Vascular dilatory function and cardiovascular risk factors in women with a history of pre-eclampsia

Women with a history of pre-eclampsia have an increased risk of cardiovascular disease in later life. The mechanisms which mediate this heightened risk are poorly understood; it was long believed that pre-eclampsia was a separate disease without any connection to other pathologies. The present study was undertaken to investigate the cardiovascular risk milieu, vascular dilatory function and cardiovascular risk factors, in women with pre-eclampsia, 5 6 years after index pregnancy. The aim was to understand better the cardiovascular risks associated with pre-eclampsia and add tools to the evaluation of cardiovascular risk in women. --- The study involved 30 women with previous severe pre-eclampsia and 21 controls. The 2-day study protocol included venous occlusion plethysmography and pulse wave analysis for assessment of vascular dilatory function and central pulse wave reflection, respectively, office and ambulatory blood pressure measurements, assessment of insulin sensitivity, using a minimal model technique, and tests regarding renal function, lipid metabolism, sympathetic activity and inflammation. Vasodilatory function was impaired in women with a history of pre-eclampsia; this was seen in both endothelium-dependent and endothelium-independent vasodilatation. Proteinuria during pre-eclampsia did not predict changes in vasodilatation, and renal function was similar in the two groups. Insulin sensitivity was related to vasodilatation and features of metabolic syndrome, but only in the patient group, despite similar insulin sensitivity in the control group. Arterial pressure was higher in the patient group than in the controls and correlated with endothelin-1 levels in the patient group, whilst the overall difference between the groups was diminished in 24 hour arterial pressure measurements. Additionally, women with previous pre-eclampsia were characterized by increased sympathetic activity. Impaired vasodilatory function at the vascular smooth muscle level seems to characterize clinically healthy women with a history of pre-eclampsia. These vascular changes and the features of metabolic syndrome may be related to the increased risk of cardiovascular disease. Furthermore, increased blood pressure in combination with enhanced sympathetic activity may be additive as regards this risk. These women should be informed about their potential cardiovascular risk profile and the possibilities to minimize it via their own actions. Medical cardiovascular risk assessment in women should include obstetric history.

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.

Inferring molecular function: contributions from functional linkages

In the current era of high-throughput sequencing and structure determination, functional annotation has become a bottleneck in biomedical science. Here, we show that automated inference of molecular function using functional linkages among genes increases the accuracy of functional assignments by >= 8% and enriches functional descriptions in >= 34% of top assignments. Furthermore, biochemical literature supports >80% of automated inferences for previously unannotated proteins. These results emphasize the benefit of incorporating functional linkages in protein annotation.

OFDM Based Distributed Space Time Coding for Asynchronous Relay Networks

Recently Li and Xia have proposed a transmission scheme for wireless relay networks based on the Alamouti space time code and orthogonal frequency division multiplexing to combat the effect of timing errors at the relay nodes. This transmission scheme is amazingly simple and achieves a diversity order of two for any number of relays. Motivated by its simplicity, this scheme is extended to a more general transmission scheme that can achieve full cooperative diversity for any number of relays. The conditions on the distributed space time block code (DSTBC) structure that admit its application in the proposed transmission scheme are identified and it is pointed out that the recently proposed full diversity four group decodable DST-BCs from precoded co-ordinate interleaved orthogonal designs and extended Clifford algebras satisfy these conditions. It is then shown how differential encoding at the source can be combined with the proposed transmission scheme to arrive at a new transmission scheme that can achieve full cooperative diversity in asynchronous wireless relay networks with no channel information and also no timing error knowledge at the destination node. Finally, four group decodable distributed differential space time block codes applicable in this new transmission scheme for power of two number of relays are also provided.

On the Average Case Communication Complexity for Detection in Sensor Networks

The problem of sensor-network-based distributed intrusion detection in the presence of clutter is considered. It is argued that sensing is best regarded as a local phenomenon in that only sensors in the immediate vicinity of an intruder are triggered. In such a setting, lack of knowledge of intruder location gives rise to correlated sensor readings. A signal-space viewpoint is introduced in which the noise-free sensor readings associated to intruder and clutter appear as surfaces $\mathcal{S_I}$ and $\mathcal{S_C}$ and the problem reduces to one of determining in distributed fashion, whether the current noisy sensor reading is best classified as intruder or clutter. Two approaches to distributed detection are pursued. In the first, a decision surface separating $\mathcal{S_I}$ and $\mathcal{S_C}$ is identified using Neyman-Pearson criteria. Thereafter, the individual sensor nodes interactively exchange bits to determine whether the sensor readings are on one side or the other of the decision surface. Bounds on the number of bits needed to be exchanged are derived, based on communication complexity (CC) theory. A lower bound derived for the two-party average case CC of general functions is compared against the performance of a greedy algorithm. The average case CC of the relevant greater-than (GT) function is characterized within two bits. In the second approach, each sensor node broadcasts a single bit arising from appropriate two-level quantization of its own sensor reading, keeping in mind the fusion rule to be subsequently applied at a local fusion center. The optimality of a threshold test as a quantization rule is proved under simplifying assumptions. Finally, results from a QualNet simulation of the algorithms are presented that include intruder tracking using a naive polynomial-regression algorithm.

Noncoherent low-decoding-complexity space-time codes for wireless relay networks

The differential encoding/decoding setup introduced by Kiran et at, Oggier et al and Jing et al for wireless relay networks that use codebooks consisting of unitary matrices is extended to allow codebooks consisting of scaled unitary matrices. For such codebooks to be used in the Jing-Hassibi protocol for cooperative diversity, the conditions that need to be satisfied by the relay matrices and the codebook are identified. A class of previously known rate one, full diversity, four-group encodable and four-group decodable Differential Space-Time Codes (DSTCs) is proposed for use as Distributed DSTCs (DDSTCs) in the proposed set up. To the best of our knowledge, this is the first known low decoding complexity DDSTC scheme for cooperative wireless networks.

Ischemia-reperfusion injury in human liver transplantation : Mechanisms and effects on graft function

Liver transplantation is an established therapy for both acute and chronic liver failure. Despite excellent long-term outcome, graft dysfunction remains a problem affecting up to 15-30% of the recipients. The etiology of dysfunction is multifactorial, with ischemia-reperfusion injury regarded as one of the most important contributors. This thesis focuses on the inflammatory response during graft procurement and reperfusion in liver transplantation in adults. Activation of protein C was examined as a potential endogenous anti-inflammatory mechanism. The effects of inflammatory responses on graft function and outcome were investigated. Seventy adult patients undergoing liver transplantation in Helsinki University Central Hospital, and 50 multiorgan donors, were studied. Blood samples from the portal and the hepatic veins were drawn before graft procurement and at several time points during graft reperfusion to assess changes within the liver. Liver biopsies were taken before graft preservation and after reperfusion. Neutrophil and monocyte CD11b and L-selectin expression were analysed by flow cytometry. Plasma TNF-α, IL-6, IL-8, sICAM-1, and HMGB1 were determined by ELISA and Western-blotting. HMGB1 immunohistochemistry was performed on liver tissue specimens. Plasma protein C and activated protein C were determined by an enzyme-capture assay. Hepatic IL-8 release during graft procurement was associated with subsequent graft dysfunction, biliary in particular, in the recipient. Biliary marker levels increased only 5 7 days after transplantation. Thus, donor inflammatory response appears to influence recipient liver function with relatively long-lasting effects. Hepatic phagocyte activation and sequestration, with concomitant HMGB1 release, occurred during reperfusion. Neither phagocyte activation nor plasma cytokines correlated with postoperative graft function. Thus, activation of the inflammatory responses within the liver during reperfusion may be of minor clinical significance. However, HMGB1 was released from hepatocytes and were also correlated with postoperative transaminase levels. Accordingly, HMGB1 appears to be a marker of hepatocellular injury.

Reengaging, reenacting and reenvisaging discourses of disaster through public space performance: Austerity, art, and the art of protest

This paper offers a mediation on disaster, recovery, resilience, and restoration of balance, in both a material and a metaphorical sense, when ‘disaster’ befalls not the body politic of the nation but the body personal. In the past few decades, of course, artists, activists and scholars have deliberately tried to avoid describing personal, physical and phenomenological experiences of the disabled body in terms of difficulty and disaster. This has been part of a political move, from a medical model, in which disability, disease and illness are positioned as personal catastrophes, to a social model, in which disability is positioned as a social construct that comes from systems, institutions and infrastructure designed to exclude different bodies. It is a move that is responsible for a certain discomfort people with disabilities, and artists with disabilities, today feel towards performances that deploy disability as a metaphor for disaster, from Hijikata, to Theatre Hora. In the past five years, though, this particular discourse has begun rising again, particularly as people with disabilities fact their own anything but natural disasters as a result of the austerity measures now widespread across the US, UK, Europe and elsewhere. Measures that threaten people’s ability to live, and take part in social and institutional life, in any meaningful way. Measures that, as artist Katherine Araniello notes, also bring additional difficulty, danger, and potential for disaster as they ripple outwards across the tides of familial ties, threatening family, friends, and careers who become bound up in the struggle to do more with less. In this paper, I consider how people with disabilities use performance, particularly public space interventionalist performance, to reengage, renact and reenvisage the discourse of national, economic, environmental or other forms of disaster, the need for austerity, the need to avoid providing people with support for desires and interests as well as basic daily needs, particularly when fraud and corruption is so right, and other such ideas that have become an all too unpleasant reality for many people. Performances, for instance, like Liz Crow’s Bedding Out, where she invited people into her bed – for people with disabilities a symbolic space, which necessarily becomes more a public living room restaurant, office and so forth than a private space when poor mobility means they spend much time it in – to talk about their lives, their difficulties, and dealing with austerity. Or, for instance, like the Bolshy Divas, who mimic public and political policy, reports and advertising paranoia to undermine their discourses about austerity. I examine the effects, politics and ethics of such interventions, including examination of the comparative effect of highly bodied interventions (like Crow’s) and highly disembodied interventions (like the Bolshy Diva’s) in discourses of difficulty, disaster and austerity on a range of target spectator communities.

Performing immobility / protesting immobility: The risks & rewards of public space protest performances

Though there is much interest in mobilities and performing mobilities as a characteristic of modern, urban, social life today, this is not always matched by attention to immobilities, as the flipside of mobility in modern life. In this paper, I investigate public space performances designed to draw attention to precisely this counterpoint to current discourses of mobilities – performances about the socially produced immobilities many people with disabilities find a more fundamental feature of day-to-day life, the fight for mobility, and the freedom found when accommodations for alternative mobilities are made available. Although public policy is increasingly aligned with a social model of disability, which sees disability as socially constructed through systems, institutions and infrastructure deliberately designed to exclude specific bodies – stairs, curbs, queues and so forth – and although governments in the US, UK, and to a lesser degree Australia, New Zealand and other Commonwealth nations aim to address these inequalities, the experience of immobility is still every-present for many people. This often comes not just from pain, or from impairment, or event from lack of accommodations for alternative mobilities, but from fellow social performers’ antipathy to, appropriation of, or destruction of accommodations designed to facilitate access for a range of different bodies in public space, and thus the public sphere. The archetypal instance of this tension between the mobile, and those needing accommodations to allow mobility, is, of course, the antipathy many able bodied people feel towards the provision of disabled parking spaces. A cursory search online shows thousands of accounts of antagonism, vitriol, and even violence prompted by disputes which began when a disabled person asked an able person to exit a designated disabled parking space. For many, it seems, expecting them to pass by such parks so others can experience the mobility they take for granted is too much. In this paper, I examine a number of protest performances in public space in which activist present actions – for example, placing wheelchairs in every regular parking space in a precinct – to give bystanders, passersby and spectators, as well as antagonistic fellow social performers, a sense of what socially produced immobility feels like. I examine responses to such protest performances, and what they say about the potential social, political and ethical impacts of such protests, in terms of their potential to produce new attitudes to mobility, alternative mobility, and access to alternative modes of mobility.

Observations of the solar wind-magnetosphere-ionosphere coupling

In this thesis, the solar wind-magnetosphere-ionosphere coupling is studied observationally, with the main focus on the ionospheric currents in the auroral region. The thesis consists of five research articles and an introductory part that summarises the most important results reached in the articles and places them in a wider context within the field of space physics. Ionospheric measurements are provided by the International Monitor for Auroral Geomagnetic Effects (IMAGE) magnetometer network, by the low-orbit CHAllenging Minisatellite Payload (CHAMP) satellite, by the European Incoherent SCATter (EISCAT) radar, and by the Imager for Magnetopause-to-Aurora Global Exploration (IMAGE) satellite. Magnetospheric observations, on the other hand, are acquired from the four spacecraft of the Cluster mission, and solar wind observations from the Advanced Composition Explorer (ACE) and Wind spacecraft. Within the framework of this study, a new method for determining the ionospheric currents from low-orbit satellite-based magnetic field data is developed. In contrast to previous techniques, all three current density components can be determined on a matching spatial scale, and the validity of the necessary one-dimensionality approximation, and thus, the quality of the results, can be estimated directly from the data. The new method is applied to derive an empirical model for estimating the Hall-to-Pedersen conductance ratio from ground-based magnetic field data, and to investigate the statistical dependence of the large-scale ionospheric currents on solar wind and geomagnetic parameters. Equations describing the amount of field-aligned current in the auroral region, as well as the location of the auroral electrojets, as a function of these parameters are derived. Moreover, the mesoscale (10-1000 km) ionospheric equivalent currents related to two magnetotail plasma sheet phenomena, bursty bulk flows and flux ropes, are studied. Based on the analysis of 22 events, the typical equivalent current pattern related to bursty bulk flows is established. For the flux ropes, on the other hand, only two conjugate events are found. As the equivalent current patterns during these two events are not similar, it is suggested that the ionospheric signatures of a flux rope depend on the orientation and the length of the structure, but analysis of additional events is required to determine the possible ionospheric connection of flux ropes.

Multilevel Dodecagonal Space Vector Generation for Open-end Winding Induction Motor Drive Using Conventional Three Level Inverters

A novel dodecagonal space vector structure for induction motor drive is presented in this paper. It consists of two dodecagons, with the radius of the outer one twice the inner one. Compared to existing dodecagonal space vector structures, to achieve the same PWM output voltage quality, the proposed topology lowers the switching frequency of the inverters and reduces the device ratings to half. At the same time, other benefits obtained from existing dodecagonal space vector structure are retained here. This includes the extension of the linear modulation range and elimination of all 6+/-1 harmonics (n=odd) from the phase voltage. The proposed structure is realized by feeding an open-end winding induction motor with two conventional three level inverters. A detailed calculation of the PWM timings for switching the space vector points is also presented. Simulation and experimental results indicate the possible application of the proposed idea for high power drives.

Structural Studies on the Second Mycobacterium smegmatis Dps: Invariant and Variable Features of Structure, Assembly and Function

A second DNA binding protein from stationary-phase cells of Mycobacterium smegmatis (MsDps2) has been identified from the bacterial genome. It was cloned, expressed and characterised and its crystal structure was determined. The core dodecameric structure of MsDps2 is the same as that of the Dps from the organism described earlier (MsDps1). However, MsDps2 possesses a long N-terminal tail instead of the C-terminal tail in MsDps1. This tail appears to be involved in DNA binding. It is also intimately involved in stabilizing the dodecamer. Partly on account of this factor, MsDps2 assembles straightway into the dodecamer, while MsDps1 does so on incubation after going through an intermediate trimeric stage. The ferroxidation centre is similar in the two proteins, while the pores leading to it exhibit some difference. The mode of sequestration of DNA in the crystalline array of molecules, as evidenced by the crystal structures, appears to be different in MsDps1 and MsDps2, highlighting the variability in the mode of Dps–DNA complexation. A sequence search led to the identification of 300 Dps molecules in bacteria with known genome sequences. Fifty bacteria contain two or more types of Dps molecules each, while 195 contain only one type. Some bacteria, notably some pathogenic ones, do not contain Dps. A sequence signature for Dps could also be derived from the analysis.