Pathophysiology of Congenital Nephrotic Syndrome of the Finnish type

Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal recessive disease which is highly enriched in the Finnish population. It is caused by mutations in the NPHS1 gene encoding for nephrin, which is a major component of the glomerular filtration barrier in the kidney. Patients with NPHS1 have heavy proteinuria and nephrotic syndrome (NS) from birth and develop renal fibrosis in early childhood. Renal transplantation (TX) is the only curative treatment for NPHS1. These patients form the largest group of pediatric kidney transplant children in our country. The NPHS1 kidneys are removed in infancy and they serve as an excellent human material for studies of the pathophysiology of proteinuric kidney diseases. Sustained proteinuria is a major factor leading to end-stage renal failure and understanding this process is crucial for nephrology. In this study we investigated the glomerular and tubulointerstitial changes that occur in the NPHS1 kidneys during infancy as well as the expression of nephrin in non-renal tissues. We also studied the pathology and management of recurrent proteinuria in kidney grafts transplanted to NPHS1 children. Severe renal lesions evolved in patients with NPHS1 during the first months of life. Glomerular sclerosis developed through progressive mesangial sclerosis, and capillary obliteration was an early consequence of this process. Shrinkage of the glomerular tuft was common, whereas occlusion of tubular opening or protrusion of the glomerular tuft into subepithelial space or through the Bowman's capsule were not detected. Few inflammatory cells were detected in the mesangial area. The glomerular epithelial cells (podocytes) showed severe ultrastructural changes and hypertrophy. Podocyte proliferation and apoptosis were rare, but moderate amounts of podocytes were detached and ended up in the urine. The results showed that endocapillary lesions not extracapillary lesions, as generally believed were important for the sclerotic process in the NPHS1 glomeruli. In the tubulointerstitium, severe lesions developed in NPHS1 kidneys during infancy. Despite heavy proteinuria, tubular epithelial cells (TECs) did not show transition into myofibroblasts. The most abundant chemokines in NPHS1 tissue were neutrophil activating protein-2 (NAP-2), macrophage inhibiting factor (MIF), and monocyte chemoattractant protein-1 (MCP-1). Interstitial inflammation and fibrosis were first detected in the paraglomerular areas and the most abundant inflammatory cells were monocytes/macrophages. Arteries and arterioles showed intimal hypertrophy, but the pericapillary microvasculature remained quite normal. However, excessive oxidative stress was evident in NPHS1 kidneys. The results indicated that TECs were relatively resistant to the heavy tubular protein load. Nephrin was at first thought to be podocyte specific, but some studies especially in experimental animals have suggested that nephrin might also be expressed in non-renal tissues such as pancreas and central nervous system. The knowledge of nephrin biology is important for the evaluation of nephrin related diseases. In our study, no significant amounts of nephrin protein or mRNA were detected in non-renal tissues of man and pig as studied by immunohistochemistry and in situ hybridization. The phenotype analysis of NPHS1 children, who totally lack nephrin, revealed no marked impairment in the neurological, testicular, or pancreatic function speaking against the idea that nephrin would play an important functional role outside the kidney. The NPHS1 kidneys do not express nephrin and antibodies against this major glomerular filter protein have been observed in NPHS1 children after renal TX most likely as an immune reaction against a novel antigen. These antibodies have been associated with the development of recurrent NS in the kidney graft of NPHS1 patients. In our study, a third of the NPHS1 patients homozygous for Fin-Major mutation developed recurrent NS in the transplanted graft. Re-transplantations were performed to patients who lost their graft due to recurrent NS and heavy proteinuria immediately developed in all cases. While 73% of the patients had detectable serum anti-nephrin antibodies, the kidney biopsy findings were minimal. Introduction of plasma exchange (PE) to the treatment of recurrent nephroses increased the remission rate from 54% to 89%. If remission was achieved, recurrent NS did not significantly deteriorate the long term graft function. In conclusion, the results show that the lack of nephrin in podocyte slit diaphragm in NPHS1 kidneys induces progressive mesangial expansion and glomerular capillary obliteration and inflicts interstitial fibrosis, inflammation, and oxidative stress with surprisingly little involvement of the TECs in this process. Nephrin appears to have no clinical significance outside the kidney. Development of antibodies against nephrin seems to be a major cause of recurrent NS in kidney grafts of NPHS1 patients and combined use of PE and cyclophosphamide markedly improved remission rates.

Psykoterapian vaikutusten arvioiminen : Keskustelunanalyttinen tutkimus arviointihaastattelun käytänteistä

In the field of psychiatry semi-structured interview is one of the central tools in assessing the psychiatric state of a patient. In semi-structured interview the interviewer participates in the interaction both by the prepared interview questions and by his or her own, unstructured turns. It has been stated that in the context of psychiatric assessment interviewers' unstructured turns help to get focused information but simultaneously may weaken the reliability of the data. This study examines the practices by which semi-structured psychiatric interviews are conducted. The method for the study is conversation analysis, which is both a theory of interaction and a methodology for its empirical, detailed analysis. Using data from 80 video-recorded psychiatric interviews with 16 patients and five interviewers it describes in detail both the structured and unstructured interviewing practices. In the analysis also psychotherapeutic concepts are used to describe phenomena that are characteristic for therapeutic discourse. The data was received from the Helsinki Psychotherapy Study (HPS). HPS is a randomized clinical trial comparing the effectiveness of four forms of psychotherapy in the treatment of depressive and anxiety disorders. A total of 326 patients were randomly assigned to one of three treatment groups: solution-focused therapy, short-term psychodynamic psychotherapy, and long-term psychodynamic psychotherapy. The patients assigned to the long-term psychodynamic psychotherapy group and 41 patients self-selected for psychoanalysis were included in a quasi-experimental design. The primary outcome measures were depressive and anxiety symptoms, while secondary measures included work ability, need for treatment, personality functions, social functioning, and life style. Cost-effectiveness was determined. The data were collected from interviews, questionnaires, psychological tests, and public health registers. The follow-up interviews were conducted five times during a 5-year follow-up. The study shows that interviewers pose elaborated questions that are formulated in a friendly and sensitive way and that make relevant patients' long and story-like responses. When receiving patients' answers interviewers use a wide variety of different interviewing practices by which they direct patients' talk or offer an understanding of the meaning of patients' response. The results of the study are two-fold. Firstly, the study shows that understanding the meaning of mental experiences requires interaction between interviewer and patient. It is stated that therefore semi-structured interview is both relevant and necessary method for collecting data in psychotherapy outcome study. Secondly, the study suggests that conversation analysis, enriched with psychotherapeutic concepts, offers methodological possibilities for psychotherapy process research, especially for process-outcome paradigm.

Search for single top quark production in pp̅ collisions at √s=1.96 TeV in the missing transverse energy plus jets topology

We report a search for single top quark production with the CDF II detector using 2.1 fb-1 of integrated luminosity of pbar p collisions at sqrt{s}=1.96 TeV. The data selected consist of events characterized by large energy imbalance in the transverse plane and hadronic jets, and no identified electrons and muons, so the sample is enriched in W -> tau nu decays. In order to suppress backgrounds, additional kinematic and topological requirements are imposed through a neural network, and at least one of the jets must be identified as a b-quark jet. We measure an excess of signal-like events in agreement with the standard model prediction, but inconsistent with a model without single top quark production by 2.1 standard deviations (sigma), with a median expected sensitivity of 1.4 sigma. Assuming a top quark mass of 175 GeV/c2 and ascribing the excess to single top quark production, the cross section is measured to be 4.9+2.5-2.2(stat+syst)pb, consistent with measurements performed in independent datasets and with the standard model prediction.

Functions of Alphavirus Macrodomain-containing protein nsP3

Alphaviruses are positive strand RNA viruses that replicate in association with cellular membranes. The viral RNA replication complex consists of four non-structural proteins nsP1-nsP4 which are essential for viral replication. The functions of nsP1, nsP2 and nsP4 are well established, but the roles of nsP3 are mainly unknown. In this work I have clarified some of the functions of nsP3 in order to better understand the importance of this protein in virus replication. Semliki Forest virus (SFV) has been mostly used as a model alphavirus during this work, but some experiments have also been conducted with Sindbis and Chikungunya viruses. NsP3 is composed of three different protein domains. The N-terminus of nsP3 contains an evolutionarily conserved macrodomain, the central part of nsP3 contains a domain that is only found in alphaviruses, and the C-terminus of the protein is hypervariable and predicted to be unstructured. In this work I have analyzed the functions of nsP3 macrodomain, and shown that viral macrodomains bind poly(ADP-ribose) and that they do not resemble cellular macrodomains in their properties. Furthermore, I have shown that some macrodomains, including viral macrodomains of SFV and hepatitis E virus, also bind poly(A). Mutations in the ligand binding pocket of SFV macrodomain hamper virus replication but do not confer lethality, indicating that macrodomain function is beneficial but not mandatory for virus replication. The hypervariable C-terminus of nsP3 is heavily phosphorylated and is enriched in proline residues. In this work it is shown that this region harbors an SH3 domain binding motif (Sh3BM) PxRxPR through which cellular amphiphysin is recruited to viral replication sites and to nsP3 containing cytoplasmic aggregate structures. The function of Sh3BM was destroyed by a single point mutation, which led to impaired viral RNA replication in HeLa cells, pointing out the functional importance of amphiphysin recruitment by the Sh3BM. In addition, evidence is provided tho show that the endosomal localization of alphavirus replication is mediated by nsP3 and that the phosphorylation of hypervariable region might be important for the endosomal targeting. Together these findings demonstrate that nsP3 contains multiple important host interaction motifs and domains, which facilitate successful viral propagation in host cells.

Geochemistry and petrology of the ferropicrite dikes and associated rocks of Vestfjella, western Dronning Maud Land, Antarctica

This study provides insights into the composition and origin of ferropicrite dikes (FeOtot = 13 17 wt. %; MgO = 13 19 wt. %) and associated meimechite, picrite, picrobasalt, and basalt dikes found at Vestfjella, western Dronning Maud Land, Antarctica. The dikes crosscut Jurassic Karoo continental flood basalts (CFB) that were emplaced during the early stages of the breakup of the Gondwana supercontinent ~180 Ma ago. Selected samples (31 overall from at least eleven dikes) were analyzed for their mineral chemical, major element, trace element, and Sr, Nd, Pb, and Os isotopic compositions. The studied samples can be divided into two geochemically distinct types: (1) The depleted type (24 samples from at least nine dikes) is relatively depleted in the most incompatible elements and exhibits isotopic characteristics (e.g., initial εNd of +4.8 to +8.3 and initial 187Os/188Os of 0.1256 0.1277 at 180 Ma) similar to those of mid-ocean ridge basalts (MORB); (2) The enriched type (7 samples from at least two dikes) exhibits relatively enriched incompatible element and isotopic characteristics (e.g., initial εNd of +1.8 to +3.6 and initial 187Os/188Os of 0.1401 0.1425 at 180 Ma) similar to those of oceanic island basalts. Both magma types have escaped significant contamination by the continental crust. The depleted type is related to the main phase of Karoo magmatism and originated as highly magnesian (MgO up to 25 wt. %) partial melts at high temperatures (mantle potential temperature >1600 °C) and pressures (~5 6 GPa) from a sublithospheric, water-bearing, depleted peridotite mantle source. The enriched type sampled pyroxene-bearing heterogeneities that can be traced down to either recycled oceanic crust or melt-metasomatized portions of the sublithospheric or lithospheric mantle. The source of the depleted type represents a sublithospheric end-member source for many Karoo lavas and has subsequently been sampled by the MORBs of the Indian Ocean. These observations, together with the purported high temperatures, indicate that the Karoo CFBs were formed in an extensive melting episode caused mainly by internal heating of the upper mantle beneath the Gondwana supercontinent. My research supports the view that ferropicritic melts can be generated in several ways: the relative Fe-enrichment of mantle partial melts is most readily achieved by (1) relatively low degree of partial melting, (2) high pressure of partial melting, and (3) melting of enriched source components (e.g., pyroxenite and metasomatized peridotite). Ferropicritic whole-rock compositions could also result from accumulation, secondary alteration, and fractional crystallization, however, and caution is required when addressing the parental magma composition.

Eläimen tuttuus ja vieraus : Fenomenologisen empatiateorian uudelleentulkinta ja sen sovellus vieraslajisia eläimiä koskevaan kokemukseen

Within the field of philosophy, animals have traditionally been studied from two perspectives: that of self-knowledge and that of ethics. The analysis of the differences between humans and animals has served our desire to understand our own specificity, whereas ethical discussions have ultimately aimed at finding the right way to treat animals. This dissertation proposes a different way of looking at non-human animals: it investigates the question of how non-human animals appear to us humans in our perceptual experience. The analysis focuses on the empathetic, embodied understanding of animals diverse movements and other expressions. The theoretical point of departure for the research is phenomenological philosophy, in particular Maurice Merleau-Ponty s phenomenology of the body. Edmund Husserl s and Edith Stein s analyses of empathy and embodiment are also crucial to the work. In this tradition, empathy means understanding the other s experience through her bodily expressions and seeing the other body as living, as well as motivated and directed towards the surrounding world. The dissertation both explicates and criticizes the earlier phenomenological notions of empathy and human specificity. In order to elucidate the fundamental structures of our experience of non-human animals, it also applies the phenomenological method, which consists of a phenomenological reduction and a free variation of the different aspects of experience. It is shown that our experiences of non-human animals involve a recognition of both similarities and differences. This recognition, however, is not primarily based on intellectual comparisons but is lived as an embodied relationship to another body, and its manifestations vary from one instant to the next. The analysis also reveals that the object of empathy is not the other s experience as such, not even as it is manifested by the other s movements, but rather the other s embodied situation, enriched by elements that remain outside the scope of the other s experience. The dissertation shows that human existence is intertwined with the existence of non-human animals on four levels: those of empathetic sensations, reciprocal communication, experience of the surrounding world and self-definitions. The animals different modes of perception prove to expand our understanding of what is perceivable and how things can be perceived. The presence of non-human animals in our perceptual world is revealed as something that both shows us the limits of our own embodiment and enables us to overcome these limits in empathetic acts. Finally, it is demonstrated that the life of non-human animals is intertwined with ours in a far more complex way than has been presupposed in traditional descriptions of human-animal differences.

Neoarchean sanukitoid series in the Karelian Province, Finland

Sanukitoid series intrusions can be found throughout the Archean Karelian Province of the Fennoscandian shield. All sanukitoids share the same controversial elemental characteristics: they have high content of incompatible elements such as K, Ba, and Sr as well as high content of the compatible elements Mg, Cr, and Ni, and high Mg#. This composition is explained by an enriched mantle wedge origin in a Neoarchean subduction setting. This study concentrates on sanukitoid intrusions and tonalite-trondhjemite-granodiorite series (TTGs) from Finnish part of the Karelian Province. The collected rock samples have been studied in the field and under microscope as well as for their whole-rock (including isotopes) and mineral compositions. The new data together with previously published analyses help us to better understand the petrogenesis, tectonic setting and reworking of the Archean rock units. TTGs from the Karelian Province form a voluminous series of granitoids and reworked migmatites. This study divides TTG series into two subgroups based on their elemental composition: low-HREE (heavy rare earth element) TTGs and high-HREE TTGs indicating pressure differences in their source. Sanukitoid series is a minor, divergent group of intrusions. These intrusions are variable sized, and the texture varies from even-grained to K-feldspar porphyritic. The elemental composition differentiates sanukitoids from more voluminous TTG groups, the SiO2 in sanukitoids varies to include series of gabbro, diorite, and granodiorite. U Pb age determinations from sanukitoid series show temporally limited emplacement between ~ 2745 2715 Ma after the main crust forming period in the area. Hafnium, neodymium, common lead, and oxygene isotopes indicate well homogenized characteristics. Recycled crust has made a variable, yet minor, contribution to sanukitoids, as evidenced by oxygene isotopes and inherited zircon cores. A proposed tectonic setting for the formation of the sanukitoid series is slab breakoff of oceanic lithosphere in subduction setting, with sanukitoids deriving from an enriched mantle wedge. The proposed setting explains some of the peculiar features of sanukitoids, such as their temporally limited occurrence and controversial elemental composition. Sanukitoids would occur after cessation of the regional growth of Archean crust, and they could be derived from mantle wedge previously enriched by melts and fluids from oceanic crust and sediments. A subsequent event during the Paleoproterozoic Svecofennian orogeny at ~1.9 Ga affected the appearance and microstructures of the rocks as well as caused redistribution of lead between minerals and whole rock. However, the deformation was not able to obliterate the original geochemical characteristics of these sanukitoids.