Sopimusoikeus ja sopimuskäytäntö : miten nettisopimuksia tehdään ja voidaan tehdä

Johdanto Työssä käsitellään sopimusten tekemistä internetissä. Tavoitteena on löytää mahdollisia nettisopimusten sopimussunnittelussa huomioon otettavia asioita. Näkökulmaksi on otettu sopimuskäytäntö. Sopimuskäytäntö lähtökohtana tutkimukselle Työssä esitellään sopimuskäytännön ja perinteisen analyyttisen sopimusoikeuden välinen ristiriita. Koska yritykset eivät halua ratkaista ongelmiaan tuomioistuimessa, tuomioistuimiin päätyy vain marginaalinen osa sopimuksista. Yritysten näkökulmasta tuomioistuimiin päätyneet sopimukset ovat olleet epäonnistuneita. Tämän takia pelkästään tuomioistuinratkaisuja tutkimalla ei tavoiteta käytännön sopimustoiminnan ongelmia ja ei pystytä tarjoamaan niihin ratkaisumalleja. Sama ongelma koskee myös kuluttajasopimuksia. Tässä työssä on tutkittu käytännön sopimustoimintaa eli sopimuskäytäntöä. Sopimusoikeuden tutkimukseen on tuotu uutta näkökulmaa. Sopimuksen syntyminen nettikaupassa Kirjoittaja esittää yleisen sopimusmallin nettisopimuksille. Sopimusmallin keskeisiä näkökohtia ovat sopimuksen prosessiluonne. Sopimusmallissa käydään läpi kaikkia niitä vaiheita, jotka voivat vaikuttaa päätökseen sitoutua sopimukseen. Työssä myös esitetään, että sopimukseen sisältö määräytyy näiden vaiheiden mukaisesti. Koska pitkällä tähtäimellä tehdyssä sopimustoiminnassa syntyy ajoittain ongelmia, työssä myös käsitellään yrityksen mahdollisuuksia hallita näitä sopimushäiriöitä. Arviot kahdesta avoimesta sopimusjärjestelmästä Tutkielmassa myös käydään läpi kaksi yleisölle avointa nettisopimusjärjestelmää. Toinen on tavarakauppa Amazon.com ja toinen Genetic Anomalies, Inc.:in tekemä tietokonepeli ChronX. Kumpaankin yritetään soveltaa esiteltyä yleistä sopimusmallia. Loppupäätelmät Keskeiseksi johtopäätökseksi tutkielmassa tulee, että yrityksen tulee pyrkiä tarjoamaan asiakkailleen mahdollisimaan hyvin tietoa heidän sopimusjärjestelmästään ja tuotteistaan. Tällä ei tarkoiteta valtavaa määrää epäselkeästi esitettyä tietoa. Tiedon jakaminen ja asiakaspalautteen hallinta ovat tutkimuksen mukaan yritysten suurin haaste nettikaupassa. Tutkielmassa myös esitetään, että näitä tuloksia saattaa voida soveltaa tavanomaiseenkin kaupankäyntiin

A novel MPLKIP-variant in three Finnish patients with non-photosensitive trichothiodystrophy type 4

Trichothiodystrophy is a group of multisystem neuroectodermal disorders with dysplastic hair as the cardinal symptom. We describe three patients from two Finnish families in whom whole-exome sequencing revealed a novel homozygous variant, c.26del, p.(Pro9Glnfs*144) in the MPLKIP-gene, confirming the diagnosis of non-photosensitive trichothiodystrophy type 4 (TTD4). The variant was confirmed by Sanger sequencing and inherited from unaffected carrier parents. This report adds to the literature by expanding the genetic and phenotypic spectra of MPLKIP-related trichothiodystrophy. We describe dysmorphic features in the patients and provide a comparison of clinical characteristics in patients with TTD4 reported to date.Peer reviewe

LRIG1 is a positive prognostic marker in Merkel cell carcinoma and Merkel cell carcinoma expresses epithelial stem cell markers

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine malignancy of the skin. The cell of origin of MCC is thus far unknown and proposed cells of origin include Merkel cells, pro-/pre- or pre-B cells, epithelial stem cells, and dermal stem cells. In this study, we aimed to shed further light on the possibility that a subset of MCC tumors arise from epithelial stem cells of the skin by examining the expression of hair follicle and epidermal stem cell markers in MCC and normal human skin. We also aimed to elucidate any correlation between the expression of these markers and tumor Merkel cell polyomavirus (MCPyV) status or other clinicopathological characteristics or patient survival. Expression of CK19, SOX9, LGR5, and LRIG1 in MCC and normal human skin was studied by immunohistochemistry, and the staining patterns or intensities were statistically correlated with patient, tumor, MCPyV, and survival parameters. In a cohort of 137 cases of MCC, we observed dot-like immunoexpression of CK19 in 30 cases (22.1%) and homogeneous expression in 103 cases (75.7%). We also observed positive immunoexpression of SOX9 in 21 cases (15.3%), LGR5 in 118 cases (86.1%), and LRIG1 in 117 cases (86.0%). Immunoexpression of LRIG1 was found to correlate with better overall and MCC-specific survival. We observed frequent immunoexpression of several hair follicle and epidermal stem cell markers in MCC and found LRIG1 to be a positive prognostic marker in MCC.Peer reviewe

von Willebrand's disease: a report from a meeting in the Åland islands

von Willebrand's disease (VWD) is probably the most common bleeding disorder, with some studies indicating that up to 1% of the population may have the condition. Over recent years interest in VWD has fallen compared to that of haemophilia, partly the result of focus on blood-borne diseases such as HIV and hepatitis. Now the time has come to revisit VWD, and in view of this some 60 international physicians with clinical and scientific interest in VWD met over 4 days in 2010 in the Åland islands to discuss state-of-the-art issues in the disease. The Åland islands are where Erik von Willebrand had first observed a bleeding disorder in a number of members of a family from Föglö, and 2010 was also the 140th anniversary of his birth. This report summarizes the main papers presented at the symposium; topics ranged from genetics and biochemistry through to classification of VWD, pharmacokinetics and laboratory assays used in the diagnosis of the disease, inhibitors, treatment guidelines in different age groups including the elderly who often have comorbid conditions that present challenges, and prophylaxis. Other topics included managing surgeries in patients with VWD and the role of FVIII in VWF replacement, a controversial subject

Distribution of the major histocompatibility complex antigens in human and rat kidney

Distribution of the major histocompatibility complex antigens in human and rat kidney. We have compared the distribution of the major histocompatibility complex (MHC) antigens in human and rat kidney using monospecific antisera to class I and II antigens of the MHC. FITC/TRITC double immunofluorescence was used to demonstrate these antigens in frozen sections and the Staphylococcus aureus Cowan I rosette assay on the cell surface. In both species, the MHC antigens were prominently present on the passenger leukocytes. Immunofluorescence analysis of human kidney demonstrated that the class I, β2-microglobulin (β2m), and class II antigens were present in the vascular endothelial cells and class I antigens in the renal tubular cells. The Staphylococcus assay demonstrated that these antigens were also exposed on the respective cell surfaces. In clear contrast, in the rat, class I, the β2m, and class II antigens were absent from the kidney vascular endothelium of large vessels and intertubular capillaries; however, large amounts of class II antigens were seen inside the proximal renal tubular cells. The Staphylococcus assay indicated that none or very little of these antigens were exposed on the kidney parenchymal cell surface. These differences may explain why rat renal transplants are relatively non-immunogenic and easily accepted, whereas human renal transplant recipients must be immunosuppressed ad infinitum.Distribution des antigènes du complexe d'histocompatibilité principal du rein d'homme et de rat. Nous avons comparé la distribution des antigènes du complexe d'histocompatibilité principal (MHC) dans du rein d'homme et de rat en utilisant des antisérums monospécifiques des antigènes des classes I et II du MHC. Une double immunofluorescence FITC/TRITC a été utilisée pour démontrer ces antigènes dans des sections congelées et le dosage des rosettes de Staphylocoque doré Cowan I pour les démontrer à la surface cellulaire. Dans les deux espèces, les antigènes MHC étaient essentiellement présents sur les leucocytes de passage. L'analyse en immunofluorescence de rein humain a démontré que les antigènes de classe I, 1 β2-microglobuline (β2m) et de classe II étaient présents dans les cellules endothéliales vasculaires, et ceux de classe I dans les cellules tubulaires rénales. Le dosage Staphylocoque a démontré que ces antigènes étaient également exposés sur les surfaces cellulaires respectives. De facon clairement opposée, chez le rat, les antigènes de classe I, 1 β2m et de classe II étaient absents de l'endothélium vasculaire rénal des gros vaisseaux et des capillaires intertubulaires; cependant, de grandes quantités d'antigènes de classe II étaient visibles à l'intérieur des cellules tubulaires rénales proximales. L'essai Staphylocoque a indiqué qu'aucun ou très peu de ces antigènes étaient exposés à la surface des cellules parenchymateuses rénales. Ces différences pourraient expliquer pourquoi les greffons rénaux de rat sont relativement non immunogènes et facilement tolérés, alors que les receveurs de transplants rénaux humains doivent être immunodéprimés indéfiniment

The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance

Plasma levels of von Willebrand factor (VWF) vary considerably in the general population and this variation has been linked to several genetic and environmental factors. Genetic factors include 2 common single nucleotide variants (SNVs) located in VWF, rs1063856 (c.2365A>G) and rs1063857 (c.2385T>C), although to date the mechanistic basis for their association with VWF level is unknown. Using genotypic/phenotypic information from a European healthy control population, in vitro analyses of recombinant VWF expressing both SNVs, and in vivo murine models, this study determined the precise nature of their association with VWF level and investigated the mechanism(s) involved. Possession of either SNV corresponded with a significant increase in plasma VWF in healthy controls (P G on VWF levels was also confirmed in vivo. This increase in VWF protein corresponded to an increase in VWF messenger RNA (mRNA) resulting, in part, from prolonged mRNA half-life. In addition, coinheritance of both SNVs was associated with a lower VWF propeptide-to-VWF antigen ratio in healthy controls (P < .05) and a longer VWF half-life in VWF knockout mice (P < .0001). Both SNVs therefore directly increase VWF plasma levels through a combined influence on VWF biosynthesis and clearance, and may have an impact on disease phenotype in both hemostatic and thrombotic disorders

Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis

To avoid pathological platelet aggregation by von Willebrand factor (VWF), VWF multimers are regulated in size and reactivity for adhesion by ADAMTS13-mediated proteolysis in a shear flow dependent manner. We examined if tensile stress in VWF under shear flow activates the VWF A2 domain for cleavage by ADAMTS13 using molecular dynamics simulations. We indeed observed stepwise unfolding of A2 and exposure of its deeply buried ADAMTS13 cleavage site. Interestingly, disulfide bonds in the adjacent and highly homologous VWF A1 and A3 domains obstruct their mechanical unfolding. We generated a full length mutant VWF featuring a homologous disulfide bond in A2 (N1493C and C1670S), in an attempt to lock A2 against unfolding. We find this mutant to feature ADAMTS13-resistant behavior in vitro. Our results yield molecular-detail evidence for the force-sensoring function of VWF A2, by revealing how tension in VWF due to shear flow selectively exposes the A2 proteolysis site to ADAMTS13 for cleavage while keeping the folded remainder of A2 intact and functional. We find the unconventional knotted Rossman fold of A2 to be the key to this mechanical response, tailored for regulating VWF size and activity. Based on our model we can explain the pathomechanism of some natural mutations in the VWF A2 domain that significantly increase the cleavage by ADAMTS13 without shearing or chemical denaturation, and provide with the cleavage-activated A2 conformation a structural basis for the design of inhibitors for VWF type 2 diseases

Novel Function of Phosphoinositide 3-Kinase in T Cell Ca\u3csup\u3e2+\u3c/sup\u3e Signaling

This study presents evidence that phosphoinositide (PI) 3-kinase is involved in T cell Ca2+ signaling via a phosphatidylinositol 3,4,5-trisphosphate PI(3,4,5)P3-sensitive Ca2+entry pathway. First, exogenous PI(3,4,5)P3 at concentrations close to its physiological levels induces Ca2+ influx in T cells, whereas PI(3,4)P2, PI(4,5)P2, and PI(3)P have no effect on [Ca2+]i. This Ca2+ entry mechanism is cell type-specific as B cells and a number of cell lines examined do not respond to PI(3,4,5)P3 stimulation. Second, inhibition of PI 3-kinase by wortmannin and by overexpression of the dominant negative inhibitor Δp85 suppresses anti-CD3-induced Ca2+response, which could be reversed by subsequent exposure to PI(3,4,5)P3. Third, PI(3,4,5)P3 is capable of stimulating Ca2+ efflux from Ca2+-loaded plasma membrane vesicles prepared from Jurkat T cells, suggesting that PI(3,4,5)P3 interacts with a Ca2+ entry system directly or via a membrane-bound protein. Fourth, although D-myo-inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) mimics PI(3,4,5)P3 in many aspects of biochemical functions such as membrane binding and Ca2+ transport, we raise evidence that Ins(1,3,4,5)P4 does not play a role in anti-CD3- or PI(3,4,5)P3-mediated Ca2+ entry. This PI(3,4,5)P3-stimulated Ca2+ influx connotes physiological significance, considering the pivotal role of PI 3-kinase in the regulation of T cell function. Given that PI 3-kinase and phospholipase C-γ form multifunctional complexes downstream of many receptor signaling pathways, we hypothesize that PI(3,4,5)P3-induced Ca2+ entry acts concertedly with Ins(1,4,5)P3-induced Ca2+ release in initiating T cell Ca2+ signaling. By using a biotinylated analog of PI(3,4,5)P3 as the affinity probe, we have detected several putative PI(3,4,5)P3-binding proteins in T cell plasma membranes

Recruitment of Slp-76 to the Membrane and Glycolipid-Enriched Membrane Microdomains Replaces the Requirement for Linker for Activation of T Cells in T Cell Receptor Signaling

Two hematopoietic-specific adapters, src homology 2 domain–containing leukocyte phosphoprotein of 76 kD (SLP-76) and linker for activation of T cells (LAT), are critical for T cell development and T cell receptor (TCR) signaling. Several studies have suggested that SLP-76 and LAT function coordinately to promote downstream signaling. In support of this hypothesis, we find that a fraction of SLP-76 localizes to glycolipid-enriched membrane microdomains (GEMs) after TCR stimulation. This recruitment of SLP-76 requires amino acids 224–244. The functional consequences of targeting SLP-76 to GEMs for TCR signaling are demonstrated using a LAT/SLP-76 chimeric protein. Expression of this construct reconstitutes TCR-inducted phospholipase Cγ1 phosphorylation, extracellular signal–regulated kinase activation, and nuclear factor of activated T cells (NFAT) promoter activity in LAT-deficient Jurkat T cells (J.CaM2). Mutation of the chimeric construct precluding its recruitment to GEMs diminishes but does not eliminate its ability to support TCR signaling. Expression of a chimera that lacks SLP-76 amino acids 224–244 restores NFAT promoter activity, suggesting that if localized, SLP-76 does not require an association with Gads to promote T cell activation. In contrast, mutation of the protein tyrosine kinase phosphorylation sites of SLP-76 in the context of the LAT/SLP-76 chimera abolishes reconstitution of TCR function. Collectively, these experiments show that optimal TCR signaling relies on the compartmentalization of SLP-76 and that one critical function of LAT is to bring SLP-76 and its associated proteins to the membrane