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.

High-rate, Single-Symbol Decodable Distributed STBCs for Partially-Coherent Cooperative Networks

Space-time block codes (STBCs) that are single-symbol decodable (SSD) in a co-located multiple antenna setting need not be SSD in a distributed cooperative communication setting. A relay network with N relays and a single source-destination pair is called a partially-coherent relay channel (PCRC) if the destination has perfect channel state information (CSI) of an the channels and the relays have only the phase information of the source-to-relay channels. In our earlier work, we had derived a set of necessary and sufficient conditions for a distributed STBC (DSTBC) to be SSD for a PCRC. Using these conditions, in this paper we show that the possibility of channel phase compensation operation at the relay nodes using partial CSI at the relays increases the possible rate of SSD DSTBCs from 2/N when the relays do not have CSI to 1/2, which is independent of N. We also show that when a DSTBC is SSD for a PCRC, then arbitrary coordinate interleaving of the in-phase and quadrature-phase components of the variables does not disturb its SSD property. Using this property we are able to construct codes that are SSD and have higher rate than 2/N but giving full diversity only for signal constellations satisfying certain conditions.

Influence of Cooling Rate on the Enthalpy Relaxation and Fragility of a Metallic Glass

Structural relaxation behavior of a rapidly quenched (RQ) and a slowly cooled Pd40Cu30Ni10P20 metallic glass was investigated and compared. Differential scanning calorimetry was employed to monitor the relaxation enthalpies at the glass transition temperature, T-g , and the Kolrausch-Williams-Watts (KWW) stretched exponential function was used to describe its variation with annealing time. It was found that the rate of enthalpy recovery is higher in the ribbon, implying that the bulk is more resistant to relaxation at low temperatures of annealing. This was attributed to the possibility of cooling rate affecting the locations where the glasses get trapped within the potential energy landscape. The RQ process traps a larger amount of free volume, resulting in higher fragility, and in turn relaxes at the slightest thermal excitation (annealing). The slowly cooled bulk metallic glass (BMG), on the other hand, entraps lower free volume and has more short-range ordering, hence requiring a large amount of perturbation to access lower energy basins.

Low-delay, high-rate, non-square STBCs from scaled complex orthogonal designs

Space-time block codes (STBCs) obtained from non-square complex orthogonal designs are bandwidth efficient compared to those from square real/complex orthogonal designs for colocated coherent MIMO systems and has other applications in (i) non-coherent MIMO systems with non-differential detection, (ii) Space-Time-Frequency codes for MIMO-OFDM systems and (iii) distributed space-time coding for relay channels. Liang (IEEE Trans. Inform. Theory, 2003) has constructed maximal rate non-square designs for any number of antennas, with rates given by [(a+1)/(2a)] when number of transmit antennas is 2a-1 or 2a. However, these designs have large delays. When large number of antennas are considered this rate is close to 1/2. Tarokh et al (IEEE Trans. Inform. Theory, 1999) have constructed rate 1/2 non-square CODs using the rate-1 real orthogonal designs for any number of antennas, where the decoding delay of these codes is less compared to the codes constructed by Liang for number of transmit antennas more than 5. In this paper, we construct a class of rate-1/2 codes for arbitrary number of antennas where the decoding delay is reduced by 50% when compared with the rate-1/2 codes given by Tarokh et al. It is also shown that even though scaling the variables helps to lower the delay it can not be used to increase the rate.

Quantitation and characterization of glutathionyl haemoglobin as an oxidative stress marker in chronic renal failure by mass spectrometry

Objectives: Glutathionyl haemoglobin (GS-Hb) belonging to the class of glutathionylated proteins has been investigated as a possible marker of oxidative stress in different chronic diseases. The purpose of this study was to examine whether glutathionyl haemoglobin can serve as an oxidative stress marker in non-diabetic chronic renal failure patients on different renal replacement therapies (RRT) through its quantitation, and characterization of the specific binding site of glutathione in haemoglobin molecule by mass spectrometric analysis. Design and methods: The study group consisted of non-diabetic chronic renal failure patients on renal replacement therapy (RRT): hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD) and renal allograft transplant (Txp) patients. Haemoglobin samples of these subjects were analyzed by liquid chromatography electrospray ionization mass spectrometry for GS-Hb quantitation. Characterization of GS-Hb was done by tandem mass spectrometry. Levels of erythrocyte glutathione (GSH) and lipid peroxidation (as thiobarbituric acid reacting substances) were measured spectrophotometrically, while glycated baernoglobin (HbA1c) was measured by HPLC. Results: GS-Hb levels were markedly elevated in the dialysis group and marginally in the transplant group as compared to the controls. GS-Hb levels correlated positively with lipid peroxidation and negatively with the erythrocyte glutathione levels in RRT groups indicating enhanced oxidative stress. De novo sequencing of the chymotryptic fragment of GS-Hb established that glutathione is attached to Cys-93 of the beta globin chain. Mass spectrometric quantitation of total glycated haemoglobin showed good agreement with HbA1c estimation by conventional HPLC method. Conclusions: Glutathionyl haemoglobin can serve as a clinical marker of oxidative stress in chronic debilitating therapies like RRT. Mass spectrometry provides a reliable analytical tool for quantitation and residue level characterization of different post-translational modifications of haemoglobin. (c) 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

The Pandolf load carriage equation is a poor predictor of metabolic rate while wearing explosive ordnance disposal protective clothing

This investigation aimed to quantify metabolic rate when wearing an explosive ordnance disposal (EOD) ensemble (~33kg) during standing and locomotion; and determine whether the Pandolf load carriage equation accurately predicts metabolic rate when wearing an EOD ensemble during standing and locomotion. Ten males completed 8 trials with metabolic rate measured through indirect calorimetry. Walking in EOD at 2.5, 4.0 and 5.5km·h−1 was significantly (p < 0.05) greater than matched trials without the EOD ensemble by 49% (127W), 65% (213W) and 78% (345W), respectively. Mean bias (95% limits of agreement) between predicted and measured metabolism during standing, 2.5, 4 and 5.5km·h−1 were 47W (19 to 75W); −111W (−172 to −49W); −122W (−189 to −54W) and −158W (−245 to −72W), respectively. The Pandolf equation significantly underestimated measured metabolic rate during locomotion. These findings have practical implications for EOD technicians during training and operation and should be considered when developing maximum workload duration models and work-rest schedules.

Gravitino phenomenology and cosmological implications of supergravity

In this thesis we consider the phenomenology of supergravity, and in particular the particle called "gravitino". We begin with an introductory part, where we discuss the theories of inflation, supersymmetry and supergravity. Gravitino production is then investigated into details, by considering the research papers here included. First we study the scattering of massive W bosons in the thermal bath of particles, during the period of reheating. We show that the process generates in the cross section non trivial contributions, which eventually lead to unitarity breaking above a certain scale. This happens because, in the annihilation diagram, the longitudinal degrees of freedom in the propagator of the gauge bosons disappear from the amplitude, by virtue of the supergravity vertex. Accordingly, the longitudinal polarizations of the on-shell W become strongly interacting in the high energy limit. By studying the process with both gauge and mass eigenstates, it is shown that the inclusion of diagrams with off-shell scalars of the MSSM does not cancel the divergences. Next, we approach cosmology more closely, and study the decay of a scalar field S into gravitinos at the end of inflation. Once its mass is comparable to the Hubble rate, the field starts coherent oscillations about the minimum of its potential and decays pertubatively. We embed S in a model of gauge mediation with metastable vacua, where the hidden sector is of the O'Raifeartaigh type. First we discuss the dynamics of the field in the expanding background, then radiative corrections to the scalar potential V(S) and to the Kähler potential are calculated. Constraints on the reheating temperature are accordingly obtained, by demanding that the gravitinos thus produced provide with the observed Dark Matter density. We modify consistently former results in the literature, and find that the gravitino number density and T_R are extremely sensitive to the parameters of the model. This means that it is easy to account for gravitino Dark Matter with an arbitrarily low reheating temperature.

Optimal configurations of active fiber composites based on asymptotic torsional analysis - art. no. 641413

Active Fiber Composites (AFC) possess desirable characteristics over a wide range of smart structure applications, such as vibration, shape and flow control as well as structural health monitoring. This type of material, capable of collocated actuation and sensing, call be used in smart structures with self-sensing circuits. This paper proposes four novel applications of AFC structures undergoing torsion: sensors and actuators shaped as strips and tubes; and concludes with a preliminary failure analysis. To enable this, a powerful mathematical technique, the Variational Asymptotic Method (VAM) was used to perform cross-sectional analyses of thin generally anisotropic AFC beams. The resulting closed form expressions have been utilized in the applications presented herein.

On the duality between rate and power optimizations

Sequence design problems are considered in this paper. The problem of sum power minimization in a spread spectrum system can be reduced to the problem of sum capacity maximization, and vice versa. A solution to one of the problems yields a solution to the other. Subsequently, conceptually simple sequence design algorithms known to hold for the white-noise case are extended to the colored noise case. The algorithms yield an upper bound of 2N - L on the number of sequences where N is the processing gain and L the number of non-interfering subsets of users. If some users (at most N - 1) are allowed to signal along a limited number of multiple dimensions, then N orthogonal sequences suffice.

On the maximal rate of non-square STBCs from complex orthogonal designs

A Linear Processing Complex Orthogonal Design (LPCOD) is a p x n matrix epsilon, (p >= n) in k complex indeterminates x(1), x(2),..., x(k) such that (i) the entries of epsilon are complex linear combinations of 0, +/- x(i), i = 1,..., k and their conjugates, (ii) epsilon(H)epsilon = D, where epsilon(H) is the Hermitian (conjugate transpose) of epsilon and D is a diagonal matrix with the (i, i)-th diagonal element of the form l(1)((i))vertical bar x(1)vertical bar(2) + l(2)((i))vertical bar x(2)vertical bar(2)+...+ l(k)((i))vertical bar x(k)vertical bar(2) where l(j)((i)), i = 1, 2,..., n, j = 1, 2,...,k are strictly positive real numbers and the condition l(1)((i)) = l(2)((i)) = ... = l(k)((i)), called the equal-weights condition, holds for all values of i. For square designs it is known. that whenever a LPCOD exists without the equal-weights condition satisfied then there exists another LPCOD with identical parameters with l(1)((i)) = l(2)((i)) = ... = l(k)((i)) = 1. This implies that the maximum possible rate for square LPCODs without the equal-weights condition is the same as that or square LPCODs with equal-weights condition. In this paper, this result is extended to a subclass of non-square LPCODs. It is shown that, a set of sufficient conditions is identified such that whenever a non-square (p > n) LPCOD satisfies these sufficient conditions and do not satisfy the equal-weights condition, then there exists another LPCOD with the same parameters n, k and p in the same complex indeterminates with l(1)((i)) = l(2)((i)) = ... = l(k)((i)) = 1.

A rate-one full-diversity low-complexity space-time-frequency block code (STFBC) for 4-Tx MIMO-OFDM

It is known that by employing space-time-frequency codes (STFCs) to frequency selective MIMO-OFDM systems, all the three diversity viz spatial, temporal and multipath can be exploited. There exists space-time-frequency block codes (STFBCs) designed using orthogonal designs with constellation precoder to get full diversity (Z.Liu, Y.Xin and G.Giannakis IEEE Trans. Signal Processing, Oct. 2002). Since orthogonal designs of rate one exists only for two transmit antennas, for more than two transmit antennas STFBCs of rate-one and full-diversity cannot be constructed using orthogonal designs. This paper presents a STFBC scheme of rate one for four transmit antennas designed using quasi-orthogonal designs along with co-ordinate interleaved orthogonal designs (Zafar Ali Khan and B. Sundar Rajan Proc: ISIT 2002). Conditions on the signal sets that give full-diversity are identified. Simulation results are presented to show the superiority of our codes over the existing ones.

A systematic design of high-rate full-diversity space-frequency codes for MIMO-OFDM systems

This paper presents a systematic construction of high-rate and full-diversity space-frequency block codes for MIMO-OFDM systems. While all prior constructions offer only a maximum rate of one complex symbol per channel use, our construction yields rate equal to the number of transmit antennas and simultaneously achieves full-diversity. The proposed construction works for arbitrary number of transmit antennas and arbitrary channel power delay profile. A key step in this construction is the generalization of the stacked matrix code design criteria given by Bolcskei et.al., (IEEE WCNC 2000). Explicit equivalence of our generalized code design criteria with the Hadamard-product based criteria of W. Su et.al., (lEEE Trans. Sig. Proc. Nov 2003) is established and new high-rate codes are constructed using our criteria.

A unified construction of space-time codes with optimal rate-diversity tradeoff

The problem of constructing space-time (ST) block codes over a fixed, desired signal constellation is considered. In this situation, there is a tradeoff between the transmission rate as measured in constellation symbols per channel use and the transmit diversity gain achieved by the code. The transmit diversity is a measure of the rate of polynomial decay of pairwise error probability of the code with increase in the signal-to-noise ratio (SNR). In the setting of a quasi-static channel model, let n(t) denote the number of transmit antennas and T the block interval. For any n(t) <= T, a unified construction of (n(t) x T) ST codes is provided here, for a class of signal constellations that includes the familiar pulse-amplitude (PAM), quadrature-amplitude (QAM), and 2(K)-ary phase-shift-keying (PSK) modulations as special cases. The construction is optimal as measured by the rate-diversity tradeoff and can achieve any given integer point on the rate-diversity tradeoff curve. An estimate of the coding gain realized is given. Other results presented here include i) an extension of the optimal unified construction to the multiple fading block case, ii) a version of the optimal unified construction in which the underlying binary block codes are replaced by trellis codes, iii) the providing of a linear dispersion form for the underlying binary block codes, iv) a Gray-mapped version of the unified construction, and v) a generalization of construction of the S-ary case corresponding to constellations of size S-K. Items ii) and iii) are aimed at simplifying the decoding of this class of ST codes.