Induction of MC-1 immunoreactivity in axons after injection of the Fc fragment of human immunoglobulins in macaque monkeys.

Although previous studies have suggested an increased activation of humoral immunity in neurodegenerative diseases, it remains unclear whether this phenomenon is secondary to lesion formation or contributes directly to their development. Using stereotaxic injections in macaque monkey cerebral cortex, we studied the effects of human immunoglobulins on the neuronal cytoskeleton. Under these conditions, several MC-1-immunoreactive axons were observed in the vicinity of injection site. No MC-1 or TG-3 staining was detected in neuronal soma. Ultrastructurally, several axons in the same area displayed curly formations and accumulation of twisted tubules but not paired helical filaments. These data suggest that Fc fragment induce conformational changes of tau and subtle structural alterations in axons in this model. Immunocytochemical analyses in human autopsy materials revealed the presence of human Fc fragments as well as Fc receptors only in large pyramidal neurons known to be vulnerable in brain aging and Alzheimer's disease, further supporting a possible role of immunoglobulins in neurodegeneration.

How accurate is the current picture of human genetic variation?

Our understanding of the distribution of worldwide human genomic diversity has greatly increased over recent years thanks to the availability of large data sets derived from short tandem repeats (STRs), insertion deletion polymorphisms (indels) and single nucleotide polymorphisms (SNPs). A concern, however, is that the current picture of worldwide human genomic diversity may be inaccurate because of biases in the selection process of genetic markers (so-called 'ascertainment bias'). To evaluate this problem, we first compared the distribution of genomic diversity between these three types of genetic markers in the populations from the HGDP-CEPH panel for evidence of bias or incongruities. In a second step, using a very relaxed set of criteria to prevent the intrusion of bias, we developed a new set of unbiased STR markers and compared the results against those from available panels. Contrarily to recent claims, our results show that the STR markers suffer from no discernible bias, and can thus be used as a baseline reference for human genetic diversity and population differentiation. The bias on SNPs is moderate compared to that on the set of indels analysed, which we recommend should be avoided for work describing the distribution of human genetic diversity or making inference on human settlement history.

Contractual allocation of decision rights and incentives: The case of automobile distribution

We analyze empirically the allocation of rights and monetary incentives in automobile franchise contracts. These contracts substantially restrict the decision rights of dealers and grant manufacturers extensive contractual completion and enforcement powers, converting the manufacturers, de facto, in a sort of quasi-judiciary instance. Variation in the allocation of decision rights andincentive intensity is explained by the incidence of moral hazard in the relation. In particular, when the cost of dealer moral hazard is higher and the risk of manufactureropportunism is lower, manufacturers enjoy more discretion in determining the performance required from their dealers and in using mechanisms such as monitoring, termination and monetary incentives to ensure such performance is provided. We also explore the existence of interdependencies between the different elements of the system. and find some complementarities between completion and termination rights, and between monitoring rights and the intensity of incentives.

The role of WNT and mTOR in human memory T cell formation

Cancer is one of the world's leading causes of death with a rising trend in incidence. These epidemiologic observations underline the need for novel treatment strategies. In this regard, a promising approach takes advantage of the adaptive effector mechanisms of the immune system, using T lymphocytes to specifically target and destroy tumour cells. However, whereas current approaches mainly depend on short-lived, terminally differentiated effector T cells, increasing evidence suggests that long lasting and maximum efficient immune responses are mediated by low differentiated memory T cells. These memory T cells should display characteristics of stem cells, such as longevity, self-renewal capacity and the ability to continuously give rise to further differentiated effectors. These stem celllike memory T (TSCM) cells are thought to be of key therapeutic value as they might not only attack differentiated tumour cells, but also eradicate the root cause of cancer, the cancer stem cells themselves. Thus, efforts are made to characterize TSCM cells and to identify the signalling pathways which mediate their induction. Recently, a human TSCM cell subset was described and the activation of the Wnt-ß-catenin signalling pathway by the drug TWS119 during naive CD8+ T (TN) cell priming was suggested to mediate their induction. However, a precise deciphering of the signalling pathways leading to TSCM cell induction and an in-depth characterization of in vitro induced and in vivo occurring TSCM cells remain to be performed. Here, evidence is presented that the induction of human and mouse CD8+ and CD4+ TSCM cells may be triggered by inhibition of mechanistic/mammalian target of rapamycin (mTOR) complex 1 with simultaneously active mTOR complex 2. This molecular mechanism arrests a fraction of activated TN cells in a stem cell-like differentiation state independently of the Wnt-ß-catenin signalling pathway. Of note, TWS119 was found to also inhibit mTORCl, thereby mediating the induction of TSCM cells. Suggesting an immunostimulatory effect, the acquired data broaden the therapeutic range of mTORCl inhibitors like rapamycin, which are, at present, exclusively used due to their immunosuppressive function. Furthermore, by performing broad metabolic analyses, a well-orchestrated interplay between intracellular signalling pathways and the T cells' metabolic programmes could be identified as important regulator of the T cells' differentiation fate. Moreover, in vitro induced CD4+ TSCM cells possess superior functional capacities and share fate-determining key factors with their naturally occurring counterparts, assessed by a first-time full transcriptome analysis of in vivo occurring CD4+ TN cell, TSCM cells and central memory (TCM) cells and in vitro induced CD4+ TSCM cells. Of interest, a group of 56 genes, with a unique expression profile in TSCM cells could be identified. Thus, a pharmacological mechanism allowing to confer sternness to activated TN cells has been found which might be highly relevant for the design of novel T cell-based cancer immunotherapies.

Role of hemodynamic forces in the ex vivo arterialization of human saphenous veins.

BACKGROUND: Human saphenous vein grafts are one of the salvage bypass conduits when endovascular procedures are not feasible or fail. Understanding the remodeling process that venous grafts undergo during exposure to arterial conditions is crucial to improve their patency, which is often compromised by intimal hyperplasia. The precise role of hemodynamic forces such as shear stress and arterial pressure in this remodeling is not fully characterized. The aim of this study was to determine the involvement of arterial shear stress and pressure on vein wall remodeling and to unravel the underlying molecular mechanisms. METHODS: An ex vivo vein support system was modified for chronic (up to 1 week), pulsatile perfusion of human saphenous veins under controlled conditions that permitted the separate control of arterial shear stress and different arterial pressure (7 mm Hg or 70 mm Hg). RESULTS: Veins perfused for 7 days under high pressure (70 mm Hg) underwent significant development of a neointima compared with veins exposed to low pressure (7 mm Hg). These structural changes were associated with altered expression of several molecular markers. Exposure to an arterial shear stress under low pressure increased the expression of matrix metalloproteinase (MMP)-2 and MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 at the transcript, protein, and activity levels. This increase was enhanced by high pressure, which also increased TIMP-2 protein expression despite decreased levels of the cognate transcript. In contrast, the expression of plasminogen activator inhibitor-1 increased with shear stress but was not modified by pressure. Levels of the venous marker Eph-B4 were decreased under arterial shear stress, and levels of the arterial marker Ephrin-B2 were downregulated under high-pressure conditions. CONCLUSIONS: This model is a valuable tool to identify the role of hemodynamic forces and to decipher the molecular mechanisms leading to failure of human saphenous vein grafts. Under ex vivo conditions, arterial perfusion is sufficient to activate the remodeling of human veins, a change that is associated with the loss of specific vein markers. Elevation of pressure generates intimal hyperplasia, even though veins do not acquire arterial markers. CLINICAL RELEVANCE: The pathological remodeling of the venous wall, which leads to stenosis and ultimately graft failure, is the main limiting factor of human saphenous vein graft bypass. This remodeling is due to the hemodynamic adaptation of the vein to the arterial environment and cannot be prevented by conventional therapy. To develop a more targeted therapy, a better understanding of the molecular mechanisms involved in intimal hyperplasia is essential, which requires the development of ex vivo models of chronic perfusion of human veins.

The Prisoner Re-Entry Initiative (PRI) Grant Program Iowa Department of Correctional Services, January 2, 2007

The Iowa Department of Corrections (DOC) and the Department of Human Rights, Division of Criminal and Juvenile Justice Planning (CJJP) entered into a contract for services from January 2, 2007 to June 30, 2008 for the purposes of assisting in the evaluation component for the two-year Prison Re-Entry Initiative (PRI) grand awarded to the DOC by the U.S. Office of Justice Programs. The PRI grant period ran from July 2006 through June 2008 and included two primary components. First, all PRI participants returning to Polk County would participate in a Lifeskills curriculum offered through the Des Moines Area Community College (DMACC) at four Iowa prison institutions located at Mitchellville, Newton, Fort Dodge and Rockwell City. Second, all PRI participants returning to Polk County would be referred to The Directors Council (TDC) for cmmunity-based wrap-around services.

Investigation of the Iowa Department of Human Services’ Oversight of a Child Care Center, September 11 , 2013

Over a three-month period in 2010, our office received three complaints alleging the Department of Human Services (DHS) was lax in its oversight of a licensed child care center. It was alleged that the DHS did not sanction the child care center in any meaningful way after finding several violations associated with children engaging in sexual behavior with each other at the center. This involved the Child Development Center (CDC) in Des Moines, which is owned and operated by Children and Families of Iowa (CFI).

Yearbook of Private International Law, Volume XIV, 2012/2013

The "Yearbook of Private International Law" provides all about the conflict of laws developments of 2012 and 2013 in one book: Volume XIV (2012/2013) includes contributions on the proposed codification of the General Part of Private International Law in Europe, on the reform of the Chinese legal system as well as on defamation and violation of personality rights (the latter in a whole section). Furthermore, the book deals with the application of EU legislation on jurisdiction and enforcement of judgements, the recognition of judgements overturned by another judgement, and the conflict of decisions in international arbitration. Reports and court decisions from the Netherlands, Turkey, India, Finland, Croatia and Switzerland and a summary of two dissertations on the role of sovereignty and choice of courts agreements complete the book.

Transnational private authority and the participation of workers' organizations in the regulatory space surrounding the employment relationship

Most corporate codes of conduct and multi-stakeholder sustainability standards guarantee workers' rights to freedom of association and collective bargaining, but many authors are sceptical about the concrete impact of codes and standards of this kind. In this paper we use Hancher and Moran's (1998) concept of 'regulatory space' to assess the potential of private transnational regulation to support the growth of trade union membership and collective bargaining relationships, drawing on some preliminary case study results from a project on the impact of the International Finance Corporation's (IFC) social conditionality on worker organization and social dialogue. One of the major effects of neoliberal economic and industrial policy has been the routine exclusion of workers' organizations from regulatory processes on the grounds that they introduce inappropriate 'political' motives into what ought to be technical decision-making processes. This, rather than any direct attack on their capacity to take action, is what seems best to explain the global decline in union influence (Cradden 2004; Howell 2007; Howe 2012). The evidence we present in the paper suggests that private labour regulation may under certain conditions contribute to a reversal of this tendency, re-establishing the legitimacy of workers' organizations within regulatory processes and by extension the legitimacy of their use of economic and social power. We argue that guarantees of freedom of association and bargaining rights within private regulation schemes are effective to the extent that they can be used by workers' organizations in support of a claim for access to the regulatory space within which the terms and conditions of the employment relationship are determined. Our case study evidence shows that certain trade unions in East Africa have indeed been able to use IFC and other private regulation schemes as levers to win recognition from employers and to establish collective bargaining relationships. Although they did not attempt to use formal procedures to make a claim for the enforcement of freedom of association rights on behalf of their members, the unions did use enterprises' adherence to private regulation schemes as a normative point of reference in argument and political exchange about worker representation. For these unions, the regulation was a useful addition to the range of arguments that they could deploy as means to justify their demand for recognition by employers. By contrast, the private regulation that helps workers' organizations to win access to regulatory processes does little to ensure that they are able to participate meaningfully, whether in terms of technical capacity or of their ability to mobilize social power as a counterweight to the economic power of employers. To the extent that our East African unions were able to make an impact on terms and conditions of employment via their participation in regulatory space it was solely on the basis of their own capacities and resources and the application of national labour law.

The Rose Bengal test in human brucellosis: a neglected test for the diagnosis of a neglected disease

Brucellosis is a highly contagious zoonosis affecting livestock and human beings. The human disease lacks pathognomonic symptoms and laboratory tests are essential for its diagnosis. However, most tests are difficult to implement in the areas and countries were brucellosis is endemic. Here, we compared the simple and cheap Rose Bengal Test (RBT) with serum agglutination, Coombs, competitive ELISA, Brucellacapt, lateral flow immunochromatography for IgM and IgG detection and immunoprecipitation with Brucella proteins. We tested 208 sera from patients with brucellosis proved by bacteriological isolation, 20 contacts with no brucellosis, and 1559 sera of persons with no recent contact or brucellosis symptoms. RBT was highly sensitive in acute and long evolution brucellosis cases and this related to its ability to detect IgM, IgG and IgA, to the absence of prozones, and to the agglutinating activity of blocking IgA at the pH of the test. RBT was also highly specific in the sera of persons with no contact with Brucella. No test in this study outperformed RBT, and none was fully satisfactory in distinguishing contacts from infected patients. When modified to test serum dilutions, a diagnostic titer >4 in RBT resulted in 87.4% sensitivity (infected patients) and 100% specificity (contacts). We discuss the limitations of serological tests in the diagnosis of human brucellosis, particularly in the more chronic forms, and conclude that simplicity and affordability of RBT make it close to the ideal test for small and understaffed hospitals and laboratories.

The Spatial Distribution of Human Capital: Can It Really Be Explained by Regional Differences in Market Access?

This paper tests the robustness of estimates of market access impact on regional variability in human capital, as previously derived in the NEG literature. Our hypothesis is that these estimates of the coefficient of market access, in fact, capture the effects of regional differences in the industrial mix and the spatial dependence in the distribution of human capital. Results for the Spanish provinces indicate that the estimated impact of market access vanishes and becomes non-significant once these two elements are included in the empirical analysis.

Outcome of human papillomavirus infection among men in the Finnish Family HPV Study

Ihmisen papilloomaviruksen taudinkuva suomalaisperheiden seurantatutkimuksen mieskohortissa Tieto ihmisen papilloomaviruksen (HPV) yhteydestä eri anatomisten alueiden sairauksien syntyyn on lisännyt mielenkiintoa miehen papilloomavirustulehduksen taudinkulun selvittämiseksi. Tämä väitöskirjatyö on osa suomalaista seurantatutkimusta, jossa tutkitaan HPVinfektioiden tartuntareittejä 329 perheessä. Väitöstyössä keskitytään tutkimukseen osallistuneiden 131 miehen aineistoon. Suun limakalvonäytteet otettiin seitsemässä aikapisteessä. Lisäksi otettiin sukuelinalueen näytteet kahdella seurantakäynnillä. Riskitekijöitä kartoittava kyselytutkimus teetettiin tutkimuksen alkutilanteessa sekä viimeisellä seurantakäynnillä. Oireettomat HPV infektiot olivat alkutilanteessa yleisiä molemmilla sukupuolilla (miesten suu 18,3 % ja sukuelinalue 35,9 %, naisten suu 17,2 % ja kohdunsuu 18,8 %), mutta HPV:n genotyyppien vastaavuus partnerien välillä oli vähäinen. Naisen, mutta ei miehen, seksuaalinen riskikäyttäytyminen oli yhteydessä pariskunnan HPV tyyppien vastaavuuteen. Partnerin ja siviilisäädyn vaihtaminen lisäsivät miehen riskiä saada uusia HPV infektioita. Miehen suun limakalvonäytteistä löytyi kaikkiaan 17 eri HPV tyyppiä. Suun HPV-tulehduksen esiintyvyys vaihteli eri aikapisteissä 15 %:sta 31 %:iin. Uusien HPV tulehdusten ilmaantumisaika vaihteli 3,9 ja 25,7 kuukauden välillä. Suun HPV infektio parani valtaosalla miehistä. Suun krooninen HPV-infektio todettiin 14 %:lla miehistä. Näiden infektioiden keskimääräinen kesto vaihteli 6.0:sta 30.7:ään kuukauteen. Tupakointi lisäsi korkean riskin HPV tyyppien aiheuttamien suun kroonisten infektioiden riskiä, kun taas aikaisemmin sairastetut sukuelinten kondyloomat suojasivat siltä. Tuloksemme osoittavat, että miehen oireeton HPV tulehdus on yleinen suussa ja sukuelinten alueella. Vakaa parisuhde suojaa uusilta HPV tulehduksilta. Tupakoinnilla on keskeinen merkitys suun HPV-infektion kroonistumisessa.

Becoming Locals in a Borderland of Exiles. Sense of Place in the Stories of Lithuania Minor Dwellers

This thesis deals with sense of place, the relation that we construct with our dwelling and the surrounding environment. The topic belongs to the field of human geography. Sense of place is deeply intertwined with the ideas of feeling at home and having a place where to return. I argue that narratives of life experience help us relate to the places we inhabit, go through, leave. My analysis concerns Lithuania Minor, the Lithuanian region lying by the border with Kaliningrad, and focuses in particular on Vilkyškiai, a village in the municipality of Pagėgiai. Most of the area’s original population disappeared in the war. After 1945, people from all over the country and the USSR settled here. This raised the prickly question of who belongs to the borderland. Refugees, migrants and settlers allow us to observe closely the development of sense of place and its main constituents. Through this analysis, I challenge the idea of people’s natural rights to places and shows how time, engagement in local-based cultural activities and recollection help foreigners become locals. To grasp the locals’ sense of place, I collected open, light-structured interviews and applied some elements of semantic analysis to interpret the materials. From my research, it emerges that the cultivation of the region’s cultural heritage and the practice of storytelling were crucial in making the respondents feel at home. Leaving aside all legalistic claims concerning the issue, I suggest that people belong to the land they dwell. I believe that their sense of place deserves consideration from the State and the other actors seeing them as migrants.

A chromatographic method for the production of a human immunoglobulin G solution for intravenous use

Immunoglobulin G (IgG) of excellent quality for intravenous use was obtained from the cryosupernatant of human plasma by a chromatographic method based on a mixture of ion-exchange, DEAE-Sepharose FF and arginine Sepharose 4B affinity chromatography and a final purification step by Sephacryl S-300 HR gel filtration. The yield of 10 experimental batches produced was 3.5 g IgG per liter of plasma. A solvent/detergent combination of 1% Tri (n-butyl) phosphate and 1% Triton X-100 was used to inactivate lipid-coated viruses. Analysis of the final product (5% liquid IgG) based on the mean for 10 batches showed 94% monomers, 5.5% dimers and 0.5% polymers and aggregates. Anticomplementary activity was 0.3 CH50/mg IgG and prekallikrein activator levels were less than 5 IU/ml. Stability at 37ºC for 30 days in the liquid state was satisfactory. IgG was stored in flasks (2.5 g/flask) at 4 to 8ºC. All the characteristics of the product were consistent with the requirements of the 1997 Pharmacopée Européenne.

Purification of human albumin by the combination of the method of Cohn with liquid chromatography

Large volumes of plasma can be fractionated by the method of Cohn at low cost. However, liquid chromatography is superior in terms of the quality of the product obtained. In order to combine the advantages of each method, we developed an integrated method for the production of human albumin and immunoglobulin G (IgG). The cryoprecipitate was first removed from plasma for the production of factor VIII and the supernatant of the cryoprecipitate was fractionated by the method of Cohn. The first precipitate, containing fractions (F)-I + II + III, was used for the production of IgG by the chromatographic method (see Tanaka K et al. (1998) Brazilian Journal of Medical and Biological Research, 31: 1375-1381). The supernatant of F-I + II + III was submitted to a second precipitation and F-IV was obtained and discarded. Albumin was obtained from the supernatant of the precipitate F-IV by liquid chromatography, ion-exchange on DEAE-Sepharose FF, filtration through Sephacryl S-200 HR and introduction of heat treatment for fatty acid precipitation. Viral inactivation was performed by pasteurization at 60ºC for 10 h. The albumin product obtained by the proposed procedure was more than 99% pure for the 15 lots of albumin produced, with a mean yield of 25.0 ± 0.5 g/l plasma, containing 99.0 to 99.3% monomer, 0.7 to 1.0% dimers, and no polymers. Prekallikrein activator levels were <=5 IU/ml. This product satisfies the requirements of the 1997 Pharmacopée Européenne.