Multiple, Independent T Cell Lymphomas Arising in an Experimentally FIV-Infected Cat during the Terminal Stage of Infection.

Our laboratory has serially reported on the virologic and immunopathologic features of a cohort of experimental feline immunodeficiency virus (FIV)-infected cats for more than eight years. At 8.09 years post infection (PI), one of these animals entered the terminal stage of infection, characterized by undulating hyperthermia, progressive anorexia, weight loss, and pancytopenia; the animal was not responsive to therapeutic interventions, necessitating euthanasia six weeks later (8.20 years PI). Subsequent analyses indicated that neoplastic lymphocytes infiltrated multiple cervical lymph nodes and a band-like region of the mucosal lamina propria within a segment of the intestine. Immunohistochemistry and T cell clonality testing determined that the nodal and intestinal lesions were independently arising from CD3 T cell lymphomas. In-situ RNA hybridization studies indicated that diffuse neoplastic lymphocytes from the cervical lymph node contained abundant viral nucleic acid, while viral nucleic acid was not detectable in lymphocytes from the intestinal lymphoma lesion. The proviral long terminal repeat (LTR) was amplified and sequenced from multiple anatomic sites, and a common clone containing a single nucleotide polymorphism was determined to be defective in response to phorbol myristate acetate (PMA)-mediated promoter activation in a reporter gene assay. This assay revealed a previously unidentified PMA response element within the FIV U3 region 3' to the TATA box. The possible implications of these results on FIV-lymphoma pathogenesis are discussed

The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies.

Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity

Hereditary systemic immunoglobulin light-chain amyloidosis

Several members of a family died from renal failure as a result of systemic amyloidosis. Extensive studies to detect previously documented gene mutations associated with amyloidosis failed to identify a causative factor. In search of the genetic basis for this syndrome, amyloid fibrils were isolated from renal tissue of a member of the kin who died while on renal dialysis. Amino acid sequencing of isolated amyloid protein identified sequences compatible with the constant region of the immunoglobulin κ light-chain. Isolation and characterization of κ light-chain protein from serum of an affected member of the kindred revealed mutation in the constant region of κ light-chain, with cysteine replacing serine at amino acid residue 131. This mutation (Ser131Cys) was confirmed by DNA analysis, which identified a single-base change of cytosine to guanine at the second position of codon 131 of the κ light-chain gene (TCT131TGT). DNA analysis of members of the extended family revealed transmission of the Ser131Cys mutation and association with systemic amyloidosis. This amyloid light-chain (AL) amyloidosis, which is a hereditary type of amyloidosis and not the result of a monoclonal plasma cell dyscrasia, may be misdiagnosed and lead to inappropriate chemotherapy

The Ile-84-->Ser amino acid substitution in transthyretin interferes with the interaction with plasma retinol-binding protein.

In plasma the thyroid hormone-binding protein transthyretin (TTR) forms a tight complex with the specific retinol carrier retinol-binding protein (RBP). The Ile-84–>Ser mutation and several other point mutations in TTR are associated with familial amyloidotic polyneuropathy, which is characterized by extracellular depositions of amyloid fibrils mainly consisting of mutated TTRs. The interactions with human RBP of recombinant human normal and Ser-84 TTRs were investigated by monitoring the fluorescence anisotropy of RBP-bound retinol. A nearly negligible affinity of the recombinant Ser-84 TTR for RBP was found. This result indicates the participation of a region on the outer surface of TTR that comprises Ile-84 in the recognition of RBP. In preliminary studies the Ser-84 TTR was the only one among several amyloidogenic variant TTRs to display negligible interaction with RBP. Therefore, in general a substantially altered binding of TTR to RBP is not associated with familial amyloidotic polyneuropathy. Instead, the altered binding of Ser-84 TTR to RBP appears to be responsible for an abnormal plasma transport of RBP. The recombinant normal TTR exhibits binding properties, in its interaction with human RBP, approximately similar to those of TTR purified from human plasma. Two independent and equivalent RBP binding sites on recombinant normal TTR are characterized by a dissociation constant of about 0.4 microM

Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis

Familial transthyretin (TTR) amyloidosis is caused by a mutation in the TTR gene, although wild-type (wt) TTR is also incorporated into the amyloid fibrils. Liver transplantation (LT) is the prevailing treatment of the disease and is performed in order to eliminate the mutant TTR from plasma. The outcome of the procedure is varied; especially problematic is a progressive cardiomyopathy seen in some patients, presumably caused by continued incorporation of wtTTR. What determines the discrepancy in outcome is not clear. We have previously shown that two structurally distinct amyloid fibrils (with or without fragmented ATTR) are found among ATTRV30M patients. In this study, we investigated the proportion of wtATTR in cardiac and adipose amyloid from patients having either fibril type. It was found that cardiac amyloid more easily incorporates wtTTR than adipose amyloid, offering a potential explanation for the vulnerability of cardiac tissue for continued amyloidosis after LT. In cardiac tissue, fibrils with fragmented ATTR contained a higher wt proportion than fibrils without, suggesting that continued incorporation of wtTTR after LT, perhaps, can take place more easily in these patients. In adipose tissue, a rapid increase in wt proportion after LT indicates that a rather fast turnover of the deposits must occur. A difference in wt proportion between the fibril types was seen post-LT but not pre-LT, possibly caused by differences in turnover rate. Conclusively, this study further establishes the basic dissimilarities between the two fibril types and demonstrates that their role in LT outcome needs to be further investigated

Beyond Genetic Factors in Familial Amyloidotic Polyneuropathy: Protein Glycation and the Loss of Fibrinogen's Chaperone Activity

Familial amyloidotic polyneuropathy (FAP) is a systemic conformational disease characterized by extracellular amyloid fibril formation from plasma transthyretin (TTR). This is a crippling, fatal disease for which liver transplantation is the only effective therapy. More than 80 TTR point mutations are associated with amyloidotic diseases and the most widely accepted disease model relates TTR tetramer instability with TTR point mutations. However, this model fails to explain two observations. First, native TTR also forms amyloid in systemic senile amyloidosis, a geriatric disease. Second, age at disease onset varies by decades for patients bearing the same mutation and some mutation carrier individuals are asymptomatic throughout their lives. Hence, mutations only accelerate the process and non-genetic factors must play a key role in the molecular mechanisms of disease. One of these factors is protein glycation, previously associated with conformational diseases like Alzheimer's and Parkinson's. The glycation hypothesis in FAP is supported by our previous discovery of methylglyoxal-derived glycation of amyloid fibrils in FAP patients. Here we show that plasma proteins are differentially glycated by methylglyoxal in FAP patients and that fibrinogen is the main glycation target. Moreover, we also found that fibrinogen interacts with TTR in plasma. Fibrinogen has chaperone activity which is compromised upon glycation by methylglyoxal. Hence, we propose that methylglyoxal glycation hampers the chaperone activity of fibrinogen, rendering TTR more prone to aggregation, amyloid formation and ultimately, disease

The Issues of Economic Security in the EU Common Foreign and Security Policy Towards Russia

Darbā tiek raksturota un analizēta ekonomiskās drošības apsvērumu ietekme uz Eiropas Savienības Kopējās ārējās un drošības politiku attiecībā uz Krieviju. Autors izvēlējies šādu tēmu, jo pēdējā laikā ir aktualizējies jautājums par to, vai un cik lielā mērā enerģētikas jautājumi ietekmē valsts ES dalībvalstu ārpolitiku atsevišķi un KĀDP kopumā. Tādējādi autors galveno uzmanību ir veltījis jautājumam par to, kā ekonomiskās drošības jautājumi ietekmē ES KĀDP attiecībā uz Krieviju. Autora galvenais pārbaudāmais uzstādījums ir analizēt, kāpēc ekonomiskās drošības apsvērumi ir nozīmīgs faktors ES KĀDP attiecībā uz Krieviju. Lai to noskaidrotu, tiek izvirzīti trīs uzdevumi, kas ir reizē arī darba trīs daļas. Pirmkārt, tiek raksturotas divas teorētiskas pieejas: merkantilais reālisms, lai skaidrotu ekonomikas saistību ar ārpolitiku; un liberālā starpvaldību pieeja, lai skaidrotu, pie kādiem nosacījumiem ES dalībvalstis ir gatavas uz ciešāku sadarbību savā starpā. Šī raksturojuma rezultātā ir iespējams piemērot teorētisko pieeju galvenās iezīmes praksē, skaidrojot gan valsts ārpolitiku kopumā, gan KĀDP atsevišķi. Otrā uzdevuma ietvaros tiek raksturota ES enerģētikas politikas un KĀDP galvenās iezīmes un attīstība pēdējā laikā. Tāpat tiek raksturoti divi notikumi enerģētikas jomā, kuriem ir bijusi arī ārpolitikas dimensija (Ukrainas un Krievijas gāzes cenu strīds; un Ziemeļeiropas gāzes vads). Šeit tiek apskatīti gan galvenie dokumenti, kas nosaka abas politikas, kā arī galveno iesaistīto aktieru pozīcijas, lai varētu raksturot abu politiku galvenās iezīmes un attīstību. Trešajā uzdevumā ir runa par to, kā ekonomiskās drošības apsvērumi ietekmē ES KĀDP. Tiek analizēti aspekti, kas visvairāk attiecas uz darba sākumā izvirzīto galveno uzstādījumu, piemērojot teorētiskos aspektus praksē. Tiek analizēts, kāpēc Krievijas nafta un gāze jāuzskata par ekonomiskās drošības apsvērumiem; kāpēc šie apsvērumi būtiski skar jebkuras ES dalībvalsts nacionālās intereses, kas ietekmē ārpolitiku; kā ekonomiskās drošības apsvērumi ietekmē KĀDP; un vai vienota enerģētikas politika ir iespējama un kā šāda iespējamība ietekmētu KĀDP raksturu. Izstrādājot darbu, autors izmantoja trīs metodes: vēsturisko, struktūras jeb sistēmas un salīdzinošo metodi. Pielietojot visas minētās metodes, bija iespējams analizēt visu izmantoto informāciju. Sekojoši materiāli tika izmantoti darba izstrādāšanas procesā: oficiāli dokumenti, analītiski raksti un periodika. Tādējādi darbs ietver analīzi par pēdējiem notikumiem šajā jautājumā. Darba nobeigumā autors piedāvā vairākus secinājumus, kas izriet no galvenā uzstādījuma, kā arī norāda uz saikni starp iespējami vienotu enerģētikas politiku un KĀDP. Maģistra darbs sastāv no 76 lapaspusēm.The thesis describes the impact of economic security considerations on the EU Common Security and Defence Policy towards Russia. The author has chosen the theme because in recent period on the top of agenda is the question about how the energy policy issues affect state’s foreign policy in particular and CFSP in common. Therefore, the author paid the main attention to the question, how economic security considerations affect the EU CFSP towards Russia. The thesis answers the question: why economic security considerations as a factor are of so high importance in EU CFSP towards Russia. In order to find out, why it is so, the author has divided the work in three parts. The first part describes two theoretical approaches of mercantile realism and liberal intergovernmentalism: mercantile realism to explain the linkage between economy and state’s foreign policy and liberal intergovernmental approach to explain on which conditions EU Member states are ready to have closer cooperation with each other. On the basis of this description it is possible to apply the main features of both approaches to the issues of state’s foreign policy and the EU CFSP. The second part describes the main features and overall development of the EU Energy policy and CFSP towards Russia. Within this task particular attention is being paid to the most recent and most important events: gas price dispute between Russia and Ukraine; and North European gas pipeline. The main official documents defining both of policies and the positions of the main actors involved are examined here. The third chapter the main attention is paid on how economic security considerations influence EU CFSP. Here the author is analyzing the main aspects, which mostly relate to the main question stated above by applying the main theoretical aspects to praxis. These main aspects are following: why Russia’s oil and gas should be regarded as economic security considerations; why these considerations substantially affect state’s national interests, which influences state’s foreign policy; how economic security considerations affect EU CFSP; and if there would exist common energy policy, would it facilitate more common CFSP. The author used three methods in the development of this thesis: the historical, the structural or systematic and the comparative methods. The use of all these methods made it possible to analyse the available information. The author used the following materials in the process of the creation of the thesis: the official documents, the analytical articles and the periodicals. Therefore the thesis includes the analysis of the most recent events. In the conclusion of the thesis the author offers the review of conclusions, as well as provides the linkage of influence between more common energy policy and CFSP. The extent of the master’s work is 76 pages

Falsification of documents in Latvia and European Union. Similarities and differences

Maģistra darba „Dokumentu viltošana Latvijā un Eiropas Savienībā. Kopīgais un atšķirīgais” mērķis ir analizēt dokumentu viltošanas krimināltiesisko institūtu Latvijā un Eiropas Savienībā, kā arī identificēt ar šo nozari saistīto problemātiku un iezīmēt iespējamos risinājumus. Dokumenta un dokumentu viltošanas jēdziena problemātika ir skatāma Latvijas normatīvajos aktos, dažādu tiesību zinātnieku doktrinārajos viedokļos, kā arī Eiropas Savienības dalībvalstu krimināltiesiskajos regulējumos. Veiktās analīzes rezultātā tiek piedāvāti secinājumi Latvijas Krimināllikuma uzlabošanai un modernizēšanai. Atslēgas vārdi: dokuments, dokumenta juridiskais spēks, noziedzīgs nodarījums, dokumenta viltošana.Master's Thesis "Falsification of documents in Latvia and European Union. Similarities and differences " target is to analyze the falsification of documents Latvian institute of Criminal Law and the European Union as well as the identification of sector-related issues and outline possible solutions. Document and document falsification notations problematics is seen in Latvian normative regulation, legal scholars of different doctrinal opinions, as well as the European Union's regulatory framework. Result of the analysis is presented by findings in Latvian Criminal regulatory modernization and improvement. Keywords: document, document legal force, forgery, falsification

PURIFICATION AND CHARACTERIZATION OF BOVINE ENTEROKINASE ISOLATED FROM DUODENAL MUCOSA.

Abstract not availabl