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.

Brain imaging of chronic pain

Acute pain has substantial survival value because of its protective function in the everyday environment. Instead, chronic pain lacks survival and adaptive function, causes great amount of individual suffering, and consumes the resources of the society due to the treatment costs and loss of production. The treatment of chronic pain has remained challenging because of inadequate understanding of mechanisms working at different levels of the nervous system in the development, modulation, and maintenance of chronic pain. Especially in unclear chronic pain conditions the treatment may be suboptimal because it can not be targeted to the underlying mechanisms. Noninvasive neuroimaging techniques have greatly contributed to our understanding of brain activity associated with pain in healthy individuals. Many previous studies, focusing on brain activations to acute experimental pain in healthy individuals, have consistently demonstrated a widely-distributed network of brain regions that participate in the processing of acute pain. The aim of the present thesis was to employ non-invasive brain imaging to better understand the brain mechanisms in patients suffering from chronic pain. In Study I, we used magnetoencephalography (MEG) to measure cortical responses to painful laser stimulation in healthy individuals for optimization of the stimulus parameters for patient studies. In Studies II and III, we monitored with MEG the cortical processing of touch and acute pain in patients with complex regional pain syndrome (CRPS). We found persisting plastic changes in the hand representation area of the primary somatosensory (SI) cortex, suggesting that chronic pain causes cortical reorganization. Responses in the posterior parietal cortex to both tactile and painful laser stimulation were attenuated, which could be associated with neglect-like symptoms of the patients. The primary motor cortex reactivity to acute pain was reduced in patients who had stronger spontaneous pain and weaker grip strength in the painful hand. The tight coupling between spontaneous pain and motor dysfunction supports the idea that motor rehabilitation is important in CRPS. In Studies IV and V we used MEG and functional magnetic resonance imaging (fMRI) to investigate the central processing of touch and acute pain in patients who suffered from recurrent herpes simplex virus infections and from chronic widespread pain in one side of the body. With MEG, we found plastic changes in the SI cortex, suggesting that many different types of chronic pain may be associated with similar cortical reorganization. With fMRI, we found functional and morphological changes in the central pain circuitry, as an indication of central contribution for the pain. These results show that chronic pain is associated with morphological and functional changes in the brain, and that such changes can be measured with functional imaging.

Low-impact Use: A New Standard

Once the ugly duckling of the lighting world, the fluorescent bulb recently has become something of an eco-darling thanks to its energy efficiency. Whereas a standard off-the-shelf incandescent bulb devotes only about five percent of its total electrical consumption to produce visible light (the remainder is released in heat), fluorescent lighting employs an entirely different process (it radiates rather than burns) that is four to six times more efficient. Fluorescents are indisputably superior in ­performance, but up to 5 milligrams of mercury, a hazardous trace metal, is included in the manufacture of each lamp

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.

Low energy properties of the SU(m|n) supersymmetric Haldane–Shastry spin chain

The ground state and low energy excitations of the SU(m|n) supersymmetric Haldane–Shastry spin chain are analyzed. In the thermodynamic limit, it is found that the ground state degeneracy is finite only for the SU(m|0) and SU(m|1) spin chains, while the dispersion relation for the low energy and low momentum excitations is linear for all values of m and n. We show that the low energy excitations of the SU(m|1) spin chain are described by a conformal field theory of m non-interacting Dirac fermions which have only positive energies; the central charge of this theory is m/2. Finally, for ngreater-or-equal, slanted1, the partition functions of the SU(m|n) Haldane–Shastry spin chain and the SU(m|n) Polychronakos spin chain are shown to be related in a simple way in the thermodynamic limit at low temperatures.

Low-frequency resistance fluctuations in metal films under current stressing at low temperature (T<0.3Tmelting)

In this paper, we report a systematic study of low frequency 1∕fα resistance fluctuation in thin metal films (Ag on Si) at different stages of damage process when the film is subjected to high current stressing. The resistance fluctuation (noise) measurement was carried out in situ using a small ac bias that has been mixed with the dc stressing current. The experiment has been carried out as a function of temperature in the range of 150–350 K. The experiment establishes that the current stressed film, as it undergoes damage due to various migration forces, develops an additional low-frequency noise spectral power that does not have the usual 1∕f spectral shape. The magnitude of extra term has an activated temperature dependence (activation energy of ≈0.1 eV) and has a 1∕f1.5 spectral dependence. The activation energy is the same as seen from the temperature dependence of the lifetime of the film. The extra 1∕f1.5 spectral power changes the spectral shape of the noise power as the damage process progress. The extra term likely arising from diffusion starts in the early stage of the migration process during current stressing and is noticeable much before any change can be detected in simultaneous resistance measurements. The experiment carried out over a large temperature range establish a strong correlation between the evolution of the migration process in a current stressed film and the low-frequency noise component that is not a 1∕f noise.

Low-Temperature Processing of ZrB2-ZrC Composites by Reactive Hot Pressing

Dense ZrB2-ZrC and ZrB2-ZrC x∼0.67 composites have been produced by reactive hot pressing (RHP) of stoichiometric and nonstoichiometric mixtures of Zr and B4C powders at 40 MPa and temperatures up to 1600 °C for 30 minutes. The role of Ni addition on reaction kinetics and densification of the composites has been studied. Composites of ∼97 pct relative density (RD) have been produced with the stoichiometric mixture at 1600 °C, while the composite with ∼99 pct RD has been obtained with excess Zr at 1200 °C, suggesting the formation of carbon deficient ZrC x that significantly aids densification by plastic flow and vacancy diffusion mechanism. Stoichiometric and nonstoichiometric composites have a hardness of ∼20 GPa. The grain sizes of ZrB2 and ZrC x∼0.67 are ∼0.6 and 0.4 μm, respectively, which are finer than those reported in the literature.

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.

Photobiomodulation by Low Power Laser Irradiation Involves Activation of Latent TGF-β1

Laser mediated stimulation of biological process was amongst its very first effects documented by Mester et al. but the ambiguous and tissue-cell context specific biological effects of laser radiation is now termed ‘Photobiomodulation’. We found many parallels between the reported biological effects of lasers and a multiface-ted growth factor, Transforming Growth Factor-β (TGF-β). This review outlines the interestingparallelsbetween the twofieldsand our rationalefor pursuingtheir potential causal correlation. We explored this correlation using an in vitro assay systems and a human clinical trial on healing wound extraction sockets that we reported in a recent publication. In conclusion we report that low power laser irradiation can activate latent TGF-β1 and β3 complexes and suggest that this might be one of the major modes of the photobiomodulatory effects of low power lasers.

Possible application of carbon nanotube bundles for low temperature sensing

We report on the R-T measurement of carbon nanotube bundles from room temperature down to 1 K. The resistance at a particular temperature depends on the diameter of the bundle. The larger the bundle diameter is, the lower the value of the resistance. The resistance increases with the decrease in temperature as in the case of carbon, carbon glass resistance thermometer, and carbon nanotubes reported in the literature. The rate of the variation of resistance depends on the resistance of the bundle at room temperature which can be explored for the low temperature thermometry. Overall, the resistance and the sensitivity of the bundle depend on the bundle diameter which can be monitored easily.

RECONNECT: A NoC for polymorphic ASICs using a low overhead single cycle router

A polymorphic ASIC is a runtime reconfigurable hardware substrate comprising compute and communication elements. It is a ldquofuture proofrdquo custom hardware solution for multiple applications and their derivatives in a domain. Interoperability between application derivatives at runtime is achieved through hardware reconfiguration. In this paper we present the design of a single cycle Network on Chip (NoC) router that is responsible for effecting runtime reconfiguration of the hardware substrate. The router design is optimized to avoid FIFO buffers at the input port and loop back at output crossbar. It provides virtual channels to emulate a non-blocking network and supports a simple X-Y relative addressing scheme to limit the control overhead to 9 bits per packet. The 8times8 honeycomb NoC (RECONNECT) implemented in 130 nm UMC CMOS standard cell library operates at 500 MHz and has a bisection bandwidth of 28.5 GBps. The network is characterized for random, self-similar and application specific traffic patterns that model the execution of multimedia and DSP kernels with varying network loads and virtual channels. Our implementation with 4 virtual channels has an average network latency of 24 clock cycles and throughput of 62.5% of the network capacity for random traffic. For application specific traffic the latency is 6 clock cycles and throughput is 87% of the network capacity.