems in relation to EHP-system improves when the share of peak load increases. Electric heat pump system's overall energy efficiency is heavily dependent on the electricity production efficiency. Economy as well as CO2-emissions were not examined in this thesis, which however, would be good topics for further study.