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Sample records for nephron stn study

  1. Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies

    PubMed Central

    Desgrange, Audrey; Cereghini, Silvia

    2015-01-01

    The nephron is the basic structural and functional unit of the vertebrate kidney. To ensure kidney functions, the nephrons possess a highly segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. During embryogenesis, nephron progenitors undergo a mesenchymal-to-epithelial transition (MET) and acquire different segment-specific cell fates along the proximo-distal axis of the nephron. Even if the morphological changes occurring during nephrogenesis are characterized, the regulatory networks driving nephron segmentation are still poorly understood. Interestingly, several studies have shown that the pronephric nephrons in Xenopus and zebrafish are segmented in a similar fashion as the mouse metanephric nephrons. Here we review functional and molecular aspects of nephron segmentation with a particular interest on the signaling molecules and transcription factors recently implicated in kidney development in these three different vertebrate model organisms. A complete understanding of the mechanisms underlying nephrogenesis in different model organisms will provide novel insights on the etiology of several human renal diseases. PMID:26378582

  2. The regulation of renal acid secretion: new observations from studies of distal nephron segments.

    PubMed

    Levine, D Z; Jacobson, H R

    1986-06-01

    In this review we have attempted to present for the general reader the new information on renal acidification that has emerged from the study of discrete segments of the distal nephron. We have structured our presentation in the context of the cation exchange hypothesis which has strongly influenced modern thinking of acid-base regulation. We have shown that distal nephron acidification is active and can proceed even in the absence of sodium. We have also shown beyond doubt, that pH or the determinants of pH can influence the rate of proton secretion in probably all of the distal nephron segments. We have drawn attention to an exciting new means by which chloride (or its substitution) could alter the rate of net bicarbonate transport. A possible role for bicarbonate secretory activity in the mammalian distal nephron has been discussed as has the influence of mineralocorticoids on acid secretion. There is no question that all of this new information has created the need for a reassessment of the validity of the cation exchange hypothesis. After all, this is a view which specifically denies that renal acid excretion is modulated by pH of the blood, and affirms that it is intrarenal sodium handling that is the "driving force", so to speak, behind acidification responses. However, it seems inappropriate at this time to insist that current data do not allow for a component of sodium transport by the distal nephron to modulate the rate of acid secretion. It is also possible, as we have suggested, that an important effect of chloride gradients, independent of blood pH, could alter bicarbonate retrieval. Most importantly, we wish to stress that much of the in vitro perfusion data does not derive from animals subjected to the chronic acid-base derangements which were precisely those situations to which the cation exchange hypothesis was directed. Simply put, the whole animal studies of Schwartz and his colleagues provided no experimental observations on intrarenal sodium

  3. Proximal Nephron

    PubMed Central

    Zhuo, Jia L.; Li, Xiao C.

    2013-01-01

    The kidney plays a fundamental role in maintaining body salt and fluid balance and blood pressure homeostasis through the actions of its proximal and distal tubular segments of nephrons. However, proximal tubules are well recognized to exert a more prominent role than distal counterparts. Proximal tubules are responsible for reabsorbing approximately 65% of filtered load and most, if not all, of filtered amino acids, glucose, solutes, and low molecular weight proteins. Proximal tubules also play a key role in regulating acid-base balance by reabsorbing approximately 80% of filtered bicarbonate. The purpose of this review article is to provide a comprehensive overview of new insights and perspectives into current understanding of proximal tubules of nephrons, with an emphasis on the ultrastructure, molecular biology, cellular and integrative physiology, and the underlying signaling transduction mechanisms. The review is divided into three closely related sections. The first section focuses on the classification of nephrons and recent perspectives on the potential role of nephron numbers in human health and diseases. The second section reviews recent research on the structural and biochemical basis of proximal tubular function. The final section provides a comprehensive overview of new insights and perspectives in the physiological regulation of proximal tubular transport by vasoactive hormones. In the latter section, attention is particularly paid to new insights and perspectives learnt from recent cloning of transporters, development of transgenic animals with knockout or knockin of a particular gene of interest, and mapping of signaling pathways using microarrays and/or physiological proteomic approaches. PMID:23897681

  4. Micropuncture study of the effect of furosemide on proximal and distal tubules of the rat nephron.

    PubMed

    Romano, G; Favret, G; Bartoli, E

    1995-01-01

    The tubular effects of furosemide were studied by micropuncture and clearance techniques on 20 rats. Collections of tubular fluid (TF) from early distal (ED) and late proximal (LP) segments of the same nephrons and of different nephrons were performed during baseline conditions. Re-collections were taken from the same sites and new collections from different nephrons after 10 mg/kg furosemide. The glomerular filtration rate (GFR) was 1,309 +/- 212 microliters/min during baseline, and 1,348 +/- 199 microliters/min after furosemide (p > 0.89); while the urine flow rate rose from 36 +/- 8 to 167 +/- 30 microliters/min (p < 0.001). The nephron filtration rate (NFR) was not different in 46 paired distal (33.3 +/- 2.6 nl/min) versus proximal samples (34.2 +/- 2.9 nl/min, p > 0.72), neither was it different during baseline (37.2 +/- 1.4, n = 120) as compared to furosemide (37.2 +/- 2.7, n = 91, p > 0.99). The percent reabsorption (PR) at the ED sampling site was 87 +/- 4% during baseline, and 89 +/- 3% in 13 paired samples during furosemide (p > 0.47). PR at the LP sampling sites was 83 +/- 2% during baseline, and 80 +/- 2% in 26 paired samples during furosemide (p > 0.63). In 31 paired ED-LP collections, PR was 82 +/- 4 (ED) versus 72 +/- 4% (LP) during baseline, and 87 +/- 3 versus 74 +/- 6%, respectively, during furosemide. The respective collection rates were 4.6 +/- 1.0 versus 9.5 +/- 1.3 nl/min during baseline (p < 0.0001), 5.8 +/- 2.3 versus 8.7 +/- 3.0 nl/min during furosemide. The LP-ED differences obtained during baseline were not different from those measured during furosemide for the collection rate, PR and NFRs. The absolute LP resorption rate was not significantly different during baseline as compared to furosemide. Thus, furosemide did not affect the difference between ED and LP collection sites in collection rate, absolute and fractional reabsorption, in the absence of changes in GFR and NFR. These data indicate that furosemide acts solely along Henle

  5. Micropuncturing the Nephron

    PubMed Central

    Vallon, Volker

    2010-01-01

    Summary To achieve the role of the kidney in maintaining body homeostasis, the renal vasculature, the glomeruli, and the various segments of the nephron and the collecting duct system have to fulfil very diverse and specific functions. These functions are dependent on a complex renal architecture and are regulated by systemic hemodynamics, hormones and nerves. As a consequence, to better understand the physiology of the kidney, methods are necessary that allow insights on the function of these diverse structures in the physiological context of the intact kidney. The renal micropuncture technique allows direct access to study superficial nephrons in vivo. In this review, the application of micropuncture techniques on the single nephron level is outlined as an approach to better understand aspects of glomerular filtration, tubular transport, and tubulo-glomerular communication. Studies from the author’s lab, including experiments in gene-targeted mice, are briefly presented to illustrate some of the approaches and show how they can further advance our understanding of the molecular mechanisms involved in the regulation of kidney function. PMID:18752000

  6. A structural study of the rat proximal and distal nephron: effect of peptide and thyroid hormones.

    PubMed

    Koechlin, N; Elalouf, J M; Kaissling, B; Roinel, N; de Rouffignac, C

    1989-05-01

    The effects of the absence of various hormones (antidiuretic hormone, thyroid hormone, parathyroid hormone, and calcitonin) on proximal and distal structures were studied in diabetes insipidus (DI) Brattleboro rats. The cross-sectional area of the first segment of proximal convoluted tubules (S1) was significantly reduced in thyroparathyroidectomized (TPTX) DI rats compared with Long-Evans rats (the strain of origin of DI rats) and untreated DI rats. Administration of triiodothyronine (T3, 10 micrograms/day for 7 days) to TPTX-DI rats restored the proximal tubule structure. In the distal convoluted tubule (DCT) the cross-sectional area of the epithelium and the number of nuclei per cross-sectional area were significantly greater in untreated ADH-deficient DI rats than in the control Long-Evans rats. Daily administration of 1-desamino-8-D-arginine vasopressin (dDAVP, 500 ng/day for 3 wk) significantly reduced the size and the number of DCT cells in DI rats. Cortical micropuncture data indicated that the Na+ concentration in the fluid delivered to the DCT and the absolute amount of Na+ reabsorbed along the DCT were higher in DI than in dDAVP-treated DI rats. It is concluded that functional changes in the PCT, subsequent to chronic TPTX, are accompanied by marked alteration of the cell anatomy of this nephron segment, and that the processes that modify the Na load delivered to the DCT and the Na transport in the DCT are accompanied by structural modifications of this segment. PMID:2719159

  7. Does nephron number matter in the development of kidney disease?

    PubMed

    Douglas-Denton, Rebecca N; McNamara, Bridgette J; Hoy, Wendy E; Hughson, Michael D; Bertram, John F

    2006-01-01

    The total number of nephrons in normal human kidneys varies over a 10-fold range. This variation in total nephron number leads us to question whether low nephron number increases the risk of renal disease in adulthood. This review considers the available evidence in humans linking low nephron number/reduced nephron endowment and the susceptibility to renal disease. Total nephron number in humans has been directly correlated with birth weight and inversely correlated with age, mean glomerular volume, and hypertension. Low nephron number may be the result of suboptimal nephrogenesis during kidney development and/or loss of nephrons once nephrogenesis has been completed. Low nephron number is frequently, but not always, associated with hypertrophy of remaining glomeruli. This compensatory hypertrophy has also been associated with a greater susceptibility for kidney disease. Three human studies have reported reduced nephron number in subjects with a history of hypertension. This correlation has been observed in White Europeans, White Americans (but not African Americans) and Australian Aborigines. Studies in additional populations are required, as well as a greater understanding of the fetal environmental and genetic determinants of low nephron number. PMID:16774009

  8. STN1 protects chromosome ends in Arabidopsis thaliana

    PubMed Central

    Song, Xiangyu; Leehy, Katherine; Warrington, Ross T.; Lamb, Jonathan C.; Surovtseva, Yulia V.; Shippen, Dorothy E.

    2008-01-01

    Telomeres shield the natural ends of chromosomes from nucleolytic attack, recognition as double-strand breaks, and inappropriate processing by DNA repair machinery. The trimeric Stn1/Ten1/Cdc13 complex is critical for chromosome end protection in Saccharomyces cerevisiae, while vertebrate telomeres are protected by shelterin, a complex of six proteins that does not include STN1 or TEN1. Recent studies demonstrate that Stn1 and Ten1 orthologs in Schizosaccharomyces pombe contribute to telomere integrity in a complex that is distinct from the shelterin components, Pot1 and Tpp1. Thus, chromosome-end protection may be mediated by distinct subcomplexes of telomere proteins. Here we report the identification of a STN1 gene in Arabidopsis that is essential for chromosome-end protection. AtSTN1 encodes an 18-kDa protein bearing a single oligonucleotide/oligosaccharide binding fold with significant sequence similarity to the yeast Stn1 proteins. Plants null for AtSTN1 display an immediate onset of growth and developmental defects and reduced fertility. These outward phenotypes are accompanied by catastrophic loss of telomeric and subtelomeric DNA, high levels of end-to-end chromosome fusions, increased G-overhang signals, and elevated telomere recombination. Thus, AtSTN1 is a crucial component of the protective telomere cap in Arabidopsis, and likely in other multicellular eukaryotes. PMID:19064932

  9. Renal blood flow and oxygenation drive nephron progenitor differentiation.

    PubMed

    Rymer, Christopher; Paredes, Jose; Halt, Kimmo; Schaefer, Caitlin; Wiersch, John; Zhang, Guangfeng; Potoka, Douglas; Vainio, Seppo; Gittes, George K; Bates, Carlton M; Sims-Lucas, Sunder

    2014-08-01

    During kidney development, the vasculature develops via both angiogenesis (branching from major vessels) and vasculogenesis (de novo vessel formation). The formation and perfusion of renal blood vessels are vastly understudied. In the present study, we investigated the regulatory role of renal blood flow and O2 concentration on nephron progenitor differentiation during ontogeny. To elucidate the presence of blood flow, ultrasound-guided intracardiac microinjection was performed, and FITC-tagged tomato lectin was perfused through the embryo. Kidneys were costained for the vasculature, ureteric epithelium, nephron progenitors, and nephron structures. We also analyzed nephron differentiation in normoxia compared with hypoxia. At embryonic day 13.5 (E13.5), the major vascular branches were perfused; however, smaller-caliber peripheral vessels remained unperfused. By E15.5, peripheral vessels started to be perfused as well as glomeruli. While the interior kidney vessels were perfused, the peripheral vessels (nephrogenic zone) remained unperfused. Directly adjacent and internal to the nephrogenic zone, we found differentiated nephron structures surrounded and infiltrated by perfused vessels. Furthermore, we determined that at low O2 concentration, little nephron progenitor differentiation was observed; at higher O2 concentrations, more differentiation of the nephron progenitors was induced. The formation of the developing renal vessels occurs before the onset of blood flow. Furthermore, renal blood flow and oxygenation are critical for nephron progenitor differentiation. PMID:24920757

  10. Renal blood flow and oxygenation drive nephron progenitor differentiation

    PubMed Central

    Rymer, Christopher; Paredes, Jose; Halt, Kimmo; Schaefer, Caitlin; Wiersch, John; Zhang, Guangfeng; Potoka, Douglas; Vainio, Seppo; Gittes, George K.; Bates, Carlton M.

    2014-01-01

    During kidney development, the vasculature develops via both angiogenesis (branching from major vessels) and vasculogenesis (de novo vessel formation). The formation and perfusion of renal blood vessels are vastly understudied. In the present study, we investigated the regulatory role of renal blood flow and O2 concentration on nephron progenitor differentiation during ontogeny. To elucidate the presence of blood flow, ultrasound-guided intracardiac microinjection was performed, and FITC-tagged tomato lectin was perfused through the embryo. Kidneys were costained for the vasculature, ureteric epithelium, nephron progenitors, and nephron structures. We also analyzed nephron differentiation in normoxia compared with hypoxia. At embryonic day 13.5 (E13.5), the major vascular branches were perfused; however, smaller-caliber peripheral vessels remained unperfused. By E15.5, peripheral vessels started to be perfused as well as glomeruli. While the interior kidney vessels were perfused, the peripheral vessels (nephrogenic zone) remained unperfused. Directly adjacent and internal to the nephrogenic zone, we found differentiated nephron structures surrounded and infiltrated by perfused vessels. Furthermore, we determined that at low O2 concentration, little nephron progenitor differentiation was observed; at higher O2 concentrations, more differentiation of the nephron progenitors was induced. The formation of the developing renal vessels occurs before the onset of blood flow. Furthermore, renal blood flow and oxygenation are critical for nephron progenitor differentiation. PMID:24920757

  11. [Application of support vector machine approach in studying nephron toxicity of Chinese medicinal materials].

    PubMed

    Zhang, Jing-fang; Jiang, Lu-di; Zhang, Yan-ling

    2015-03-01

    On the basis of web databases, 111 compounds with nephrotoxicity and 90 compounds without nephrotoxicity were collected as data set of nephrotoxicity discrimination model, 39 compounds with tubular necrosis and 39 compounds without tubular necrosis were collected as data set of tubular necrosis discrimination model. The 6 122 molecular descriptors, including physicochemical, charge distribution and geometrical descriptors were calculated to characterize the molecular structure of the above-mentioned compounds. CfsSubsetEval valuation method and BestFirst-D1-N5 searching method were used to select molecular descriptors. Two models with high accuracy were built based on the support vector machine (SVM) approach, respectively. Accuracy, sensitivity, specificity and matthew's correlation coefficient of the two models were all above 70%. By using 22 nephrotoxicity compounds of Chinese medicine, the nephrotoxicity discrimination model was further verified with an accuracy of 72.73%. Using the tubular necrosis discrimination model, 10 potential compounds which can cause tubular necrosis were screened from the positive results of nephrotoxicity discrimination model, 6 of them have been verified by literatures. The results demonstrated that the discrimination models can be applied to screen nephrotoxic compounds from Chinese medicinal materials, and they also offer a new research idea for the further studies on the mechanism of nephrotoxicity. PMID:26226759

  12. Stn1-Ten1 is an Rpa2-Rpa3-like complex at telomeres

    SciTech Connect

    Sun, Jia; Yu, Eun Young; Yang, Yuting; Confer, Laura A; Sun, Steven H; Wan, Ke; Lue, Neal F; Lei, Ming

    2010-09-02

    In budding yeast, Cdc13, Stn1, and Ten1 form a heterotrimeric complex (CST) that is essential for telomere protection and maintenance. Previous bioinformatics analysis revealed a putative oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus of Stn1 (Stn1N) that shows limited sequence similarity to the OB fold of Rpa2, a subunit of the eukaryotic ssDNA-binding protein complex replication protein A (RPA). Here we present functional and structural analyses of Stn1 and Ten1 from multiple budding and fission yeast. The crystal structure of the Candida tropicalis Stn1N complexed with Ten1 demonstrates an Rpa2N-Rpa3-like complex. In both structures, the OB folds of the two components pack against each other through interactions between two C-terminal helices. The structure of the C-terminal domain of Saccharomyces cerevisiae Stn1 (Stn1C) was found to comprise two related winged helix-turn-helix (WH) motifs, one of which is most similar to the WH motif at the C terminus of Rpa2, again supporting the notion that Stn1 resembles Rpa2. The crystal structure of the fission yeast Schizosaccharomyces pombe Stn1N-Ten1 complex exhibits a virtually identical architecture as the C. tropicalis Stn1N-Ten1. Functional analyses of the Candida albicans Stn1 and Ten1 proteins revealed critical roles for these proteins in suppressing aberrant telomerase and recombination activities at telomeres. Mutations that disrupt the Stn1-Ten1 interaction induce telomere uncapping and abolish the telomere localization of Ten1. Collectively, our structural and functional studies illustrate that, instead of being confined to budding yeast telomeres, the CST complex may represent an evolutionarily conserved RPA-like telomeric complex at the 3' overhangs that works in parallel with or instead of the well-characterized POT1-TPP1/TEBP{alpha}-{beta} complex.

  13. Effects of STN DBS on Memory Guided Force Control in Parkinson’s Disease (June 2007)

    PubMed Central

    Prodoehl, Janey; Corcos, Daniel M.; Rothwell, John C.; Metman, Leo Verhagen; Bakay, Roy A. E.; Vaillancourt, David E.

    2008-01-01

    This study examined the control of elbow force in nine patients with Parkinson’s disease when visual feedback was available and when visual feedback was removed to determine how medication (Meds) and unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) affect memory guided force control. Patients were examined in each of four treatment conditions: 1) off treatment; 2) Meds; 3) STN DBS; and 4) Meds plus STN DBS. With visual feedback available, there was no difference in force output across treatment conditions. When visual feedback was removed force output drifted under the target in both the off-treatment and the Meds conditions. However, when on STN DBS or Meds plus STN DBS force output drifted above the target. As such, only STN DBS had a significant effect on force output in the vision removed condition. Increased force output when on STN DBS may have occurred due to disruptions in the basal ganglia-thalamo-cortical circuitry. We suggest that modulation of output of the internal segment of the globus pallidus by STN DBS may drive the effect of STN DBS on memory guided force control. PMID:17601184

  14. Effects of STN DBS on memory guided force control in Parkinson's disease (June 2007).

    PubMed

    Prodoehl, Janey; Corcos, Daniel M; Rothwell, John C; Metman, Leo Verhagen; Bakay, Roy A E; Vaillancourt, David E

    2007-06-01

    This study examined the control of elbow force in nine patients with Parkinson's disease when visual feedback was available and when visual feedback was removed to determine how medication (Meds) and unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) affect memory guided force control. Patients were examined in each of four treatment conditions: 1) off treatment; 2) Meds; 3) STN DBS; and 4) Meds plus STN DBS. With visual feedback available, there was no difference in force output across treatment conditions. When visual feedback was removed force output drifted under the target in both the off-treatment and the Meds conditions. However, when on STN DBS or Meds plus STN DBS force output drifted above the target. As such, only STN DBS had a significant effect on force output in the vision removed condition. Increased force output when on STN DBS may have occurred due to disruptions in the basal ganglia-thalamo-cortical circuitry. We suggest that modulation of output of the internal segment of the globus pallidus by STN DBS may drive the effect of STN DBS on memory guided force control. PMID:17601184

  15. Visualization of Three-Dimensional Nephron Structure With Microcomputed Tomography

    SciTech Connect

    Bentley,M.; Jorgensen, S.; Lerman, L.; Ritman, E.; Romero, J.

    2007-01-01

    The three-dimensional architecture of nephrons in situ and their interrelationship with other nephrons are difficult to visualize by microscopic methods. The present study uses microcomputed X-ray tomography (micro-CT) to visualize intact nephrons in situ. Rat kidneys were perfusion-fixed with buffered formalin and their vasculature was subsequently perfused with radiopaque silicone. Cortical tissue was stained en bloc with osmium tetroxide, embedded in plastic, scanned, and reconstructed at voxel resolutions of 6, 2, and 1 {mu}m. At 6 {mu}m resolution, large blood vessels and glomeruli could be visualized but nephrons and their lumens were small and difficult to visualize. Optimal images were obtained using a synchrotron radiation source at 2 {mu}m resolution where nephron components could be identified, correlated with histological sections, and traced. Proximal tubules had large diameters and opaque walls, whereas distal tubules, connecting tubules, and collecting ducts had smaller diameters and less opaque walls. Blood vessels could be distinguished from nephrons by the luminal presence of radiopaque silicone. Proximal tubules were three times longer than distal tubules. Proximal and distal tubules were tightly coiled in the outer cortex but were loosely coiled in the middle and inner cortex. The connecting tubules had the narrowest diameters of the tubules and converged to form arcades that paralleled the radial vessels as they extended to the outer cortex. These results illustrate a potential use of micro-CT to obtain three-dimensional information about nephron architecture and nephron interrelationships, which could be useful in evaluating experimental tubular hypertrophy, atrophy, and necrosis.

  16. Live nephron imaging by MRI.

    PubMed

    Qian, Chunqi; Yu, Xin; Pothayee, Nikorn; Dodd, Stephen; Bouraoud, Nadia; Star, Robert; Bennett, Kevin; Koretsky, Alan

    2014-11-15

    The local sensitivity of MRI can be improved with small MR detectors placed close to regions of interest. However, to maintain such sensitivity advantage, local detectors normally need to communicate with the external amplifier through cable connections, which prevent the use of local detectors as implantable devices. Recently, an integrated wireless amplifier was developed that can efficiently amplify and broadcast locally detected signals, so that the local sensitivity was enhanced without the need for cable connections. This integrated detector enabled the live imaging of individual glomeruli using negative contrast introduced by cationized ferritin, and the live imaging of renal tubules using positive contrast introduced by gadopentetate dimeglumine. Here, we utilized the high blood flow to image individual glomeruli as hyperintense regions without any contrast agent. These hyperintense regions were identified for pixels with signal intensities higher than the local average. Addition of Mn(2+) allowed the simultaneous detection of both glomeruli and renal tubules: Mn(2+) was primarily reabsorbed by renal tubules, which would be distinguished from glomeruli due to higher enhancement in T1-weighted MRI. Dynamic studies of Mn(2+) absorption confirmed the differential absorption affinity of glomeruli and renal tubules, potentially enabling the in vivo observation of nephron function. PMID:25186296

  17. Closed-loop stimulation of a delayed neural fields model of parkinsonian STN-GPe network: a theoretical and computational study

    PubMed Central

    Detorakis, Georgios Is.; Chaillet, Antoine; Palfi, Stéphane; Senova, Suhan

    2015-01-01

    Several disorders are related to pathological brain oscillations. In the case of Parkinson's disease, sustained low-frequency oscillations (especially in the β-band, 13–30 Hz) correlate with motor symptoms. It is still under debate whether these oscillations are the cause of parkinsonian motor symptoms. The development of techniques enabling selective disruption of these β-oscillations could contribute to the understanding of the underlying mechanisms, and could be exploited for treatments. A particularly appealing technique is Deep Brain Stimulation (DBS). With clinical electrical DBS, electrical currents are delivered at high frequency to a region made of potentially heterogeneous neurons (the subthalamic nucleus (STN) in the case of Parkinson's disease). Even more appealing is DBS with optogenetics, which is until now a preclinical method using both gene transfer and deep brain light delivery and enabling neuromodulation at the scale of one given neural network. In this work, we rely on delayed neural fields models of STN and the external Globus Pallidus (GPe) to develop, theoretically validate and test in silico a closed-loop stimulation strategy to disrupt these sustained oscillations with optogenetics. First, we rely on tools from control theory to provide theoretical conditions under which sustained oscillations can be attenuated by a closed-loop stimulation proportional to the measured activity of STN. Second, based on this theoretical framework, we show numerically that the proposed closed-loop stimulation efficiently attenuates sustained oscillations, even in the case when the photosensitization effectively affects only 50% of STN neurons. We also show through simulations that oscillations disruption can be achieved when the same light source is used for the whole STN population. We finally test the robustness of the proposed strategy to possible acquisition and processing delays, as well as parameters uncertainty. PMID:26217171

  18. Maternal Fat Feeding Augments Offspring Nephron Endowment in Mice

    PubMed Central

    Hokke, Stacey; Puelles, Victor G.; Armitage, James A.; Fong, Karen; Bertram, John F.; Cullen-McEwen, Luise A.

    2016-01-01

    Increasing consumption of a high fat 'Western' diet has led to a growing number of pregnancies complicated by maternal obesity. Maternal overnutrition and obesity have health implications for offspring, yet little is known about their effects on offspring kidney development and renal function. Female C57Bl6 mice were fed a high fat diet (HFD, 21% fat) or matched normal fat diet (NFD, 6% fat) for 6 weeks prior to pregnancy and throughout gestation and lactation. HFD dams were overweight and glucose intolerant prior to mating but not in late gestation. Offspring of NFD and HFD dams had similar body weights at embryonic day (E)15.5, E18.5 and at postnatal day (PN)21. HFD offspring had normal ureteric tree development and nephron number at E15.5. However, using unbiased stereology, kidneys of HFD offspring were found to have 20–25% more nephrons than offspring of NFD dams at E18.5 and PN21. Offspring of HFD dams with body weight and glucose profiles similar to NFD dams prior to pregnancy also had an elevated nephron endowment. At 9 months of age, adult offspring of HFD dams displayed mild fasting hyperglycaemia but similar body weights to NFD offspring. Renal function and morphology, measured by transcutaneous clearance of FITC-sinistrin and stereology respectively, were normal. This study demonstrates that maternal fat feeding augments offspring nephron endowment with no long-term consequences for offspring renal health. Future studies assessing the effects of a chronic stressor on adult mice with augmented nephron number are warranted, as are studies investigating the molecular mechanisms that result in high nephron endowment. PMID:27547968

  19. Maternal Fat Feeding Augments Offspring Nephron Endowment in Mice.

    PubMed

    Hokke, Stacey; Puelles, Victor G; Armitage, James A; Fong, Karen; Bertram, John F; Cullen-McEwen, Luise A

    2016-01-01

    Increasing consumption of a high fat 'Western' diet has led to a growing number of pregnancies complicated by maternal obesity. Maternal overnutrition and obesity have health implications for offspring, yet little is known about their effects on offspring kidney development and renal function. Female C57Bl6 mice were fed a high fat diet (HFD, 21% fat) or matched normal fat diet (NFD, 6% fat) for 6 weeks prior to pregnancy and throughout gestation and lactation. HFD dams were overweight and glucose intolerant prior to mating but not in late gestation. Offspring of NFD and HFD dams had similar body weights at embryonic day (E)15.5, E18.5 and at postnatal day (PN)21. HFD offspring had normal ureteric tree development and nephron number at E15.5. However, using unbiased stereology, kidneys of HFD offspring were found to have 20-25% more nephrons than offspring of NFD dams at E18.5 and PN21. Offspring of HFD dams with body weight and glucose profiles similar to NFD dams prior to pregnancy also had an elevated nephron endowment. At 9 months of age, adult offspring of HFD dams displayed mild fasting hyperglycaemia but similar body weights to NFD offspring. Renal function and morphology, measured by transcutaneous clearance of FITC-sinistrin and stereology respectively, were normal. This study demonstrates that maternal fat feeding augments offspring nephron endowment with no long-term consequences for offspring renal health. Future studies assessing the effects of a chronic stressor on adult mice with augmented nephron number are warranted, as are studies investigating the molecular mechanisms that result in high nephron endowment. PMID:27547968

  20. The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment.

    PubMed

    Cebrian, Cristina; Asai, Naoya; D'Agati, Vivette; Costantini, Frank

    2014-04-10

    Nephrons, the functional units of the kidney, develop from progenitor cells (cap mesenchyme [CM]) surrounding the epithelial ureteric bud (UB) tips. Reciprocal signaling between UB and CM induces nephrogenesis and UB branching. Although low nephron number is implicated in hypertension and renal disease, the mechanisms that determine nephron number are obscure. To test the importance of nephron progenitor cell number, we genetically ablated 40% of these cells, asking whether this would limit kidney size and nephron number or whether compensatory mechanisms would allow the developing organ to recover. The reduction in CM cell number decreased the rate of branching, which in turn allowed the number of CM cells per UB tip to normalize, revealing a self-correction mechanism. However, the retarded UB branching impaired kidney growth, leaving a permanent nephron deficit. Thus, the number of fetal nephron progenitor cells is an important determinant of nephron endowment, largely via its effect on UB branching. PMID:24656820

  1. Three-dimensional reconstruction of the rat nephron.

    PubMed

    Christensen, Erik I; Grann, Birgitte; Kristoffersen, Inger B; Skriver, Elisabeth; Thomsen, Jesper S; Andreasen, Arne

    2014-03-15

    This study gives a three-dimensional (3D) structural analysis of rat nephrons and their connections to collecting ducts. Approximately 4,500 2.5-μm-thick serial sections from the renal surface to the papillary tip were obtained from each of 3 kidneys of Wistar rats. Digital images were recorded and aligned into three image stacks and traced from image to image. Short-loop nephrons (SLNs), long-loop nephrons (LLNs), and collecting ducts (CDs) were reconstructed in 3D. We identified a well-defined boundary between the outer stripe and the inner stripe of the outer medulla corresponding to the transition of descending thick limbs to descending thin limbs and between the inner stripe and the inner medulla, i.e., the transition of ascending thin limbs into ascending thick limbs of LLNs. In all nephrons, a mosaic pattern of proximal tubule (PT) cells and descending thin limb (DTL) cells was observed at the transition between the PT and the DTL. The course of the LLNs revealed tortuous proximal "straight" tubules and winding of the DTLs within the outer half of the inner stripe. The localization of loop bends of SLNs in the inner stripe of the outer medulla and the bends of LLNs in the inner medulla reflected the localization of their glomeruli; i.e., the deeper the glomerulus, the deeper the bend. Each CD drained approximately three to six nephrons with a different pattern than previously established in mice. This information will provide a basis for evaluation of structural changes within nephrons as a result of physiological or pharmaceutical intervention. PMID:24477686

  2. Nephron organoids derived from human pluripotent stem cells model kidney development and injury.

    PubMed

    Morizane, Ryuji; Lam, Albert Q; Freedman, Benjamin S; Kishi, Seiji; Valerius, M Todd; Bonventre, Joseph V

    2015-11-01

    Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) may enable organ regeneration, disease modeling and drug screening. We report an efficient, chemically defined protocol for differentiating hPSCs into multipotent nephron progenitor cells (NPCs) that can form nephron-like structures. By recapitulating metanephric kidney development in vitro, we generate SIX2+ SALL1+ WT1+ PAX2+ NPCs with 90% efficiency within 9 days of differentiation. The NPCs possess the developmental potential of their in vivo counterparts and form PAX8+ LHX1+ renal vesicles that self-organize into nephron structures. In both two- and three-dimensional culture, NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle and distal tubules in an organized, continuous arrangement that resembles the nephron in vivo. We also show that this organoid culture system can be used to study mechanisms of human kidney development and toxicity. PMID:26458176

  3. Transcriptional Control of Terminal Nephron Differentiation

    PubMed Central

    El-Dahr, Samir S.; Aboudehen, Karam; Saifudeen, Zubaida

    2008-01-01

    Terminal differentiation of epithelial cells into more specialized cell types is a critical step of organogenesis. Throughout the process of terminal differentiation, epithelial progenitors acquire or up-regulate expression of renal function genes and cease to proliferate, while expression of embryonic genes is repressed. This exquisite coordination of gene expression is accomplished by signaling networks and transcription factors which couple the external environment with the new functional demands of the cell. While there has been much progress in understanding the early steps involved in renal epithelial cell differentiation, a major gap remains in our knowledge of the factors that control the steps of terminal differentiation. A number of signaling molecules and transcription factors have been recently implicated in determining segmental nephron identity and functional differentiation. While some of these factors (the p53 gene family, HNF1β) promote the terminal epithelial differentiation fate, others (Notch, Brn-1, IRX, KLF4 and Foxi1) tend to regulate differentiation of specific nephron segments and individual cell types. This article summarizes current knowledge related to these transcription factors and discusses how diverse cellular signals are integrated to generate a transcriptional output during the process of terminal differentiation. Since these transcriptional processes are accompanied by profound changes in nuclear chromatin structure involving the genes responsible for creating and maintaining the differentiated cell phenotype, future studies should focus on identifying the nature of these epigenetic events and factors, how they are regulated temporally and spatially, and the chromatin environment they eventually reside in. PMID:18287399

  4. Towards Automated Three-Dimensional Tracking of Nephrons through Stacked Histological Image Sets

    PubMed Central

    Bhikha, Charita; Andreasen, Arne; Christensen, Erik I.; Letts, Robyn F. R.; Pantanowitz, Adam; Rubin, David M.; Thomsen, Jesper S.; Zhai, Xiao-Yue

    2015-01-01

    An automated approach for tracking individual nephrons through three-dimensional histological image sets of mouse and rat kidneys is presented. In a previous study, the available images were tracked manually through the image sets in order to explore renal microarchitecture. The purpose of the current research is to reduce the time and effort required to manually trace nephrons by creating an automated, intelligent system as a standard tool for such datasets. The algorithm is robust enough to isolate closely packed nephrons and track their convoluted paths despite a number of nonideal, interfering conditions such as local image distortions, artefacts, and interstitial tissue interference. The system comprises image preprocessing, feature extraction, and a custom graph-based tracking algorithm, which is validated by a rule base and a machine learning algorithm. A study of a selection of automatically tracked nephrons, when compared with manual tracking, yields a 95% tracking accuracy for structures in the cortex, while those in the medulla have lower accuracy due to narrower diameter and higher density. Limited manual intervention is introduced to improve tracking, enabling full nephron paths to be obtained with an average of 17 manual corrections per mouse nephron and 58 manual corrections per rat nephron. PMID:26170896

  5. Glomerular and tubular adaptive responses to acute nephron loss in the rat. Effect of prostaglandin synthesis inhibition.

    PubMed Central

    Pelayo, J C; Shanley, P F

    1990-01-01

    These studies, using in vivo micropuncture techniques in the Munich-Wistar rat, document the magnitude of changes in glomerular and tubular function and structure 24 h after approximately 75% nephron loss (Nx) and compared these results with those obtained in sham-operated rats. The contribution of either nephron hypertrophy or renal prostaglandin to these adjustments in nephron function was also explored. After acute Nx, single nephron GFR (SNGFR) was increased, on average by approximately 30%, due primarily to glomerular hyperperfusion and hypertension. The approximately 45% reduction in preglomerular and the constancy in postglomerular vascular resistances was entirely responsible for these adaptations. Although increases in fluid reabsorption in proximal convoluted tubules correlated closely with increase in SNGFR, the fractional fluid reabsorption between late proximal and early distal tubular segments was depressed. Nephron hypertrophy could not be substantiated based on either measurements of protein content in renal tissue homogenates or morphometric analysis of proximal convoluted tubules. However, acute Nx was associated with increased urinary excretory rates per functional nephron for 6-keto-PGF1 alpha and TXB2. Prostaglandin synthesis inhibition did not affect function in control nephrons, but this maneuver was associated with normalization of glomerular and tubular function in remnant nephrons. The results suggest that enhanced synthesis of cyclooxygenase-dependent products is one of the earliest responses to Nx, and even before hypertrophy the pathophysiologic effects of prostaglandin may be important contributors to the adaptations in remnant nephron function. PMID:1693376

  6. Perceived Changes in Communication as an Effect of STN Surgery in Parkinson's Disease: A Qualitative Interview Study

    PubMed Central

    Ahlberg, Emilia; Laakso, Katja; Hartelius, Lena

    2011-01-01

    The aim of the present study was to explore four individuals' perspective of the way their speech and communication changed as a result of subthalamic nucleus deep brain stimulation treatment for Parkinson's disease. Interviews of two men and two women were analyzed using qualitative content analysis. Three themes emerged as a result of the analysis. The first theme included sub-themes describing both increased and unexpected communication difficulties such as a more vulnerable speech function, re-emerging stuttering and cognitive difficulties affecting communication. The second theme comprised strategies to improve communication, using different speech techniques and communicative support, as well as trying to achieve changes in medical and stimulation parameters. The third theme included descriptions of mixed feelings surrounding the surgery. Participants described the surgery as an unavoidable dramatic change, associated both with improved quality of life but also uncertainty and lack of information, particularly regarding speech and communication changes. Despite negative effects on speech, the individuals were generally very pleased with the surgical outcome. More information before surgery regarding possible side effects on speech, meeting with a previously treated patient and possibly voice and speech therapy before or after surgery are suggested to facilitate the adjustment to the new speech conditions. PMID:21876840

  7. Perceived Changes in Communication as an Effect of STN Surgery in Parkinson's Disease: A Qualitative Interview Study.

    PubMed

    Ahlberg, Emilia; Laakso, Katja; Hartelius, Lena

    2011-01-01

    The aim of the present study was to explore four individuals' perspective of the way their speech and communication changed as a result of subthalamic nucleus deep brain stimulation treatment for Parkinson's disease. Interviews of two men and two women were analyzed using qualitative content analysis. Three themes emerged as a result of the analysis. The first theme included sub-themes describing both increased and unexpected communication difficulties such as a more vulnerable speech function, re-emerging stuttering and cognitive difficulties affecting communication. The second theme comprised strategies to improve communication, using different speech techniques and communicative support, as well as trying to achieve changes in medical and stimulation parameters. The third theme included descriptions of mixed feelings surrounding the surgery. Participants described the surgery as an unavoidable dramatic change, associated both with improved quality of life but also uncertainty and lack of information, particularly regarding speech and communication changes. Despite negative effects on speech, the individuals were generally very pleased with the surgical outcome. More information before surgery regarding possible side effects on speech, meeting with a previously treated patient and possibly voice and speech therapy before or after surgery are suggested to facilitate the adjustment to the new speech conditions. PMID:21876840

  8. Deep brain stimulation induces BOLD activation in motor and non-motor networks: An fMRI comparison study of STN and EN/GPi DBS in large animals

    PubMed Central

    Min, Hoon-Ki; Hwang, Sun-Chul; Marsh, Michael P.; Kim, Inyong; Knight, Emily; Striemer, Bryan; Felmlee, Joel P.; Welker, Kirk M.; Blaha, Charles D.; Chang, Su-Youne; Bennet, Kevin E.; Lee, Kendall H.

    2012-01-01

    The combination of deep brain stimulation (DBS) and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. The goal of this study was to trace DBS-induced global neuronal network activation in a large animal model by monitoring the blood oxygenation level-dependent (BOLD) response on fMRI. We conducted DBS in normal anesthetized pigs, targeting the subthalamic nucleus (STN) (n=7) and the entopeduncular nucleus (EN), the non-primate analogue of the primate globus pallidus interna (n=4). Using a normalized functional activation map for group analysis and the application of general linear modeling across subjects, we found that both STN and EN DBS significantly increased BOLD activation in the ipsilateral sensorimotor network (FDR < 0.001). In addition, we found differential, target-specific, non-motor network effects. In each group the activated brain areas showed a distinctive correlation pattern forming a group of network connections. Results suggest that the scope of DBS extends beyond an ablation-like effect and that it may have modulatory effects not only on circuits that facilitate motor function but also on those involved in higher cognitive and emotional processing. Taken together, our results show that the swine model for DBS fMRI, which conforms to human implanted DBS electrode configurations and human neuroanatomy, may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS. PMID:22967832

  9. Cystic gene dosage influences kidney lesions after nephron reduction.

    PubMed

    Le Corre, Stéphanie; Viau, Amandine; Burtin, Martine; El-Karoui, Khalil; Cnops, Yvette; Terryn, Sara; Debaix, Huguette; Bérissi, Sophie; Gubler, Marie-Claire; Devuyst, Olivier; Terzi, Fabiola

    2015-01-01

    Cystic kidney disease is characterized by the progressive development of multiple fluid-filled cysts. Cysts can be acquired, or they may appear during development or in postnatal life due to specific gene defects and lead to renal failure. The most frequent form of this disease is the inherited polycystic kidney disease (PKD). Experimental models of PKD showed that an increase of cellular proliferation and apoptosis as well as defects in apico-basal and planar cell polarity or cilia play a critical role in cyst development. However, little is known about the mechanisms and the mediators involved in acquired cystic kidney diseases (ACKD). In this study, we used the nephron reduction as a model to study the mechanisms underlying cyst development in ACKD. We found that tubular dilations after nephron reduction recapitulated most of the morphological features of ACKD. The development of tubular dilations was associated with a dramatic increase of cell proliferation. In contrast, the apico-basal polarity and cilia did not seem to be affected. Interestingly, polycystin 1 and fibrocystin were markedly increased and polycystin 2 was decreased in cells lining the dilated tubules, whereas the expression of several other cystic genes did not change. More importantly, Pkd1 haploinsufficiency accelerated the development of tubular dilations after nephron reduction, a phenotype that was associated to a further increase of cell proliferation. These data were relevant to humans ACKD, as cystic genes expression and the rate of cell proliferation were also increased. In conclusion, our study suggests that the nephron reduction can be considered a suitable model to study ACKD and that dosage of genes involved in PKD is also important in ACKD. PMID:25531116

  10. Reduced nephron endowment in the neonates of Indigenous Australian peoples.

    PubMed

    Kandasamy, Y; Smith, R; Wright, I M R; Lumbers, E R

    2014-02-01

    Rates of chronic kidney disease (CKD) among Indigenous groups in Australia exceed non-Indigenous rates eight-fold. Using kidney volume as a surrogate for nephron number, we carried out a study to determine if Indigenous neonates have a smaller kidney volume (and thus a reduced nephron number) from birth compared with non-Indigenous neonates. We recruited term and preterm neonates (<32 weeks) at a tertiary care neonatal unit over a 12 months period. Preterm neonates were assessed (renal sonography and renal function measurement) at 32 weeks corrected age (CA) and again at 38 weeks CA when blood pressure was also measured. All term neonates were assessed in the first post-natal week, including renal sonography, renal function and blood pressure measurement. The primary outcome measured was total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) was a secondary outcome. Data was available for 44 preterm (11 Indigenous) and 39 term (13 Indigenous) neonates. TKV of Indigenous neonates was significantly lower at 32 weeks [12.0 (2.0) v. 15.4 (5.1) ml; P=0.03] and 38 weeks CA [18.6 (4.0) v. 22.6 (5.9) ml; P=0.04] respectively. Term Indigenous neonates also had smaller kidney volumes compared with non-Indigenous neonates. Despite a smaller kidney volume (and reduced nephron number), Indigenous neonates did not have a significantly lower eGFR. Indigenous neonates achieve similar eGFRs to Non-Indigenous neonates, presumably through a higher single nephron filtration rate. This places Indigenous neonates at a greater risk of long-term kidney damage later in life. PMID:24847688

  11. SCIENTIFIC AND TECHNICAL INFORMATION NETWORK (STN INTERNATIONAL)

    EPA Science Inventory

    STN International (the Scientific and Technical Information Network) offers both a fee based online search service that provides accurate, up-to-date, specific information from over 200 scientific, technical, business, and patent databases, and also fee based WWW access to select...

  12. Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis

    PubMed Central

    Xu, Jingyue; Liu, Han; Park, Joo-Seop; Lan, Yu; Jiang, Rulang

    2014-01-01

    Mammalian kidney organogenesis involves reciprocal epithelial-mesenchymal interactions that drive iterative cycles of nephron formation. Recent studies have demonstrated that the Six2 transcription factor acts cell autonomously to maintain nephron progenitor cells, whereas canonical Wnt signaling induces nephron differentiation. How Six2 maintains the nephron progenitor cells against Wnt-directed commitment is not well understood, however. We report here that Six2 is required to maintain expression of Osr1, a homolog of the Drosophila odd-skipped zinc-finger transcription factor, in the undifferentiated cap mesenchyme. Tissue-specific inactivation of Osr1 in the cap mesenchyme caused premature depletion of nephron progenitor cells and severe renal hypoplasia. We show that Osr1 and Six2 act synergistically to prevent premature differentiation of the cap mesenchyme. Furthermore, although both Six2 and Osr1 could form protein interaction complexes with TCF proteins, Osr1, but not Six2, enhances TCF interaction with the Groucho family transcriptional co-repressors. Moreover, we demonstrate that loss of Osr1 results in β-catenin/TCF-mediated ectopic activation of Wnt4 enhancer-driven reporter gene expression in the undifferentiated nephron progenitor cells in vivo. Together, these data indicate that Osr1 plays crucial roles in Six2-dependent maintenance of nephron progenitors during mammalian nephrogenesis by stabilizing TCF-Groucho transcriptional repressor complexes to antagonize Wnt-directed nephrogenic differentiation. PMID:24598167

  13. STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice

    PubMed Central

    Williams, Nolan R.; Foote, Kelly D.; Okun, Michael S.

    2014-01-01

    When formulating a deep brain stimulation (DBS) treatment plan for a patient with Parkinson’s disease (PD), two critical questions should be addressed: 1- Which brain target should be chosen to optimize this patient’s outcome? and 2- Should this patient’s DBS operation be unilateral or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the subthalamic nucleus (STN) and the globus pallidus internus (GPi). While the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all Parkinson’s disease cases (Figure 1). This bilateral STN “one-size-fits-all” approach was challenged by an editorial entitled “STN vs. GPi: The Rematch,” which appeared in the Archives of Neurology in 2005. Since 2005, a series of well designed clinical trials and follow-up studies have addressed the question as to whether a more tailored approach to DBS therapy might improve overall outcomes. Such a tailored approach would include the options of targeting the GPi, or choosing a unilateral operation. The results of the STN vs. GPi ‘rematch’ studies support the conclusion that bilateral STN DBS may not be the best option for every Parkinson’s disease surgical patient. Off period motor symptoms and tremor improve in both targets, and with either unilateral or bilateral stimulation. Advantages of the STN target include more medication reduction, less frequent battery changes, and a more favorable economic profile. Advantages of GPi include more robust dyskinesia suppression, easier programming, and greater flexibility in adjusting medications. In cases where unilateral stimulation is anticipated, the data favor GPi DBS. This review summarizes the accumulated evidence regarding the use of bilateral vs. unilateral DBS and the selection of STN vs. GPi DBS, including definite and possible advantages of different targets and approaches. Based on this evidence, a more patient-tailored, symptom specific

  14. Nephron organoids derived from human pluripotent stem cells model kidney development and injury

    PubMed Central

    Morizane, Ryuji; Lam, Albert Q.; Freedman, Benjamin S.; Kishi, Seiji; Valerius, M. Todd; Bonventre, Joseph V.

    2015-01-01

    Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) would enable organ regeneration, disease modeling, and drug screening in vitro. We established an efficient, chemically defined protocol for differentiating hPSCs into multipotent nephron progenitor cells (NPCs) that can form nephron-like structures. By recapitulating metanephric kidney development in vitro, we generate SIX2+SALL1+WT1+PAX2+ NPCs with 90% efficiency within 9 days of differentiation. The NPCs possess the developmental potential of their in vivo counterparts and form PAX8+LHX1+ renal vesicles that self-pattern into nephron structures. In both 2D and 3D culture, NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle, and distal tubules in an organized, continuous arrangement that resembles the nephron in vivo. We also show that this organoid culture system can be used to study mechanisms of human kidney development and toxicity. PMID:26458176

  15. Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth

    PubMed Central

    Tomita, Mayumi; Asada, Misako; Asada, Nariaki; Nakamura, Jin; Oguchi, Akiko; Higashi, Atsuko Y.; Endo, Shuichiro; Robertson, Elizabeth; Kimura, Takeshi; Kita, Toru; Economides, Aris N.; Kreidberg, Jordan; Yanagita, Motoko

    2013-01-01

    The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarified. Germline knockout of bone morphogenetic protein 7 (Bmp7) results in massive apoptosis of the kidney progenitor cells and defects in early stages of nephrogenesis. This phenotype has precluded analysis of Bmp7 function in the later stage of nephrogenesis. In this study, utilization of conditional null allele of Bmp7 in combination with systemic inducible Cre deleter mice enabled us to analyze Bmp7 function at desired time points during kidney development, and to discover the novel function of Bmp7 to inhibit the precocious differentiation of the progenitor cells to nephron. Systemic knockout of Bmp7 in vivo after the initiation of kidney development results in the precocious differentiation of the kidney progenitor cells to nephron, in addition to the prominent apoptosis of progenitor cells. We also confirmed that in vitro knockout of Bmp7 in kidney explant culture results in the accelerated differentiation of progenitor population. Finally we utilized colony-forming assays and demonstrated that Bmp7 inhibits epithelialization and differentiation of the kidney progenitor cells. These results indicate that the function of Bmp7 to inhibit the precocious differentiation of the progenitor cells together with its anti-apoptotic effect on progenitor cells coordinately maintains renal progenitor pool in undifferentiated status, and determines the nephron number at birth. PMID:23991197

  16. Reevaluation of erythropoietin production by the nephron.

    PubMed

    Nagai, Takanori; Yasuoka, Yukiko; Izumi, Yuichiro; Horikawa, Kahori; Kimura, Miho; Nakayama, Yushi; Uematsu, Takayuki; Fukuyama, Takashi; Yamazaki, Taiga; Kohda, Yukimasa; Hasuike, Yukiko; Nanami, Masayoshi; Kuragano, Takahiro; Kobayashi, Noritada; Obinata, Masuo; Tomita, Kimio; Tanoue, Akito; Nakanishi, Takeshi; Kawahara, Katsumasa; Nonoguchi, Hiroshi

    2014-06-27

    Erythropoietin production has been reported to occur in the peritubular interstitial fibroblasts in the kidney. Since the erythropoietin production in the nephron is controversial, we reevaluated the erythropoietin production in the kidney. We examined mRNA expressions of erythropoietin and HIF PHD2 using high-sensitive in situ hybridization system (ISH) and protein expression of HIF PHD2 using immunohistochemistry in the kidney. We further investigated the mechanism of erythropoietin production by hypoxia in vitro using human liver hepatocell (HepG2) and rat intercalated cell line (IN-IC cells). ISH in mice showed mRNA expression of erythropoietin in proximal convoluted tubules (PCTs), distal convoluted tubules (DCTs) and cortical collecting ducts (CCDs) but not in the peritubular cells under normal conditions. Hypoxia induced mRNA expression of erythropoietin largely in peritubular cells and slightly in PCTs, DCTs, and CCDs. Double staining with AQP3 or AE1 indicated that erythropoietin mRNA expresses mainly in β-intercalated or non α/non β-intercalated cells of the collecting ducts. Immunohistochemistry in rat showed the expression of HIF PHD2 in the collecting ducts and peritubular cells and its increase by anemia in peritubular cells. In IN-IC cells, hypoxia increased mRNA expression of erythropoietin, erythropoietin concentration in the medium and protein expression of HIF PHD2. These data suggest that erythropoietin is produced by the cortical nephrons mainly in the intercalated cells, but not in the peritubular cells, in normal hematopoietic condition and by mainly peritubular cells in hypoxia, suggesting the different regulation mechanism between the nephrons and peritubular cells. PMID:24832733

  17. Suppression of STN1 enhances the cytotoxicity of chemotherapeutic agents in cancer cells by elevating DNA damage

    PubMed Central

    Zhou, Qing; Chai, Weihang

    2016-01-01

    DNA damage-inducing agents are among the most effective treatment regimens in clinical chemotherapy. However, drug resistance and severe side effects caused by these agents greatly limit their efficacy. Sensitizing malignant cells to chemotherapeutic agents has long been a goal of chemotherapy. In the present study, suppression of STN1, a gene important for safeguarding genome stability, potentiated the anticancer effect of chemotherapeutic agents in tumor cells. Using multiple cancer cells from a variety of origins, it was observed that downregulation of STN1 resulted in a significant decrease in the half maximal inhibitory concentration values of several conventional anticancer agents. When cells are treated with anticancer agents, STN1 suppression leads to a decline in colony formation and diminished anchorage-independent growth. Furthermore, it was additionally observed that STN1 knockdown augmented the levels of DNA damage caused by damage-inducing agents. The present study concluded that suppression of STN1 enhances the cytotoxicity of damage-inducing chemotherapeutic agents by increasing DNA damage in cancer cells. PMID:27446354

  18. Synchronization of period-doubling oscillations in vascular coupled nephrons

    NASA Astrophysics Data System (ADS)

    Laugesen, J. L.; Mosekilde, E.; Holstein-Rathlou, N.-H.

    2011-09-01

    The mechanisms by which the individual functional unit (nephron) of the kidney regulates the incoming blood flow give rise to a number of nonlinear dynamic phenomena, including period-doubling bifurcations and intra-nephron synchronization between two different oscillatory modes. Interaction between the nephrons produces complicated and time-dependent inter-nephron synchronization patterns. In order to understand the processes by which a pair of vascular coupled nephrons synchronize, the paper presents a detailed analysis of the bifurcations that occur at the threshold of synchronization. We show that, besides infinite cascades of saddle-node bifurcations, these transitions involve mutually connected cascades of torus and homoclinic bifurcations. To illustrate the broader range of occurrence of this bifurcation structure for coupled period-doubling systems, we show that a similar structure arises in a system of two coupled, non-identical Rössler oscillators.

  19. Microarrays and RNA-Seq identify molecular mechanisms driving the end of nephron production

    PubMed Central

    2011-01-01

    Background The production of nephrons suddenly ends in mice shortly after birth when the remaining cells of the multi-potent progenitor mesenchyme begin to differentiate into nephrons. We exploited this terminal wave of nephron production using both microarrays and RNA-Seq to serially evaluate gene transcript levels in the progenitors. This strategy allowed us to define the changing gene expression states following induction and the onset of differentiation after birth. Results Microarray and RNA-Seq studies of the progenitors detected a change in the expression profiles of several classes of genes early after birth. One functional class, a class of genes associated with cellular proliferation, was activated. Analysis of proliferation with a nucleotide analog demonstrated in vivo that entry into the S-phase of the cell cycle preceded increases in transcript levels of genetic markers of differentiation. Microarrays and RNA-Seq also detected the onset of expression of markers of differentiation within the population of progenitors prior to detectable Six2 repression. Validation by in situ hybridization demonstrated that the markers were expressed in a subset of Six2 expressing progenitors. Finally, the studies identified a third set of genes that provide indirect evidence of an altered cellular microenvironment of the multi-potential progenitors after birth. Conclusions These results demonstrate that Six2 expression is not sufficient to suppress activation of genes associated with growth and differentiation of nephrons. They also better define the sequence of events after induction and suggest mechanisms contributing to the rapid end of nephron production after birth in mice. PMID:21396121

  20. Comparative phosphoproteome profiling reveals a function of the STN8 kinase in fine-tuning of cyclic electron flow (CEF)

    PubMed Central

    Reiland, Sonja; Finazzi, Giovanni; Endler, Anne; Willig, Adrian; Baerenfaller, Katja; Grossmann, Jonas; Gerrits, Bertran; Rutishauser, Dorothea; Gruissem, Wilhelm; Rochaix, Jean-David; Baginsky, Sacha

    2011-01-01

    Important aspects of photosynthetic electron transport efficiency in chloroplasts are controlled by protein phosphorylation. Two thylakoid-associated kinases, STN7 and STN8, have distinct roles in short- and long-term photosynthetic acclimation to changes in light quality and quantity. Although some substrates of STN7 and STN8 are known, the complexity of this regulatory kinase system implies that currently unknown substrates connect photosynthetic performance with the regulation of metabolic and regulatory functions. We performed an unbiased phosphoproteome-wide screen with Arabidopsis WT and stn8 mutant plants to identify unique STN8 targets. The phosphorylation status of STN7 was not affected in stn8, indicating that kinases other than STN8 phosphorylate STN7 under standard growth conditions. Among several putative STN8 substrates, PGRL1-A is of particular importance because of its possible role in the modulation of cyclic electron transfer. The STN8 phosphorylation site on PGRL1-A is absent in both monocotyledonous plants and algae. In dicots, spectroscopic measurements with Arabidopsis WT, stn7, stn8, and stn7/stn8 double-mutant plants indicate a STN8-mediated slowing down of the transition from cyclic to linear electron flow at the onset of illumination. This finding suggests a possible link between protein phosphorylation by STN8 and fine-tuning of cyclic electron flow during this critical step of photosynthesis, when the carbon assimilation is not commensurate to the electron flow capacity of the chloroplast. PMID:21768351

  1. Coordinated reset stimulation in a large-scale model of the STN-GPe circuit

    PubMed Central

    Ebert, Martin; Hauptmann, Christian; Tass, Peter A.

    2014-01-01

    Synchronization of populations of neurons is a hallmark of several brain diseases. Coordinated reset (CR) stimulation is a model-based stimulation technique which specifically counteracts abnormal synchrony by desynchronization. Electrical CR stimulation, e.g., for the treatment of Parkinson's disease (PD), is administered via depth electrodes. In order to get a deeper understanding of this technique, we extended the top-down approach of previous studies and constructed a large-scale computational model of the respective brain areas. Furthermore, we took into account the spatial anatomical properties of the simulated brain structures and incorporated a detailed numerical representation of 2 · 104 simulated neurons. We simulated the subthalamic nucleus (STN) and the globus pallidus externus (GPe). Connections within the STN were governed by spike-timing dependent plasticity (STDP). In this way, we modeled the physiological and pathological activity of the considered brain structures. In particular, we investigated how plasticity could be exploited and how the model could be shifted from strongly synchronized (pathological) activity to strongly desynchronized (healthy) activity of the neuronal populations via CR stimulation of the STN neurons. Furthermore, we investigated the impact of specific stimulation parameters especially the electrode position on the stimulation outcome. Our model provides a step forward toward a biophysically realistic model of the brain areas relevant to the emergence of pathological neuronal activity in PD. Furthermore, our model constitutes a test bench for the optimization of both stimulation parameters and novel electrode geometries for efficient CR stimulation. PMID:25505882

  2. Nephron Hypertrophy and Glomerulosclerosis and Their Association with Kidney Function and Risk Factors among Living Kidney Donors

    PubMed Central

    Elsherbiny, Hisham E.; Alexander, Mariam P.; Kremers, Walter K.; Park, Walter D.; Poggio, Emilio D.; Prieto, Mikel; Lieske, John C.

    2014-01-01

    Background and objectives The relationship of kidney function and CKD risk factors to structural changes in the renal parenchyma of normal adults is unclear. This study assessed whether nephron hypertrophy and nephrosclerosis had similar or different associations with kidney function and risk factors. Design, setting, participants, & measurements From 1999 to 2009, 1395 living kidney donors had a core needle biopsy of their donated kidney during transplant surgery. The mean nonsclerotic glomerular volume and glomerular density (globally sclerotic and nonsclerotic) were estimated using the Weibel and Gomez stereologic methods. All tubules were counted in 1 cm2 of cortex to determine a mean profile tubular area. Nephron hypertrophy was identified by larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density. Nephrosclerosis was identified by higher globally sclerotic glomerular density. Results The mean (±SD) age was 44±12 years, 24-hour urine albumin excretion was 5±7 mg, measured GFR was 103±17 ml/min per 1.73 m2, uric acid was 5.2±1.4 mg/dl, and body mass index was 28±5 kg/m2. Of the study participants, 43% were men, 11% had hypertension, and 52% had a family history of ESRD. Larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density were correlated. Male sex, higher 24-hour urine albumin excretion, family history of ESRD, and higher body mass index were independently associated with each of these measures of nephron hypertrophy. Higher uric acid, higher GFR, and older age were also independently associated with some of these measures of nephron hypertrophy. Hypertension was not independently associated with measures of nephron hypertrophy. However, hypertension and older age were independently associated with higher globally sclerotic glomerular density. Conclusions Nephron hypertrophy and nephrosclerosis are structural characteristics in normal adults that relate differently to

  3. The Student Telescope Network (STN) experiment

    NASA Astrophysics Data System (ADS)

    Hannahoe, Ryan M.; Stencel, Robert E.; Bisque, Steve; Rice, Mike

    2003-02-01

    support of this effort, and acknowleedge in-kind support from the estate of William Herschel Womble. Details at website www.du.edu/~rstencel/stn.htm.

  4. Odd E. Hanssen and the Hanssen method for measurement of single-nephron glomerular filtration rate.

    PubMed

    Aukland, K

    2001-09-01

    In the middle of the twentieth century, the suspicion that deep and superficial nephrons might serve different functions created a demand for measurement of single-nephron glomerular filtration rate (SNGFR). Rather unexpectedly, the answer came from Odd E. Hanssen (1917-1964), a Norwegian physician working on his own in the Department of Pathological Anatomy, University of Oslo, with minimal support and no interaction with renal physiologists. In 1963, after nearly 10 years of work, he presented the ferrocyanide method, allowing simultaneous estimates of SNGFR in a large number of nephrons in all layers of the kidney. This review first describes his early visions of the method and the elaborate and extremely time-consuming studies in mice to verify the technique. As a byproduct came valuable information on the relationship between nephron size and SNGFR, glomerular intermittency, and the emptying of the tubules on filtration stop. Hanssen died from a cerebral hemorrhage in 1964, and for several years the method seemed entirely forgotten. Fortunately, Andrew Baines took up the use of ferrocyanide in 1963-1964 while working on his thesis in Toronto, but his first publication came in 1969 from Saclay, France, in collaboration with Christian de Rouffignac. Modifications allowing determination of absolute SNGFR were worked out by de Rouffignac and by Jaime Coehlo in New York. Thereafter, the "Hanssen method" spread rapidly, and in the early 1980s about 50 reports had been published from 17 laboratories in 9 countries. The distribution of SNGFR in mammals, birds, and fish was described, as well as the response to water and salt loads, vasoactive substances, hormones, varying perfusion pressure, blood loss, etc. Finally, after mentioning two recent methods inspired by the Hanssen technique but using other filtration markers, the review concludes that most of our present knowledge on SNGFR distribution and regulation has been obtained by the method developed by Hanssen 40

  5. Ultrastructure of the nephron in the soft-shelled turtle, Pelodiscus sinensis (Reptilia, Chelonia, Trionychidae).

    PubMed

    Xu, Chun-Sheng; Yang, Ping; Bao, Hui-Jun; Bian, Xun-Guang; Chen, Qiu-Sheng

    2013-01-01

    The structure of the nephron in adult soft-shelled turtles (Pelodiscus sinensis) was studied by light microscopy, transmission and scanning electron microscopy. The kidney contained 5-6 renal lobes. Nephrons of P. sinensis are composed of a renal corpuscle (RC) and of a renal tubule that appears divided morphologically into five distinct segments: neck segment (NS) (This segment is only present in approximately 10% of the nephrons), proximal tubule (PT), intermediate segment (IS), distal tubule (DT), and collecting duct (CD). The RCs and most of the convoluted DTs lie in the central zone, while the PTs and the CDs lie in the peripheral zone of the renal lobe. The renal corpuscle is relatively large with especial processes in podocytes and a thick basement membrane. The podocyte processes covering a large capillary area can be observed by TEM, and the major podocyte processes formed a very specific pattern in SEM. The podocyte processes expand to form a flattened network over the whole capillary loops surface, and only may observe little filtration slits in glomerular area. The neck segment when presentis short and has a relatively narrow lumen, consisting of cuboidal or squamous cells. There is a well-developed endocytic-lysosomal apparatus in the apical cytoplasm of the PT. The proximal tubule and intermediate segment cells show some differences between male and female. It showed that proximal tubule cells of male soft-shelt turtle contain lateral intercellular spaces, into which extensions of the cell membrane protrude, and the basal cell membrane forms a conspicuous labyrinth. Whereas, the basal and lateral cell membranes of the female are smooth, and no later-basal intercellular spaces. The differences between male and female in the middle segment cells is similar to proximal tubule cells. Not previously reported in vertebrate kidneys. The IS is the narrowest nephron segment, formed by multiciliated as well as nonciliated cells. In DT cells, basolateral

  6. The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension

    PubMed Central

    Goodwin, Julie E.; Zhang, Junhui; Velazquez, Heino; Geller, David S.

    2010-01-01

    Glucocorticoids are used as a treatment for a variety of conditions and hypertension is a well-recognized side effect of their use. The mechanism of glucocorticoid-induced hypertension is incompletely understood and has traditionally been attributed to promiscuous activation of the mineralocorticoid receptor by cortisol. Multiple lines of evidence, however, point to the glucocorticoid receptor as an important mediator as well. We have developed a mouse model of glucocorticoid-induced hypertension, which is dependent on the glucocorticoid receptor. To determine the site(s) of glucocorticoid receptor action relevant to the development of hypertension, we studied glucocorticoid-induced hypertension in a mouse with a tissue-specific knockout of the glucocorticoid receptor in the distal nephron. Although knockout mice had similar body weight, nephron number and renal histology compared to littermate controls, their baseline blood pressure was mildly elevated. Nevertheless, distal nephron glucocorticoid receptor knockout mice and controls had a similar hypertensive response to dexamethasone. Urinary excretion of electrolytes, both before and after administration of glucocorticoid was also indistinguishable between the two groups. We conclude that the glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension in our model. PMID:20188070

  7. RNA sequencing of the nephron transcriptome: a technical note

    PubMed Central

    Lee, Jae Wook

    2015-01-01

    To understand the functions of the kidney, the transcriptome of each part of the nephron needs to be profiled using a highly sensitive and unbiased tool. RNA sequencing (RNA-seq) has revolutionized transcriptomic research, enabling researchers to define transcription activity and functions of genomic elements with unprecedented sensitivity and precision. Recently, RNA-seq for polyadenylated messenger RNAs [poly(A)′-mRNAs] and classical microdissection were successfully combined to investigate the transcriptome of glomeruli and 14 different renal tubule segments. A rat kidney is perfused with and incubated in collagenase solution, and the digested kidney was manually dissected under a stereomicroscope. Individual glomeruli and renal tubule segments are identified by their anatomical and morphological characteristics and collected in phosphate-buffered saline. Poly(A)′-tailed mRNAs are released from cell lysate, captured by oligo-dT primers, and made into complementary DNAs (cDNAs) using a highly sensitive reverse transcription method. These cDNAs are sheared by sonication and prepared into adapter-ligated cDNA libraries for Illumina sequencing. Nucleotide sequences reported from the sequencing reaction are mapped to the rat reference genome for gene expression analysis. These RNA-seq transcriptomic data were highly consistent with prior knowledge of gene expression along the nephron. The gene expression data obtained in this work are available as a public Web page (https://helixweb.nih.gov/ESBL/Database/NephronRNAseq/) and can be used to explore the transcriptomic landscape of the nephron. PMID:26779425

  8. Development of a Manipulative for Nephron Physiology Education

    ERIC Educational Resources Information Center

    Giffen, Zane C.; Carvalho, Helena

    2015-01-01

    Some physiological concepts, such as physiology of filtration and absorption in the different nephron segments, are so detailed that they can be a challenge to be memorized. This article describes an exercise that solidifies learning as students manipulate, using paper models, "transporters" and "electrolytes" in the…

  9. Distinct effects of dopamine vs STN stimulation therapies in associative learning and retention in Parkinson disease.

    PubMed

    Ventre-Dominey, Jocelyne; Mollion, Hélène; Thobois, Stephane; Broussolle, Emmanuel

    2016-04-01

    Evidence has been provided in Parkinson's disease patients of cognitive impairments including visual memory and learning which can be partially compensated by dopamine medication or subthalamic nucleus stimulation. The effects of these two therapies can differ according to the learning processes involving the dorsal vs ventral part of the striatum. Here we aimed to investigate and compare the outcomes of dopamine vs stimulation treatment in Parkinson patient's ability to acquire and maintain over successive days their performance in visual working memory. Parkinson patients performed conditional associative learning embedded in visual (spatial and non spatial) working memory tasks over two consecutive days either ON or OFF dopaminergic drugs or STN stimulation depending on the group of patients studied. While Parkinson patients were more accurate and faster in memory tasks ON vs OFF stimulation independent of the day of testing, performance in medicated patients differed depending on the medication status during the initial task acquisition. Patients who learnt the task ON medication the first day were able to maintain or even improve their memory performance both OFF and ON medication on the second day after consolidation. These effects were observed only in patients with dopamine replacement with or without motor fluctuations. This enhancement in memory performance after having learnt under dopamine medication and not under STN stimulation was mostly significant in visuo-spatial working memory tasks suggesting that dopamine replacement in the depleted dorsal striatum is essential for retention and consolidation of learnt skill. PMID:26778783

  10. Upper tract urothelial carcinoma: Paradigm shift towards nephron sparing management

    PubMed Central

    Fiuk, Julia V; Schwartz, Brad F

    2016-01-01

    Upper tract urothelial carcinoma (UTUC) is relatively rare compared to urothelial carcinoma of the lower tract, comprising only 5%-10% of all urothelial cancers. Although both entities share histologic properties, UTUC tends to be more invasive at diagnosis and portend a worse prognosis, with a 5 year overall mortality of 23%. To date, the gold standard management of UTUC has been radical nephroureterectomy (RNU), with nephron sparing techniques reserved for solitary kidneys or cases where the patient could not tolerate radical surgery. Limited data from these series, as well as select series where nephron-sparing endoscopic management has been offered to a broader patient base, suggest that minimally invasive, nephron sparing techniques can offer comparable oncologic and survival outcomes to RNU in appropriately selected patients. We review the current literature on the topic and discuss long term outcomes and sequelae of the gold standard treatment, RNU. We also discuss the oncologic outcomes of minimally invasive, endoscopic management of UTUC. Our goal is to provide the reader a comprehensive overview of the current state of the field in order to inform and guide their treatment decisions. PMID:26981440

  11. A Shunt Model of the Inner Medullary Nephron with Pre-Bend Transitions

    NASA Astrophysics Data System (ADS)

    Gonzalez, M. T.; Hegarty, A. F.; Thomas, S. R.

    2009-09-01

    Mathematical models of the renal medulla face the problem of representing water and solute transfer among tens of thousands of nephrons and blood vessels of various lengths, arranged in countercurrent fashion. Published models fall into two broad categories with respect to this issue: multi-nephron models, which explicitly represent a large number of individual nephrons, or lumped models with virtual shunts that represent the turning back of nephrons and vessels at varying depths. Shunt models have the advantage of a compact description and relatively rapid execution time but are ill-suited to faithfully represent features such as prebend transitions of epithelial permeabilities in nephrons of different lengths. A new shunt model approach that can accommodate pre-bend transitions of nephrons at all medullary depths is presented in this work together with the results of simulation of predicted flows and concentrations.

  12. SOURCE APPORTIONMENT OF SEATTLE PM 2.5: A COMPARISON OF IMPROVE AND ENHANCED STN DATA SETS

    EPA Science Inventory

    Seattle, WA, STN and IMPROVE data sets with STN temperature resolved carbon peaks were analyzed with both the PMF and Unmix receptor models. In addition, the IMPROVE trace element data was combined with the major STN species to examine the role of IMPROVE metals. To compare the ...

  13. Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis

    PubMed Central

    Terker, Andrew S.; Zhang, Chong; Erspamer, Kayla J.; Gamba, Gerardo; Yang, Chao-Ling; Ellison, David H.

    2015-01-01

    Dietary potassium deficiency activates thiazide-sensitive sodium chloride cotransport along the distal nephron. This may explain, in part, the hypertension and cardiovascular mortality observed in individuals who consume a low potassium diet. Recent data suggest plasma potassium affects the distal nephron directly by influencing intracellular chloride, an inhibitor of the With no lysine kinase (WNK)-Ste20p-related proline-and alanine-rich kinase (SPAK) pathway. Since previous studies used extreme dietary manipulations, we sought to determine if the relationship between potassium and NCC is physiologically relevant and clarify the mechanisms involved. We report that modest changes in both dietary and plasma potassium affect the thiazide-sensitive sodium-chloride cotransporter, NCC, in vivo. Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3. Also, chloride inhibited WNK4 within the range of distal cell chloride. Mutation of a previously identified WNK chloride-binding motif converted WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. Disruption of this motif in WNKs 1, 3 and 4 had different effects on NCC, consistent with the three WNKs having different chloride sensitivities. Thus, potassium effects on NCC are graded within the physiological range, which explains how unique chloride-sensing properties of WNK4 enable kinase mediating effects of potassium on NCC in vivo. PMID:26422504

  14. Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.

    PubMed

    Terker, Andrew S; Zhang, Chong; Erspamer, Kayla J; Gamba, Gerardo; Yang, Chao-Ling; Ellison, David H

    2016-01-01

    Dietary potassium deficiency activates thiazide-sensitive sodium chloride cotransport along the distal nephron. This may explain, in part, the hypertension and cardiovascular mortality observed in individuals who consume a low-potassium diet. Recent data suggest that plasma potassium affects the distal nephron directly by influencing intracellular chloride, an inhibitor of the with-no-lysine kinase (WNK)-Ste20p-related proline- and alanine-rich kinase (SPAK) pathway. As previous studies used extreme dietary manipulations, we sought to determine whether the relationship between potassium and NaCl cotransporter (NCC) is physiologically relevant and clarify the mechanisms involved. We report that modest changes in both dietary and plasma potassium affect NCC in vivo. Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3. Also, chloride inhibited WNK4 within the range of distal cell chloride concentration. Mutation of a previously identified WNK chloride-binding motif converted WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. Disruption of this motif in WNKs 1, 3, and 4 had different effects on NCC, consistent with the three WNKs having different chloride sensitivities. Thus, potassium effects on NCC are graded within the physiological range, which explains how unique chloride-sensing properties of WNK4 enable it to mediate effects of potassium on NCC in vivo. PMID:26422504

  15. Effects of renal pelvic high-pressure perfusion on nephrons in a porcine pyonephrosis model.

    PubMed

    Wang, Jian; Zhou, DA-Qing; He, Meng; Li, Wen-Gang; Pang, Xiang; Yu, Xiao-Xiang; Jiang, Bo

    2013-05-01

    The aim of this study was to investigate the effects of various renal pelvic pressure gradients on nephrons with purulent infection. Five miniature test pigs were selected. One side of the kidney was used to prepare the pyonephrosis model and the other side was used as the healthy control. A piezometer and a water fill tube were inserted into the renal pelvis through the ureter. Prior to perfusion, punctures were made on the healthy and purulent sides of the kidneys to obtain tissues (as controls). Subsequently, a puncture biopsy was conducted on the kidneys at five pressure levels: 10, 20, 30, 40 and 50 mmHg. Once the renal pelvic pressure had increased, the healthy and injured kidneys presented pathological changes, including dilation of the renal tubule and capsule and compression of the renal glomerulus. When the renal pelvic pressure exceeded 20 mmHg, the injured kidney presented more damage. Electron microscopy revealed that the increase in pressure resulted in the following: the podocyte gap widened, the epithelial cells of the renal capsule separated from the basement membrane, the basement membrane thickness became uneven, the continuity of the basement membrane was interrupted at multiple positions and the renal tubule microvillus arrangement became disorganised. The manifestations in the pyonephrosis model were more distinct compared with those in the healthy kidney. As the renal pelvic pressure exceeds 20 mmHg under a renal purulent infection status, the nephrons become damaged. The extent of the damage is aggravated as the pressure is increased. PMID:23737886

  16. Effects of renal pelvic high-pressure perfusion on nephrons in a porcine pyonephrosis model

    PubMed Central

    WANG, JIAN; ZHOU, DA-QING; HE, MENG; LI, WEN-GANG; PANG, XIANG; YU, XIAO-XIANG; JIANG, BO

    2013-01-01

    The aim of this study was to investigate the effects of various renal pelvic pressure gradients on nephrons with purulent infection. Five miniature test pigs were selected. One side of the kidney was used to prepare the pyonephrosis model and the other side was used as the healthy control. A piezometer and a water fill tube were inserted into the renal pelvis through the ureter. Prior to perfusion, punctures were made on the healthy and purulent sides of the kidneys to obtain tissues (as controls). Subsequently, a puncture biopsy was conducted on the kidneys at five pressure levels: 10, 20, 30, 40 and 50 mmHg. Once the renal pelvic pressure had increased, the healthy and injured kidneys presented pathological changes, including dilation of the renal tubule and capsule and compression of the renal glomerulus. When the renal pelvic pressure exceeded 20 mmHg, the injured kidney presented more damage. Electron microscopy revealed that the increase in pressure resulted in the following: the podocyte gap widened, the epithelial cells of the renal capsule separated from the basement membrane, the basement membrane thickness became uneven, the continuity of the basement membrane was interrupted at multiple positions and the renal tubule microvillus arrangement became disorganised. The manifestations in the pyonephrosis model were more distinct compared with those in the healthy kidney. As the renal pelvic pressure exceeds 20 mmHg under a renal purulent infection status, the nephrons become damaged. The extent of the damage is aggravated as the pressure is increased. PMID:23737886

  17. Discrete control of TRPV4 channel function in the distal nephron by protein kinases A and C.

    PubMed

    Mamenko, Mykola; Zaika, Oleg L; Boukelmoune, Nabila; Berrout, Jonathan; O'Neil, Roger G; Pochynyuk, Oleh

    2013-07-12

    We have recently documented that the Ca(2+)-permeable TRPV4 channel, which is abundantly expressed in distal nephron cells, mediates cellular Ca(2+) responses to elevated luminal flow. In this study, we combined Fura-2-based [Ca(2+)]i imaging with immunofluorescence microscopy in isolated split-opened distal nephrons of C57BL/6 mice to probe the molecular determinants of TRPV4 activity and subcellular distribution. We found that activation of the PKC pathway with phorbol 12-myristate 13-acetate significantly increased [Ca(2+)]i responses to flow without affecting the subcellular distribution of TRPV4. Inhibition of PKC with bisindolylmaleimide I diminished cellular responses to elevated flow. In contrast, activation of the PKA pathway with forskolin did not affect TRPV4-mediated [Ca(2+)]i responses to flow but markedly shifted the subcellular distribution of the channel toward the apical membrane. These actions were blocked with the specific PKA inhibitor H-89. Concomitant activation of the PKA and PKC cascades additively enhanced the amplitude of flow-induced [Ca(2+)]i responses and greatly increased basal [Ca(2+)]i levels, indicating constitutive TRPV4 activation. This effect was precluded by the selective TRPV4 antagonist HC-067047. Therefore, the functional status of the TRPV4 channel in the distal nephron is regulated by two distinct signaling pathways. Although the PKA-dependent cascade promotes TRPV4 trafficking and translocation to the apical membrane, the PKC-dependent pathway increases the activity of the channel on the plasma membrane. PMID:23709216

  18. Discrete Control of TRPV4 Channel Function in the Distal Nephron by Protein Kinases A and C*

    PubMed Central

    Mamenko, Mykola; Zaika, Oleg L.; Boukelmoune, Nabila; Berrout, Jonathan; O'Neil, Roger G.; Pochynyuk, Oleh

    2013-01-01

    We have recently documented that the Ca2+-permeable TRPV4 channel, which is abundantly expressed in distal nephron cells, mediates cellular Ca2+ responses to elevated luminal flow. In this study, we combined Fura-2-based [Ca2+]i imaging with immunofluorescence microscopy in isolated split-opened distal nephrons of C57BL/6 mice to probe the molecular determinants of TRPV4 activity and subcellular distribution. We found that activation of the PKC pathway with phorbol 12-myristate 13-acetate significantly increased [Ca2+]i responses to flow without affecting the subcellular distribution of TRPV4. Inhibition of PKC with bisindolylmaleimide I diminished cellular responses to elevated flow. In contrast, activation of the PKA pathway with forskolin did not affect TRPV4-mediated [Ca2+]i responses to flow but markedly shifted the subcellular distribution of the channel toward the apical membrane. These actions were blocked with the specific PKA inhibitor H-89. Concomitant activation of the PKA and PKC cascades additively enhanced the amplitude of flow-induced [Ca2+]i responses and greatly increased basal [Ca2+]i levels, indicating constitutive TRPV4 activation. This effect was precluded by the selective TRPV4 antagonist HC-067047. Therefore, the functional status of the TRPV4 channel in the distal nephron is regulated by two distinct signaling pathways. Although the PKA-dependent cascade promotes TRPV4 trafficking and translocation to the apical membrane, the PKC-dependent pathway increases the activity of the channel on the plasma membrane. PMID:23709216

  19. Dissecting Stages of Human Kidney Development and Tumorigenesis with Surface Markers Affords Simple Prospective Purification of Nephron Stem Cells

    PubMed Central

    Pode-Shakked, Naomi; Pleniceanu, Oren; Gershon, Rotem; Shukrun, Rachel; Kanter, Itamar; Bucris, Efrat; Pode-Shakked, Ben; Tam, Gal; Tam, Hadar; Caspi, Revital; Pri-Chen, Sara; Vax, Einav; Katz, Guy; Omer, Dorit; Harari-Steinberg, Orit; Kalisky, Tomer; Dekel, Benjamin

    2016-01-01

    When assembling a nephron during development a multipotent stem cell pool becomes restricted as differentiation ensues. A faulty differentiation arrest in this process leads to transformation and initiation of a Wilms’ tumor. Mapping these transitions with respective surface markers affords accessibility to specific cell subpopulations. NCAM1 and CD133 have been previously suggested to mark human renal progenitor populations. Herein, using cell sorting, RNA sequencing, in vitro studies with serum-free media and in vivo xenotransplantation we demonstrate a sequential map that links human kidney development and tumorigenesis; In nephrogenesis, NCAM1+CD133− marks SIX2+ multipotent renal stem cells transiting to NCAM1+CD133+ differentiating segment-specific SIX2− epithelial progenitors and NCAM1−CD133+ differentiated nephron cells. In tumorigenesis, NCAM1+CD133− marks SIX2+ blastema that includes the ALDH1+ WT cancer stem/initiating cells, while NCAM1+CD133+ and NCAM1−CD133+ specifying early and late epithelial differentiation, are severely restricted in tumor initiation capacity and tumor self-renewal. Thus, negative selection for CD133 is required for defining NCAM1+ nephron stem cells in normal and malignant nephrogenesis. PMID:27020553

  20. Stn1 is critical for telomere maintenance and long-term viability of somatic human cells

    PubMed Central

    Boccardi, Virginia; Razdan, Neetu; Kaplunov, Jessica; Mundra, Jyoti J; Kimura, Masayuki; Aviv, Abraham; Herbig, Utz

    2015-01-01

    Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells. PMID:25684230

  1. Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development

    PubMed Central

    Hartwig, Sunny; Ho, Jacqueline; Pandey, Priyanka; MacIsaac, Kenzie; Taglienti, Mary; Xiang, Michael; Alterovitz, Gil; Ramoni, Marco; Fraenkel, Ernest; Kreidberg, Jordan A.

    2010-01-01

    Summary The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarray (ChIP-chip) using chromatin prepared from embryonic mouse kidney tissue. We identified 1663 genes bound by WT1, 86% of which contain a previously identified, conserved, high-affinity WT1 binding site. To investigate functional interactions between WT1 and candidate target genes in nephron progenitors, we used a novel, modified WT1 morpholino loss-of-function model in embryonic mouse kidney explants to knock down WT1 expression in nephron progenitors ex vivo. Low doses of WT1 morpholino resulted in reduced WT1 target gene expression specifically in nephron progenitors, whereas high doses of WT1 morpholino arrested kidney explant development and were associated with increased nephron progenitor cell apoptosis, reminiscent of the phenotype observed in Wt1−/− embryos. Collectively, our results provide a comprehensive description of endogenous WT1 target genes in nephron progenitor cells in vivo, as well as insights into the transcriptional signaling networks controlled by WT1 that might direct nephron progenitor fate during renal development. PMID:20215353

  2. Integrated Control of Na Transport along the Nephron

    PubMed Central

    Schnermann, Jürgen

    2015-01-01

    The kidney filters vast quantities of Na at the glomerulus but excretes a very small fraction of this Na in the final urine. Although almost every nephron segment participates in the reabsorption of Na in the normal kidney, the proximal segments (from the glomerulus to the macula densa) and the distal segments (past the macula densa) play different roles. The proximal tubule and the thick ascending limb of the loop of Henle interact with the filtration apparatus to deliver Na to the distal nephron at a rather constant rate. This involves regulation of both filtration and reabsorption through the processes of glomerulotubular balance and tubuloglomerular feedback. The more distal segments, including the distal convoluted tubule (DCT), connecting tubule, and collecting duct, regulate Na reabsorption to match the excretion with dietary intake. The relative amounts of Na reabsorbed in the DCT, which mainly reabsorbs NaCl, and by more downstream segments that exchange Na for K are variable, allowing the simultaneous regulation of both Na and K excretion. PMID:25098598

  3. Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney

    PubMed Central

    Mugford, Joshua W.; Sipilä, Petra; McMahon, Jill A.; McMahon, Andrew P.

    2008-01-01

    The mammalian metanephric kidney is derived from the intermediate mesoderm. In this report, we use molecular fate mapping to demonstrate that the majority of cell types within the metanephric kidney arise from an Osr1+ population of metanephric progenitor cells. These include the ureteric epithelium of the collecting duct network, the cap mesenchyme and its nephron epithelia derivatives, the interstitial mesenchyme, vasculature and smooth muscle. Temporal fate mapping shows a progressive restriction of Osr1+ cell fates such that at the onset of active nephrogenesis, Osr1 activity is restricted to the Six2+ cap mesenchyme nephron progenitors. However, low-level labeling of Osr1+ cells suggests that the specification of interstitial mesenchyme and cap mesenchyme progenitors occurs within the Osr1+ population prior to the onset of metanephric development. Furthermore, although Osr1+ progenitors give rise to much of the kidney, Osr1 function is only essential for the development of the nephron progenitor compartment. These studies provide new insights into the cellular origins of metanephric kidney structures and lend support to a model where Osr1 function is limited to establishing the nephron progenitor pool. PMID:18835385

  4. Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney.

    PubMed

    Mugford, Joshua W; Sipilä, Petra; McMahon, Jill A; McMahon, Andrew P

    2008-12-01

    The mammalian metanephric kidney is derived from the intermediate mesoderm. In this report, we use molecular fate mapping to demonstrate that the majority of cell types within the metanephric kidney arise from an Osr1(+) population of metanephric progenitor cells. These include the ureteric epithelium of the collecting duct network, the cap mesenchyme and its nephron epithelia derivatives, the interstitial mesenchyme, vasculature and smooth muscle. Temporal fate mapping shows a progressive restriction of Osr1(+) cell fates such that at the onset of active nephrogenesis, Osr1 activity is restricted to the Six2(+) cap mesenchyme nephron progenitors. However, low-level labeling of Osr1(+) cells suggests that the specification of interstitial mesenchyme and cap mesenchyme progenitors occurs within the Osr1(+) population prior to the onset of metanephric development. Furthermore, although Osr1(+) progenitors give rise to much of the kidney, Osr1 function is only essential for the development of the nephron progenitor compartment. These studies provide new insights into the cellular origins of metanephric kidney structures and lend support to a model where Osr1 function is limited to establishing the nephron progenitor pool. PMID:18835385

  5. High-resolution gene expression analysis of the developing mouse kidney defines novel cellular compartments within the nephron progenitor population.

    PubMed

    Mugford, Joshua W; Yu, Jing; Kobayashi, Akio; McMahon, Andrew P

    2009-09-15

    The functional unit of the kidney is the nephron. During its organogenesis, the mammalian metanephric kidney generates thousands of nephrons over a protracted period of fetal life. All nephrons are derived from a population of self-renewing multi-potent progenitor cells, termed the cap mesenchyme. However, our understanding of the molecular and cellular mechanisms underlying nephron development is at an early stage. In order to identify factors involved in nephrogenesis, we performed a high-resolution, spatial profiling of a number of transcriptional regulators expressed within the cap mesenchyme and early developing nephron. Our results demonstrate novel, stereotypic, spatially defined cellular sub-domains within the cap mesenchyme, which may, in part, reflect induction of nephron precursors. These results suggest a hitherto unappreciated complexity of cell states that accompany the assembly of the metanephric kidney, likely reflecting diverse regulatory actions such as the maintenance and induction of nephron progenitors. PMID:19591821

  6. High-resolution gene expression analysis of the developing mouse kidney defines novel cellular compartments within the nephron progenitor population

    PubMed Central

    Mugford, Joshua W.; Yu, Jing; Kobayashi, Akio; McMahon, Andrew P.

    2009-01-01

    The functional unit of the kidney is the nephron. During its organogenesis, the mammalian metanephric kidney generates thousands of nephrons over a protracted period of fetal life. All nephrons are derived from a population of self-renewing multi-potent progenitor cells, termed the cap mesenchyme. However, our understanding of the molecular and cellular mechanisms underlying nephron development is at an early stage. In order to identify factors involved in nephrogenesis, we performed a high-resolution, spatial profiling of a number of transcriptional regulators expressed within the cap mesenchyme and early developing nephron. Our results demonstrate novel, stereotypic, spatially defined cellular sub-domains within the cap mesenchyme, which may, in part, reflect induction of nephron precursors. These results suggest a hitherto unappreciated complexity of cell states that accompany the assembly of the metanephric kidney, likely reflecting diverse regulatory actions such as the maintenance and induction of nephron progenitors. PMID:19591821

  7. Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators.

    PubMed

    O'Brien, Lori L; Guo, Qiuyu; Lee, YoungJin; Tran, Tracy; Benazet, Jean-Denis; Whitney, Peter H; Valouev, Anton; McMahon, Andrew P

    2016-02-15

    Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. By contrast, Six2 maintains later progenitor self-renewal from the onset of nephrogenesis. We compared the regulatory actions of Six2 in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Furthermore, RNA-seq and immunostaining revealed overlapping SIX1 and SIX2 activity in 16 week human fetal nephron progenitors. Comparative bioinformatic analysis of human SIX1 and SIX2 ChIP-seq showed each factor targeted a similar set of cis-regulatory modules binding an identical target recognition motif. In contrast to the mouse where Six2 binds its own enhancers but does not interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. By contrast, the mouse establishes only an auto-regulatory Six2 loop. These data suggest differential SIX-factor regulation might have contributed to species differences in nephron progenitor programs such as the duration of nephrogenesis and the final nephron count. PMID:26884396

  8. Nephron-sparing surgery for multifocal and hereditary renal tumors

    PubMed Central

    Metwalli, Adam R.; Linehan, W. Marston

    2015-01-01

    Purpose of the Review Despite the controversy surrounding the benefits of nephron sparing surgery (NSS), multiple absolute indications for NSS still exist including the classic indications of hereditary and bilateral kidney tumors. Recent Findings Multiple genetic mutations have been identified that lead to hereditary kidney cancer conditions. These are briefly reviewed because the surgical management of hereditary kidney tumors depends on the genetic and histologic subtypes involved. Clear understanding of these hereditary conditions is crucial for proper surgical management of these tumors. Summary Complex partial nephrectomy for multiple renal tumors, or multiplex partial nephrectomy, requires not only exceptional surgical skill but expertise of numerous non-surgical methodologies such as hands-on intraoperative ultrasonography and interpretation of multiple imaging modalities. In addition, multi-disciplinary management is crucial for optimal outcomes in patient care. This review evaluates the most advanced surgical techniques and peri-operative management required to successfully care for these challenging cases. PMID:25014245

  9. Adenylate cyclase responsiveness to hormones in various portions of the human nephron.

    PubMed Central

    Chabardès, D; Gagnan-Brunette, M; Imbert-Teboul, M; Gontcharevskaia, O; Montégut, M; Clique, A; Morel, F

    1980-01-01

    The action sites for parathyroid hormone (PTH), salmon calcitonin (SCT), and arginine-vasopressin (AVP) were investigated along the human nephron by measuring adenylate cyclase activity, using a single tubule in vitro microassay. Well-localized segments of tubule were isolated by microdissection from five human kidneys unsuitable for transplantation. PTH (10 IU/ml) increased adenylate cyclase activity in the convoluted and the straight proximal tubule, in the medullary and cortical portions of the thick ascending limb, and in the early portion of the distal convoluted tubule (corresponding stimulated:basal activity ratios were 64, 19, 10, 18, and 22, respectively). SCT (10 ng/ml) increased adenylate cyclase activity in the medullary and cortical portions of the thick ascending limb, in the early portion of the distal convoluted tubule, and, to a lesser extent, in the cortical and the medullay collecting tubule (activity ratios were 7, 14, 15, 3, and 3, respectively). AVP (1 microM) stimulated adenylate cyclase activity in the terminal nephron segments only, i.e., the late portion of the distal convoluted tubule, the cortical and medullary portions of the collecting tubule (activity ratios 81, 51, and 97, respectively). As measured in one experiment, nearly one-half maximal responses were obtained with 0.1 IU/ml PTH or 0.3 ng/ml SCT in thick ascending limbs and with 1 nM AVP in collecting tubules, suggesting that enzyme sensitivity to hormones as well preserved under the conditions used in this study. PMID:7356689

  10. Construction and validation of a Sambucus nigra biosensor for cancer-associated STn antigen.

    PubMed

    Silva, M Luísa S; Gutiérrez, Evelin; Rodríguez, José A; Gomes, Catarina; David, Leonor

    2014-07-15

    A label-free electrochemical impedance spectroscopy biosensor for selective detection and discrimination of the cancer-associated sialyl-Tn (STn) antigen was developed by using Sambucus nigra agglutinin type I (SNA-I) as the recognition element. The SNA-I biosensor was constructed by immobilizing the lectin on screen-printed gold electrodes. The formation of a complex between SNA-I and STn-containing glycoproteins (transferrin and bovine submaxillary mucin) was monitored by measuring the impedance increase of the biosensor. The increase in electron transfer resistance was linearly proportional to the concentration of the glycoproteins up to 70 ng of transferrin and 40 ng of bovine submaxillary mucin, with a limit of detection of 20 ng for transferrin. Albumin, the most abundant serum protein, did not interfere in the detection of the STn-glycoproteins up to a concentration of 0.2 mg ml(-1). The developed lectin-based biosensor was used to evaluate the STn-expression in serum samples and discriminate samples from healthy individuals and patients with different types of malignant tumors, mostly carcinomas, where the increased expression of STn aberrant glycans is well established. This work demonstrates the feasibility of employing SNA-I to selectively recognize the STn epitope in glycoproteins and the use of the constructed biosensor was effective in the analysis of serum samples with the ability to discriminate in a fast way between cancer and healthy status. The proposed biosensor could be used for high-throughput, label-free profiling of the cancer-associated STn glycan expression in serum for diagnosis and therapy monitoring. PMID:24594592

  11. Nonmuscle Myosin II Regulates the Morphogenesis of Metanephric Mesenchyme–Derived Immature Nephrons

    PubMed Central

    Recuenco, Mariam C.; Ohmori, Tomoko; Tanigawa, Shunsuke; Taguchi, Atsuhiro; Fujimura, Sayoko; Conti, Mary Anne; Wei, Qize; Kiyonari, Hiroshi; Abe, Takaya; Adelstein, Robert S.

    2015-01-01

    The kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud. The mesenchyme transforms into epithelia and forms complicated nephron structures, whereas the ureteric bud extends its pre-existing epithelial ducts. Although the roles are well established for extracellular stimuli, such as Wnt and Notch, it is unclear how the intracellular cytoskeleton regulates these morphogenetic processes. Myh9 and Myh10 encode nonmuscle myosin II heavy chains, and Myh9 mutations in humans are implicated in congenital kidney diseases and focal segmental glomerulosclerosis in adults. Here, we analyzed the roles of Myh9 and Myh10 in the developing kidney. Ureteric bud-specific depletion of Myh9 resulted in no apparent phenotypes, whereas mesenchyme-specific Myh9 deletion caused proximal tubule dilations and renal failure. Mesenchyme-specific Myh9/Myh10 mutant mice died shortly after birth and showed a severe defect in nephron formation. The nascent mutant nephrons failed to form a continuous lumen, which likely resulted from impaired apical constriction of the elongating tubules. In addition, nephron progenitors lacking Myh9/Myh10 or the possible interactor Kif26b were less condensed at midgestation and reduced at birth. Taken together, nonmuscle myosin II regulates the morphogenesis of immature nephrons derived from the metanephric mesenchyme and the maintenance of nephron progenitors. Our data also suggest that Myh9 deletion in mice results in failure to maintain renal tubules but not in glomerulosclerosis. PMID:25168025

  12. Activation of the Stt7/STN7 Kinase through Dynamic Interactions with the Cytochrome b6f Complex1[OPEN

    PubMed Central

    Shapiguzov, Alexey; Chai, Xin; Fucile, Geoffrey; Longoni, Paolo; Zhang, Lixin

    2016-01-01

    Photosynthetic organisms have the ability to adapt to changes in light quality by readjusting the cross sections of the light-harvesting systems of photosystem II (PSII) and photosystem I (PSI). This process, called state transitions, maintains the redox poise of the photosynthetic electron transfer chain and ensures a high photosynthetic yield when light is limiting. It is mediated by the Stt7/STN7 protein kinase, which is activated through the cytochrome b6f complex upon reduction of the plastoquinone pool. Its probable major substrate, the light-harvesting complex of PSII, once phosphorylated, dissociates from PSII and docks to PSI, thereby restoring the balance of absorbed light excitation energy between the two photosystems. Although the kinase is known to be inactivated under high-light intensities, the molecular mechanisms governing its regulation remain unknown. In this study we monitored the redox state of a conserved and essential Cys pair of the Stt7/STN7 kinase and show that it forms a disulfide bridge. We could not detect any change in the redox state of these Cys during state transitions and high-light treatment. It is only after prolonged anaerobiosis that this disulfide bridge is reduced. It is likely to be mainly intramolecular, although kinase activation may involve a transient covalently linked kinase dimer with two intermolecular disulfide bonds. Using the yeast two-hybrid system, we have mapped one interaction site of the kinase on the Rieske protein of the cytochrome b6f complex. PMID:26941194

  13. Effects of STN DBS on Rigidity in Parkinson’s Disease

    PubMed Central

    Shapiro, Mark B.; Vaillancourt, David E.; Sturman, Molly M.; Metman, Leo Verhagen; Bakay, Roy A. E.; Corcos, Daniel M.

    2008-01-01

    We quantified the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and medication on Parkinsonian rigidity using an objective measure of work about the elbow joint during a complete cycle of imposed 1-Hz sinusoidal oscillations. Resting and activated rigidity were analyzed in four experimental conditions: 1) off treatment; 2) on DBS; 3) on medication; and 4) on DBS plus medication. Rigidity at the elbow joint was also assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). We tested ten patients who received STN DBS and ten age-matched neurologically healthy control subjects. The activated rigidity condition increased work in both Parkinson’s disease (PD) patients and control subjects. In PD patients, STN DBS reduced both resting and activated rigidity as indicated by work and the UPDRS rigidity score. This is the first demonstration that STN stimulation reduces rigidity using an objective measure such as work. In contrast, the presurgery dose of antiparkinsonian medication did not significantly improve the UPDRS rigidity score and reduced work only in the activated rigidity condition. Our results suggest that STN DBS may be more effective in alleviating rigidity in the upper limb of PD patients than medications administered at presurgery dosage level. PMID:17601186

  14. Articulatory Changes in Vowel Production following STN DBS and Levodopa Intake in Parkinson's Disease

    PubMed Central

    Martel Sauvageau, Vincent; Roy, Johanna-Pascale; Cantin, Léo; Prud'Homme, Michel; Langlois, Mélanie; Macoir, Joël

    2015-01-01

    Purpose. To investigate the impact of deep brain stimulation of the subthalamic nucleus (STN DBS) and levodopa intake on vowel articulation in dysarthric speakers with Parkinson's disease (PD). Methods. Vowel articulation was assessed in seven Quebec French speakers diagnosed with idiopathic PD who underwent STN DBS. Assessments were conducted on- and off-medication, first prior to surgery and then 1 year later. All recordings were made on-stimulation. Vowel articulation was measured using acoustic vowel space and formant centralization ratio. Results. Compared to the period before surgery, vowel articulation was reduced after surgery when patients were off-medication, while it was better on-medication. The impact of levodopa intake on vowel articulation changed with STN DBS: before surgery, levodopa impaired articulation, while it no longer had a negative effect after surgery. Conclusions. These results indicate that while STN DBS could lead to a direct deterioration in articulation, it may indirectly improve it by reducing the levodopa dose required to manage motor symptoms. These findings suggest that, with respect to speech production, STN DBS and levodopa intake cannot be investigated separately because the two are intrinsically linked. Along with motor symptoms, speech production should be considered when optimizing therapeutic management of patients with PD. PMID:26558134

  15. Methods for Surgical Targeting of the STN in Early-Stage Parkinson's Disease.

    PubMed

    Camalier, Corrie R; Konrad, Peter E; Gill, Chandler E; Kao, Chris; Remple, Michael R; Nasr, Hana M; Davis, Thomas L; Hedera, Peter; Phibbs, Fenna T; Molinari, Anna L; Neimat, Joseph S; Charles, David

    2014-01-01

    Patients with Parkinson's disease (PD) experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn-Yahr Stage III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery, the ability to identify this nucleus in early-stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN in 15 patients with early PD (Hoehn-Yahr Stage II), using a combination of image guided surgery, microelectrode recordings, and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates and root mean squared activity) have previously been found to be lower than in later-stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson's patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early-stage PD using traditional methods. PMID:24678307

  16. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects.

    PubMed

    Simon, Amos J; Lev, Atar; Zhang, Yong; Weiss, Batia; Rylova, Anna; Eyal, Eran; Kol, Nitzan; Barel, Ortal; Cesarkas, Keren; Soudack, Michalle; Greenberg-Kushnir, Noa; Rhodes, Michele; Wiest, David L; Schiby, Ginette; Barshack, Iris; Katz, Shulamit; Pras, Elon; Poran, Hana; Reznik-Wolf, Haike; Ribakovsky, Elena; Simon, Carlos; Hazou, Wadi; Sidi, Yechezkel; Lahad, Avishay; Katzir, Hagar; Sagie, Shira; Aqeilan, Haifa A; Glousker, Galina; Amariglio, Ninette; Tzfati, Yehuda; Selig, Sara; Rechavi, Gideon; Somech, Raz

    2016-07-25

    The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach. PMID:27432940

  17. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development

    PubMed Central

    Kobayashi, Akio; Valerius, M. Todd; Mugford, Joshua W.; Carroll, Thomas J.; Self, Michelle; Oliver, Guillermo; McMahon, Andrew P.

    2008-01-01

    SUMMARY Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process is unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell-types of the main body of the nephron, during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell-autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population. PMID:18682239

  18. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.

    PubMed

    Kobayashi, Akio; Valerius, M Todd; Mugford, Joshua W; Carroll, Thomas J; Self, Michelle; Oliver, Guillermo; McMahon, Andrew P

    2008-08-01

    Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population. PMID:18682239

  19. Inhibition of Serratia marcescens Smj-11 biofilm formation by Alcaligenes faecalis STN17 crude extract

    NASA Astrophysics Data System (ADS)

    Lutfi, Zainal; Usup, Gires; Ahmad, Asmat

    2014-09-01

    Serratia marcescens biofilms are formed when they are bound to surfaces in aqueous environments. S. marcescens utilizes N-acylhomoserine lactone (AHL) as its quorum sensing signal molecule. The accumulation of AHL indicates the bacteria to produce matrices to form biofilms. Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosin), which causes red pigmentation in the colonies, are also produced when the AHL reaches a certain threshold. The Alcaligenes faecalis STN17 crude extract is believed to inhibit quorum sensing in the S. marcescens Smj-11 and, thus, impedes its biofilm formation ability. A. faecalis STN17 was grown in marine broth, and ethyl acetate extraction was carried out. The crude compound of A. faecalis STN17 was diluted at high concentration (0.2-6.4 mg/mL) and was taken to confirm anti-biofilm activity through the crystal violet method in 96-wells plate. Then, the crude extract underwent purification using simple solvents partitioning test to discern the respective compounds that had the anti-biofilm activity under the crystal violet method. The crystal violet test showed that the crude did have anti-biofilm activity on S. marcescens Smj-11, but did not kill the cells. This finding signifies that the suppression of biofilm formation in S. marcescens by A. faecalis STN17 has a strong correlation. The partitioning test showed that A. faecalis STN17 crude extract has several compounds and only the compound(s) in chloroform showed activities. In conclusion, the crude extract of A. faecalis STN17 has the ability to inhibit S. marcescens Smj-11 biofilm formation.

  20. Inhibition of Serratia marcescens Smj-11 biofilm formation by Alcaligenes faecalis STN17 crude extract

    SciTech Connect

    Lutfi, Zainal; Ahmad, Asmat; Usup, Gires

    2014-09-03

    Serratia marcescens biofilms are formed when they are bound to surfaces in aqueous environments. S. marcescens utilizes N-acylhomoserine lactone (AHL) as its quorum sensing signal molecule. The accumulation of AHL indicates the bacteria to produce matrices to form biofilms. Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosin), which causes red pigmentation in the colonies, are also produced when the AHL reaches a certain threshold. The Alcaligenes faecalis STN17 crude extract is believed to inhibit quorum sensing in the S. marcescens Smj-11 and, thus, impedes its biofilm formation ability. A. faecalis STN17 was grown in marine broth, and ethyl acetate extraction was carried out. The crude compound of A. faecalis STN17 was diluted at high concentration (0.2-6.4 mg/mL) and was taken to confirm anti-biofilm activity through the crystal violet method in 96-wells plate. Then, the crude extract underwent purification using simple solvents partitioning test to discern the respective compounds that had the anti-biofilm activity under the crystal violet method. The crystal violet test showed that the crude did have anti-biofilm activity on S. marcescens Smj-11, but did not kill the cells. This finding signifies that the suppression of biofilm formation in S. marcescens by A. faecalis STN17 has a strong correlation. The partitioning test showed that A. faecalis STN17 crude extract has several compounds and only the compound(s) in chloroform showed activities. In conclusion, the crude extract of A. faecalis STN17 has the ability to inhibit S. marcescens Smj-11 biofilm formation.

  1. Dicer1 activity in the stromal compartment regulates nephron differentiation and vascular patterning during mammalian kidney organogenesis.

    PubMed

    Nakagawa, Naoki; Xin, Cuiyan; Roach, Allie M; Naiman, Natalie; Shankland, Stuart J; Ligresti, Giovanni; Ren, Shuyu; Szak, Suzanne; Gomez, Ivan G; Duffield, Jeremy S

    2015-06-01

    MicroRNAs, activated by the enzyme Dicer1, control post-transcriptional gene expression. Dicer1 has important roles in the epithelium during nephrogenesis, but its function in stromal cells during kidney development is unknown. To study this, we inactivated Dicer1 in renal stromal cells. This resulted in hypoplastic kidneys, abnormal differentiation of the nephron tubule and vasculature, and perinatal mortality. In mutant kidneys, genes involved in stromal cell migration and activation were suppressed as were those involved in epithelial and endothelial differentiation and maturation. Consistently, polarity of the proximal tubule was incorrect, distal tubule differentiation was diminished, and elongation of Henle's loop attenuated resulting in lack of inner medulla and papilla in stroma-specific Dicer1 mutants. Glomerular maturation and capillary loop formation were abnormal, whereas peritubular capillaries, with enhanced branching and increased diameter, formed later. In Dicer1-null renal stromal cells, expression of factors associated with migration, proliferation, and morphogenic functions including α-smooth muscle actin, integrin-α8, -β1, and the WNT pathway transcriptional regulator LEF1 were reduced. Dicer1 mutation in stroma led to loss of expression of distinct microRNAs. Of these, miR-214, -199a-5p, and -199a-3p regulate stromal cell functions ex vivo, including WNT pathway activation, migration, and proliferation. Thus, Dicer1 activity in the renal stromal compartment regulates critical stromal cell functions that, in turn, regulate differentiation of the nephron and vasculature during nephrogenesis. PMID:25651362

  2. Dicer1 activity in the stromal compartment regulates nephron differentiation and vascular patterning during mammalian kidney organogenesis

    PubMed Central

    Nakagawa, Naoki; Xin, Cuiyan; Roach, Allie M.; Naiman, Natalie; Shankland, Stuart J.; Ligresti, Giovanni; Ren, Shuyu; Szak, Suzanne; Gomez, Ivan G.; Duffield, Jeremy S.

    2015-01-01

    MicroRNAs, activated by the enzyme Dicer1, control post-transcriptional gene expression. Dicer1 has important roles in the epithelium during nephrogenesis, but its function in stromal cells during kidney development is unknown. To study this we inactivated Dicer1 in renal stromal cells. This resulted in hypoplastic kidneys, abnormal differentiation of the nephron tubule and vasculature, and perinatal mortality. In mutant kidneys, genes involved in stromal cell migration and activation were suppressed as were those involved in epithelial and endothelial differentiation and maturation. Consistently, polarity of the proximal tubule was incorrect, distal tubule differentiation was diminished, and elongation of Henle’s loop attenuated resulting in lack of inner medulla and papilla in stroma-specific Dicer1 mutants. Glomerular maturation and capillary loop formation were abnormal while peritubular capillaries, with enhanced branching and increased diameter, formed later. In Dicer1-null renal stromal cells, expression of factors associated with migration, proliferation and morphogenic functions including α-smooth muscle actin, integrin-α8, -β1, and the WNT pathway transcriptional regulator LEF1 were reduced. Dicer1 mutation in stroma led to loss of expression of distinct microRNAs. Of these, miR-214, -199a-5p and -199a-3p regulate stromal cell functions ex vivo, including WNT pathway activation, migration and proliferation. Thus, Dicer1 activity in the renal stromal compartment regulates critical stromal cell functions that, in turn, regulate differentiation of the nephron and vasculature during nephrogenesis. PMID:25651362

  3. Compensatory Growth of Congenital Solitary Kidneys in Pigs Reflects Increased Nephron Numbers Rather Than Hypertrophy

    PubMed Central

    van Vuuren, Stefan H.; Sol, Chalana M.; Broekhuizen, Roel; Lilien, Marc R.; Oosterveld, Michiel J. S.; Nguyen, Tri Q.

    2012-01-01

    Background Patients with unilateral MultiCystic Kidney Dysplasia (MCKD) or unilateral renal agenesis (URA) have a congenital solitary functioning kidney (CSFK) that is compensatory enlarged. The question whether this enlargement is due to increased nephron numbers and/or to nephron hypertrophy is unresolved. This question is of utmost clinical importance, since hypertrophy is associated with a risk of developing hypertension and proteinuria later in life with consequent development of CKD and cardiovascular disease. Methodology/Principal Findings In a cohort of 32,000 slaughter pigs, 7 congenital solitary functioning kidneys and 7 control kidneys were identified and harvested. Cortex volume was measured and with a 3-dimensional stereologic technique the number and volume of glomeruli was determined and compared. The mean total cortex volume was increased by more than 80% and the mean number of glomeruli per kidney was 50% higher in CSFKs than in a single control kidney, equaling 75% of the total nephron number in both kidneys of control subjects. The mean total glomerular volume in the CSFKs was not increased relative to the controls. Conclusions/Significance Thus, in pigs, compensatory enlargement of a CSFK is based on increased nephron numbers. Extrapolation of these findings to the human situation suggests that patients with a CSFK might not be at increased risk for developing hyperfiltration-associated renal and cardiovascular disease in later life due to a lower nephron number. PMID:23185419

  4. STN area detection using K-NN classifiers for MER recordings in Parkinson patients during neurostimulator implant surgery

    NASA Astrophysics Data System (ADS)

    Schiaffino, L.; Rosado Muñoz, A.; Guerrero Martínez, J.; Francés Villora, J.; Gutiérrez, A.; Martínez Torres, I.; Kohan, y. D. R.

    2016-04-01

    Deep Brain Stimulation (DBS) applies electric pulses into the subthalamic nucleus (STN) improving tremor and other symptoms associated to Parkinson’s disease. Accurate STN detection for proper location and implant of the stimulating electrodes is a complex task and surgeons are not always certain about final location. Signals from the STN acquired during DBS surgery are obtained with microelectrodes, having specific characteristics differing from other brain areas. Using supervised learning, a trained model based on previous microelectrode recordings (MER) can be obtained, being able to successfully classify the STN area for new MER signals. The K Nearest Neighbours (K-NN) algorithm has been successfully applied to STN detection. However, the use of the fuzzy form of the K-NN algorithm (KNN-F) has not been reported. This work compares the STN detection algorithm of K-NN and KNN-F. Real MER recordings from eight patients where previously classified by neurophysiologists, defining 15 features. Sensitivity and specificity for the classifiers are obtained, Wilcoxon signed rank non-parametric test is used as statistical hypothesis validation. We conclude that the performance of KNN-F classifier is higher than K-NN with p<0.01 in STN specificity.

  5. Harvest and primary culture of the murine aldosterone-sensitive distal nephron

    PubMed Central

    Labarca, Mariana; Nizar, Jonathan M.; Walczak, Elisabeth M.; Dong, Wuxing; Pao, Alan C.

    2015-01-01

    The aldosterone-sensitive distal nephron (ASDN) exhibits axial heterogeneity in structure and function from the distal convoluted tubule to the medullary collecting duct. Ion and water transport is primarily divided between the cortex and medulla of the ASDN, respectively. Transcellular transport in this segment is highly regulated in health and disease and is integrated across different cell types. We currently lack an inexpensive, high-yield, and tractable technique to harvest and culture cells for the study of gene expression and physiological properties of mouse cortical ASDN. To address this need, we harvested tubules bound to Dolichos biflorus agglutinin lectin-coated magnetic beads from the kidney cortex and characterized these cell preparations. We determined that these cells are enriched for markers of distal convoluted tubule, connecting tubule, and cortical collecting duct, including principal and intercalated cells. In primary culture, these cells develop polarized monolayers with high resistance (1,000-1,500 Ω * cm2) and maintain expression and activity of key channels. These cells demonstrate an amiloride-sensitive short-circuit current that can be enhanced with aldosterone and maintain measurable potassium and anion secretion. Our method can be easily adopted to study the biology of the ASDN and to investigate phenotypic differences between wild-type and transgenic mouse models. PMID:25810438

  6. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development

    PubMed Central

    Costantini, Frank; Kopan, Raphael

    2010-01-01

    Summary The two major components of the kidney, the collecting system and the nephron, have different developmental histories. The collecting system arises by the reiterated branching of a simple epithelial tube, while the nephron forms from a cloud of mesenchymal cells that coalesces into epithelial vesicles. Each develops into a morphologically complex and highly differentiated structure, and together they provide essential filtration and resorption functions. In this review we will consider their embryological origin, and the genes controlling their morphogenesis, patterning and differentiation, focusing on recent advances in several areas. PMID:20493806

  7. Motor and non-motor circuitry activation induced by subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson’s disease patients: Intraoperative fMRI for DBS

    PubMed Central

    Knight, Emily J.; Testini, Paola; Min, Hoon-Ki; Gibson, William S.; Gorny, Krzysztof R.; Favazza, Christopher P.; Felmlee, Joel P.; Kim, Inyong; Welker, Kirk M.; Clayton, Daniel A.; Klassen, Bryan T.; Chang, Su-youne; Lee, Kendall H.

    2015-01-01

    Objective To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with PD would affect the activity of both motor and non-motor networks, we applied intraoperative fMRI to patients receiving DBS. Patients and Methods Ten patients receiving STN DBS for PD underwent intraoperative 1.5T fMRI during high frequency stimulation delivered via an external pulse generator. The study was conducted between the dates of January 1, 2013 and September 30, 2014. Results We observed blood oxygen level dependent (BOLD) signal changes (FDR<.001) in the motor circuitry, including primary motor, premotor, and supplementary motor cortices, thalamus, pedunculopontine nucleus (PPN), and cerebellum, as well as in the limbic circuitry, including cingulate and insular cortices. Activation of the motor network was observed also after applying a Bonferroni correction (p<.001) to our dataset, suggesting that, across subjects, BOLD changes in the motor circuitry are more consistent compared to those occurring in the non-motor network. Conclusions These findings support the modulatory role of STN DBS on the activity of motor and non-motor networks, and suggest complex mechanisms at the basis of the efficacy of this treatment modality. Furthermore, these results suggest that, across subjects, BOLD changes in the motor circuitry are more consistent compared to those occurring in the non-motor network. With further studies combining the use of real time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning, but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. PMID:26046412

  8. Synthesis and immunological evaluation of MUC1 glycopeptide conjugates bearing N-acetyl modified STn derivatives as anticancer vaccines.

    PubMed

    Xiao, An; Zheng, Xiu-Jing; Song, Chengcheng; Gui, Yue; Huo, Chang-Xin; Ye, Xin-Shan

    2016-07-26

    Glycoprotein MUC1 is an attractive target for anti-tumor vaccine development. However, the weak immunogenicity of MUC1 remains a significant problem. To solve this problem, several STn derivatives with N-acetyl modifications were synthesized and incorporated into a 20-amino acid MUC1 tandem repeat sequence. The modified STn-MUC1 glycopeptides were further connected to a carrier protein keyhole limpet hemocyanin (KLH). The immunological effects of these synthetic vaccine conjugates were evaluated using the BALB/c mouse model. The results showed that vaccine V2 elicited higher titers of antibodies which cross-reacted with the native STn-MUC1 antigen. Moreover, the elicited antisera reacted with the STn-MUC1 antigen-positive tumor cells, indicating that the carbohydrate antigen modification strategy may hold potential to overcome the weak immunogenicity of natural MUC1 glycopeptides. PMID:27380866

  9. Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney.

    PubMed

    Camarata, Troy; Howard, Alexis; Elsey, Ruth M; Raza, Sarah; O'Connor, Alice; Beatty, Brian; Conrad, Jack; Solounias, Nikos; Chow, Priscilla; Mukta, Saima; Vasilyev, Aleksandr

    2016-01-01

    New nephron formation (nephrogenesis) ceases in mammals around birth and is completely absent in adults. In contrast, postembryonic nephrogenesis is well documented in the mesonephric kidneys of fishes and amphibians. The transient mesonephros in reptiles (including birds) and mammals is replaced by the metanephros during embryogenesis. Thus, one may speculate that postembryonic nephrogenesis is restricted to the mesonephric kidney. Previous reports have suggested the metanephros of non-avian reptiles (hereafter reptiles) may continually form nephrons throughout life. We investigated the presence of adult nephrogenesis in reptiles by examining adult kidneys from several species including Trachemys scripta, Chrysemys picta, Boa constrictor, Tupinambis tegu, Anolis carolinensis, and Alligator mississipiensis among others. We found that all major reptilian groups (Testudines, Crocodylia, and Squamates) showed the presence of adult nephrogenesis. The total amount of nephrogenesis varied greatly between species with turtles displaying the highest density of nephrogenesis. In contrast, we were unable to detect adult nephrogenesis in monotremes, and in the iguanid A. carolinensis. Nephron progenitor cells express the transcription factor Six2, which in mammals, becomes downregulated as the progenitor cell population is exhausted and nephrogenesis ends. Using the alligator as a model, we were able to detect Six2-positive cap mesenchyme cells in the adult kidney, which spatially correlated with areas of nephrogenesis. These results suggest that the metanephric kidney of reptiles has maintained the ability to continually grow new nephrons during postembryonic life, a process lost early in mammalian evolution, likely due to the persistence of a Six2-expressing progenitor cell population. PMID:27144443

  10. Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney

    PubMed Central

    Camarata, Troy; Howard, Alexis; Elsey, Ruth M.; Raza, Sarah; O’Connor, Alice; Beatty, Brian; Conrad, Jack; Solounias, Nikos; Chow, Priscilla; Mukta, Saima; Vasilyev, Aleksandr

    2016-01-01

    New nephron formation (nephrogenesis) ceases in mammals around birth and is completely absent in adults. In contrast, postembryonic nephrogenesis is well documented in the mesonephric kidneys of fishes and amphibians. The transient mesonephros in reptiles (including birds) and mammals is replaced by the metanephros during embryogenesis. Thus, one may speculate that postembryonic nephrogenesis is restricted to the mesonephric kidney. Previous reports have suggested the metanephros of non-avian reptiles (hereafter reptiles) may continually form nephrons throughout life. We investigated the presence of adult nephrogenesis in reptiles by examining adult kidneys from several species including Trachemys scripta, Chrysemys picta, Boa constrictor, Tupinambis tegu, Anolis carolinensis, and Alligator mississipiensis among others. We found that all major reptilian groups (Testudines, Crocodylia, and Squamates) showed the presence of adult nephrogenesis. The total amount of nephrogenesis varied greatly between species with turtles displaying the highest density of nephrogenesis. In contrast, we were unable to detect adult nephrogenesis in monotremes, and in the iguanid A. carolinensis. Nephron progenitor cells express the transcription factor Six2, which in mammals, becomes downregulated as the progenitor cell population is exhausted and nephrogenesis ends. Using the alligator as a model, we were able to detect Six2-positive cap mesenchyme cells in the adult kidney, which spatially correlated with areas of nephrogenesis. These results suggest that the metanephric kidney of reptiles has maintained the ability to continually grow new nephrons during postembryonic life, a process lost early in mammalian evolution, likely due to the persistence of a Six2-expressing progenitor cell population. PMID:27144443

  11. p53 Enables metabolic fitness and self-renewal of nephron progenitor cells.

    PubMed

    Li, Yuwen; Liu, Jiao; Li, Wencheng; Brown, Aaron; Baddoo, Melody; Li, Marilyn; Carroll, Thomas; Oxburgh, Leif; Feng, Yumei; Saifudeen, Zubaida

    2015-04-01

    Contrary to its classic role in restraining cell proliferation, we demonstrate here a divergent function of p53 in the maintenance of self-renewal of the nephron progenitor pool in the embryonic mouse kidney. Nephron endowment is regulated by progenitor availability and differentiation potential. Conditional deletion of p53 in nephron progenitor cells (Six2Cre(+);p53(fl/fl)) induces progressive depletion of Cited1(+)/Six2(+) self-renewing progenitors and loss of cap mesenchyme (CM) integrity. The Six2(p53-null) CM is disorganized, with interspersed stromal cells and an absence of a distinct CM-epithelia and CM-stroma interface. Impaired cell adhesion and epithelialization are indicated by decreased E-cadherin and NCAM expression and by ineffective differentiation in response to Wnt induction. The Six2Cre(+);p53(fl/fl) cap has 30% fewer Six2(GFP(+)) cells. Apoptotic index is unchanged, whereas proliferation index is significantly reduced in accordance with cell cycle analysis showing disproportionately fewer Six2Cre(+);p53(fl/fl) cells in the S and G2/M phases compared with Six2Cre(+);p53(+/+) cells. Mutant kidneys are hypoplastic with fewer generations of nascent nephrons. A significant increase in mean arterial pressure is observed in early adulthood in both germline and conditional Six2(p53-null) mice, linking p53-mediated defects in kidney development to hypertension. RNA-Seq analyses of FACS-isolated wild-type and Six2(GFP(+)) CM cells revealed that the top downregulated genes in Six2Cre(+);p53(fl/fl) CM belong to glucose metabolism and adhesion and/or migration pathways. Mutant cells exhibit a ∼ 50% decrease in ATP levels and a 30% decrease in levels of reactive oxygen species, indicating energy metabolism dysfunction. In summary, our data indicate a novel role for p53 in enabling the metabolic fitness and self-renewal of nephron progenitors. PMID:25804735

  12. p53 enables metabolic fitness and self-renewal of nephron progenitor cells

    PubMed Central

    Li, Yuwen; Liu, Jiao; Li, Wencheng; Brown, Aaron; Baddoo, Melody; Li, Marilyn; Carroll, Thomas; Oxburgh, Leif; Feng, Yumei; Saifudeen, Zubaida

    2015-01-01

    Contrary to its classic role in restraining cell proliferation, we demonstrate here a divergent function of p53 in the maintenance of self-renewal of the nephron progenitor pool in the embryonic mouse kidney. Nephron endowment is regulated by progenitor availability and differentiation potential. Conditional deletion of p53 in nephron progenitor cells (Six2Cre+;p53fl/fl) induces progressive depletion of Cited1+/Six2+ self-renewing progenitors and loss of cap mesenchyme (CM) integrity. The Six2(p53-null) CM is disorganized, with interspersed stromal cells and an absence of a distinct CM-epithelia and CM-stroma interface. Impaired cell adhesion and epithelialization are indicated by decreased E-cadherin and NCAM expression and by ineffective differentiation in response to Wnt induction. The Six2Cre+;p53fl/fl cap has 30% fewer Six2(GFP+) cells. Apoptotic index is unchanged, whereas proliferation index is significantly reduced in accordance with cell cycle analysis showing disproportionately fewer Six2Cre+;p53fl/fl cells in the S and G2/M phases compared with Six2Cre+;p53+/+ cells. Mutant kidneys are hypoplastic with fewer generations of nascent nephrons. A significant increase in mean arterial pressure is observed in early adulthood in both germline and conditional Six2(p53-null) mice, linking p53-mediated defects in kidney development to hypertension. RNA-Seq analyses of FACS-isolated wild-type and Six2(GFP+) CM cells revealed that the top downregulated genes in Six2Cre+;p53fl/fl CM belong to glucose metabolism and adhesion and/or migration pathways. Mutant cells exhibit a ∼50% decrease in ATP levels and a 30% decrease in levels of reactive oxygen species, indicating energy metabolism dysfunction. In summary, our data indicate a novel role for p53 in enabling the metabolic fitness and self-renewal of nephron progenitors. PMID:25804735

  13. Nephron sparing endoscopic treatment for primary carcinoma of the renal calyx: A case report and literature review

    PubMed Central

    WANG, QI; OU, TONG-WEN; XU, JIA-WEI; LI, JIN; BORAZJANI, ALI; JIA, CHUN-SONG; WANG, XU; YAN, HAO

    2016-01-01

    Primary carcinoma of the renal calyx is extremely rare. The present study reported nephron sparing endoscopic treatment for primary carcinoma of the renal calyx. An 81-year-old female presented with a 1-year history of intermittent painless gross hematuria. Computed tomography and X-ray of the urinary tract were unable to definitively identify any lesion. Flexible ureteroscopic examination revealed a tumor with epicenter in the lower calyx of the right kidney, with additional involvement around the calyx. Biopsies were obtained and pathology revealed low-grade urothelial carcinoma. Considering additional co-morbidities, the patient elected to undergo endoscopic management with thulium laser. The present report described the feasibility of flexible ureteroscopic thulium laser resection for the treatment of renal calyx carcinoma. PMID:27330785

  14. STN-DBS Reduces Saccadic Hypometria but Not Visuospatial Bias in Parkinson's Disease Patients.

    PubMed

    Fischer, Petra; Ossandón, José P; Keyser, Johannes; Gulberti, Alessandro; Wilming, Niklas; Hamel, Wolfgang; Köppen, Johannes; Buhmann, Carsten; Westphal, Manfred; Gerloff, Christian; Moll, Christian K E; Engel, Andreas K; König, Peter

    2016-01-01

    In contrast to its well-established role in alleviating skeleto-motor symptoms in Parkinson's disease, little is known about the impact of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on oculomotor control and attention. Eye-tracking data of 17 patients with left-hemibody symptom onset was compared with 17 age-matched control subjects. Free-viewing of natural images was assessed without stimulation as baseline and during bilateral DBS. To examine the involvement of ventral STN territories in oculomotion and spatial attention, we employed unilateral stimulation via the left and right ventralmost contacts respectively. When DBS was off, patients showed shorter saccades and a rightward viewing bias compared with controls. Bilateral stimulation in therapeutic settings improved saccadic hypometria but not the visuospatial bias. At a group level, unilateral ventral stimulation yielded no consistent effects. However, the evaluation of electrode position within normalized MNI coordinate space revealed that the extent of early exploration bias correlated with the precise stimulation site within the left subthalamic area. These results suggest that oculomotor impairments "but not higher-level exploration patterns" are effectively ameliorable by DBS in therapeutic settings. Our findings highlight the relevance of the STN topography in selecting contacts for chronic stimulation especially upon appearance of visuospatial attention deficits. PMID:27199693

  15. STN-DBS Reduces Saccadic Hypometria but Not Visuospatial Bias in Parkinson's Disease Patients

    PubMed Central

    Fischer, Petra; Ossandón, José P.; Keyser, Johannes; Gulberti, Alessandro; Wilming, Niklas; Hamel, Wolfgang; Köppen, Johannes; Buhmann, Carsten; Westphal, Manfred; Gerloff, Christian; Moll, Christian K. E.; Engel, Andreas K.; König, Peter

    2016-01-01

    In contrast to its well-established role in alleviating skeleto-motor symptoms in Parkinson's disease, little is known about the impact of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on oculomotor control and attention. Eye-tracking data of 17 patients with left-hemibody symptom onset was compared with 17 age-matched control subjects. Free-viewing of natural images was assessed without stimulation as baseline and during bilateral DBS. To examine the involvement of ventral STN territories in oculomotion and spatial attention, we employed unilateral stimulation via the left and right ventralmost contacts respectively. When DBS was off, patients showed shorter saccades and a rightward viewing bias compared with controls. Bilateral stimulation in therapeutic settings improved saccadic hypometria but not the visuospatial bias. At a group level, unilateral ventral stimulation yielded no consistent effects. However, the evaluation of electrode position within normalized MNI coordinate space revealed that the extent of early exploration bias correlated with the precise stimulation site within the left subthalamic area. These results suggest that oculomotor impairments “but not higher-level exploration patterns” are effectively ameliorable by DBS in therapeutic settings. Our findings highlight the relevance of the STN topography in selecting contacts for chronic stimulation especially upon appearance of visuospatial attention deficits. PMID:27199693

  16. Maintenance of Mouse Nephron Progenitor Cells in Aggregates with Gamma-Secretase Inhibitor

    PubMed Central

    Yuri, Shunsuke; Nishikawa, Masaki; Yanagawa, Naomi; Jo, Oak D.; Yanagawa, Norimoto

    2015-01-01

    Knowledge on how to maintain and expand nephron progenitor cells (NPC) in vitro is important to provide a potentially valuable source for kidney replacement therapies. In our present study, we examined the possibility of optimizing NPC maintenance in the "re-aggregate" system. We found that Six2-expressing (Six2+)-NPC could be maintained in aggregates reconstituted with dispersed cells from E12.5 mouse embryonic kidneys for at least up to 21 days in culture. The maintenance of Six2+-NPC required the presence of ureteric bud cells. The number of Six2+-NPC increased by more than 20-fold at day 21, but plateaued after day 14. In an attempt to further sustain NPC proliferation by passage subculture, we found that the new (P1) aggregates reconstituted from the original (P0) aggregates failed to maintain NPC. However, based on the similarity between P1 aggregates and aggregates derived from E15.5 embryonic kidneys, we suspected that the differentiated NPC in P1 aggregates may interfere with NPC maintenance. In support of this notion, we found that preventing NPC differentiation by DAPT, a γ-secretase inhibitor that inhibits Notch signaling pathway, was effective to maintain and expand Six2+-NPC in P1 aggregates by up to 65-fold. The Six2+-NPC in P1 aggregates retained their potential to epithelialize upon exposure to Wnt signal. In conclusion, we demonstrated in our present study that the "re-aggregation" system can be useful for in vitro maintenance of NPC when combined with γ-secretase inhibitor. PMID:26075891

  17. An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron.

    PubMed

    Carrisoza-Gaytan, Rolando; Carattino, Marcelo D; Kleyman, Thomas R; Satlin, Lisa M

    2016-02-15

    Flow-induced K secretion (FIKS) in the aldosterone-sensitive distal nephron (ASDN) is mediated by large-conductance, Ca(2+)/stretch-activated BK channels composed of pore-forming α-subunits (BKα) and accessory β-subunits. This channel also plays a critical role in the renal adaptation to dietary K loading. Within the ASDN, the cortical collecting duct (CCD) is a major site for the final renal regulation of K homeostasis. Principal cells in the ASDN possess a single apical cilium whereas the surfaces of adjacent intercalated cells, devoid of cilia, are decorated with abundant microvilli and microplicae. Increases in tubular (urinary) flow rate, induced by volume expansion, diuretics, or a high K diet, subject CCD cells to hydrodynamic forces (fluid shear stress, circumferential stretch, and drag/torque on apical cilia and presumably microvilli/microplicae) that are transduced into increases in principal (PC) and intercalated (IC) cell cytoplasmic Ca(2+) concentration that activate apical voltage-, stretch- and Ca(2+)-activated BK channels, which mediate FIKS. This review summarizes studies by ourselves and others that have led to the evolving picture that the BK channel is localized in a macromolecular complex at the apical membrane, composed of mechanosensitive apical Ca(2+) channels and a variety of kinases/phosphatases as well as other signaling molecules anchored to the cytoskeleton, and that an increase in tubular fluid flow rate leads to IC- and PC-specific responses determined, in large part, by the cell-specific composition of the BK channels. PMID:26632600

  18. Short-term nonpressor angiotensin II infusion stimulates sodium transporters in proximal tubule and distal nephron

    PubMed Central

    Nguyen, Mien T X; Han, Jiyang; Ralph, Donna L; Veiras, Luciana C; McDonough, Alicia A

    2015-01-01

    In Sprague Dawley rats, 2-week angiotensin II (AngII) infusion increases Na+ transporter abundance and activation from cortical thick ascending loop of Henle (TALH) to medullary collecting duct (CD) and raises blood pressure associated with a pressure natriuresis, accompanied by depressed Na+ transporter abundance and activation from proximal tubule (PT) through medullary TALH. This study tests the hypothesis that early during AngII infusion, before blood pressure raises, Na+ transporters’ abundance and activation increase all along the nephron. Male Sprague Dawley rats were infused via osmotic minipumps with a subpressor dose of AngII (200 ng/kg/min) or vehicle for 3 days. Overnight urine was collected in metabolic cages and sodium transporters’ abundance and phosphorylation were determined by immunoblotting homogenates of renal cortex and medulla. There were no significant differences in body weight gain, overnight urine volume, urinary Na+ and K+ excretion, or rate of excretion of a saline challenge between AngII and vehicle infused rats. The 3-day nonpressor AngII infusion significantly increased the abundance of PT Na+/H+ exchanger 3 (NHE3), cortical TALH Na-K-2Cl cotransporter 2 (NKCC2), distal convoluted tubule (DCT) Na-Cl cotransporter (NCC), and cortical CD ENaC subunits. Additionally, phosphorylation of cortical NKCC2, NCC, and STE20/SPS1-related proline–alanine-rich kinase (SPAK) were increased; medullary NKCC2 and SPAK were not altered. In conclusion, 3-day AngII infusion provokes PT NHE3 accumulation as well as NKCC2, NCC, and SPAK accumulation and activation in a prehypertensive phase before evidence for intrarenal angiotensinogen accumulation. PMID:26347505

  19. RhBG and RhCG, the putative ammonia transporters, are expressed in the same cells in the distal nephron.

    PubMed

    Quentin, Fabienne; Eladari, Dominique; Cheval, Lydie; Lopez, Claude; Goossens, Dominique; Colin, Yves; Cartron, Jean-Pierre; Paillard, Michel; Chambrey, Régine

    2003-03-01

    Two nonerythroid homologs of the blood group Rh proteins, RhCG and RhBG, which share homologies with specific ammonia transporters in primitive organisms and plants, could represent members of a new family of proteins involved in ammonia transport in the mammalian kidney. Consistent with this hypothesis, the expression of RhCG was recently reported at the apical pole of all connecting tubule (CNT) cells as well as in intercalated cells of collecting duct (CD). To assess the localization along the nephron of RhBG, polyclonal antibodies against the Rh type B glycoprotein were generated. In immunoblot experiments, a specific polypeptide of Mr approximately 50 kD was detected in rat kidney cortex and in outer and inner medulla membrane fractions. Immunocytochemical studies revealed RhBG expression in distal nephron segments within the cortical labyrinth, medullary rays, and outer and inner medulla. RhBG expression was restricted to the basolateral membrane of epithelial cells. The same localization was observed in rat and mouse kidney. RT-PCR analysis on microdissected rat nephron segments confirmed that RhBG mRNAs were chiefly expressed in CNT and cortical and outer medullary CD. Double immunostaining with RhCG demonstrated that RhBG and RhCG were coexpressed in the same cells, but with a basolateral and apical localization, respectively. In conclusion, RhBG and RhCG are present in a major site of ammonia secretion in the kidney, i.e., the CNT and CD, in agreement with their putative role in ammonium transport. PMID:12595489

  20. Nephron proximal tubule patterning and corpuscles of Stannius formation are regulated by the sim1a transcription factor and retinoic acid in zebrafish.

    PubMed

    Cheng, Christina N; Wingert, Rebecca A

    2015-03-01

    The mechanisms that establish nephron segments are poorly understood. The zebrafish embryonic kidney, or pronephros, is a simplified yet conserved genetic model to study this renal development process because its nephrons contain segments akin to other vertebrates, including the proximal convoluted and straight tubules (PCT, PST). The zebrafish pronephros is also associated with the corpuscles of Stannius (CS), endocrine glands that regulate calcium and phosphate homeostasis, but whose ontogeny from renal progenitors is largely mysterious. Initial patterning of zebrafish renal progenitors in the intermediate mesoderm (IM) involves the formation of rostral and caudal domains, the former being reliant on retinoic acid (RA) signaling, and the latter being repressed by elevated RA levels. Here, using expression profiling to gain new insights into nephrogenesis, we discovered that the gene single minded family bHLH transcription factor 1a (sim1a) is dynamically expressed in the renal progenitors-first marking the caudal domain, then becoming restricted to the proximal segments, and finally exhibiting specific CS expression. In loss of function studies, sim1a knockdown expanded the PCT and abrogated both the PST and CS populations. Conversely, overexpression of sim1a modestly expanded the PST and CS, while it reduced the PCT. These results show that sim1a activity is necessary and partially sufficient to induce PST and CS fates, and suggest that sim1a may inhibit PCT fate and/or negotiate the PCT/PST boundary. Interestingly, the sim1a expression domain in renal progenitors is responsive to altered levels of RA, suggesting that RA regulates sim1a, directly or indirectly, during nephrogenesis. sim1a deficient embryos treated with exogenous RA formed nephrons that were predominantly composed of PCT segments, but lacked the enlarged PST observed in RA treated wild-types, indicating that RA is not sufficient to rescue the PST in the absence of sim1a expression. Alternately

  1. Nephron proximal tubule patterning and corpuscles of Stannius formation are regulated by the sim1a transcription factor and retinoic acid in zebrafish

    PubMed Central

    Cheng, Christina N.; Wingert, Rebecca A.

    2014-01-01

    The mechanisms that establish nephron segments are poorly understood. The zebrafish embryonic kidney, or pronephros, is a simplified yet conserved genetic model to study this renal development process because its nephrons contain segments akin to other vertebrates, including the proximal convoluted and straight tubules (PCT, PST). The zebrafish pronephros is also associated with the corpuscles of Stannius (CS), endocrine glands that regulate calcium and phosphate homeostasis, but whose ontogeny from renal progenitors is largely mysterious. Initial patterning of zebrafish renal progenitors in the intermediate mesoderm (IM) involves the formation of rostral and caudal domains, the former being reliant on retinoic acid (RA) signaling, and the latter being repressed by elevated RA levels. Here, using expression profiling to gain new insights into nephrogenesis, we discovered that the gene single minded family bHLH transcription factor 1a (sim1a) is dynamically expressed in the renal progenitors—first marking the caudal domain, then becoming restricted to the proximal segments, and finally exhibiting specific CS expression. In loss of function studies, sim1a knockdown expanded the PCT and abrogated both the PST and CS populations. Conversely, overexpression of sim1a modestly expanded the PST and CS, while it reduced the PCT. These results show that sim1a activity is necessary and partially sufficient to induce PST and CS fates, and suggest that sim1a may inhibit PCT fate and/or negotiate the PCT/PST boundary. Interestingly, the sim1a expression domain in renal progenitors is responsive to altered levels of RA, suggesting that RA regulates sim1a, directly or indirectly, during nephrogenesis. sim1a deficient embryos treated with exogenous RA formed nephrons that were predominantly composed of PCT segments, but lacked the enlarged PST observed in RA treated wild-types, indicating that RA is not sufficient to rescue the PST in the absence of sim1a expression. Alternately

  2. Differential regulation of ROMK (Kir1.1) in distal nephron segments by dietary potassium.

    PubMed

    Wade, James B; Fang, Liang; Coleman, Richard A; Liu, Jie; Grimm, P Richard; Wang, Tong; Welling, Paul A

    2011-06-01

    ROMK channels are well-known to play a central role in renal K secretion, but the absence of highly specific and avid-ROMK antibodies has presented significant roadblocks toward mapping the extent of expression along the entire distal nephron and determining whether surface density of these channels is regulated in response to physiological stimuli. Here, we prepared new ROMK antibodies verified to be highly specific, using ROMK knockout mice as a control. Characterization with segmental markers revealed a more extensive pattern of ROMK expression along the entire distal nephron than previously thought, localizing to distal convoluted tubule regions, DCT1 and DCT2; the connecting tubule (CNT); and cortical collecting duct (CD). ROMK was diffusely distributed in intracellular compartments and at the apical membrane of each tubular region. Apical labeling was significantly increased by high-K diet in DCT2, CNT1, CNT2, and CD (P < 0.05) but not in DCT1. Consistent with the large increase in apical ROMK, dramatically increased mature glycosylation was observed following dietary potassium augmentation. We conclude 1) our new antibody provides a unique tool to characterize ROMK channel localization and expression and 2) high-K diet causes a large increase in apical expression of ROMK in DCT2, CNT, and CD but not in DCT1, indicating that different regulatory mechanisms are involved in K diet-regulated ROMK channel functions in the distal nephron. PMID:21454252

  3. Prediction of STN-DBS Electrode Implantation Track in Parkinson's Disease by Using Local Field Potentials.

    PubMed

    Telkes, Ilknur; Jimenez-Shahed, Joohi; Viswanathan, Ashwin; Abosch, Aviva; Ince, Nuri F

    2016-01-01

    Optimal electrophysiological placement of the DBS electrode may lead to better long term clinical outcomes. Inter-subject anatomical variability and limitations in stereotaxic neuroimaging increase the complexity of physiological mapping performed in the operating room. Microelectrode single unit neuronal recording remains the most common intraoperative mapping technique, but requires significant expertise and is fraught by potential technical difficulties including robust measurement of the signal. In contrast, local field potentials (LFPs), owing to their oscillatory and robust nature and being more correlated with the disease symptoms, can overcome these technical issues. Therefore, we hypothesized that multiple spectral features extracted from microelectrode-recorded LFPs could be used to automate the identification of the optimal track and the STN localization. In this regard, we recorded LFPs from microelectrodes in three tracks from 22 patients during DBS electrode implantation surgery at different depths and aimed to predict the track selected by the neurosurgeon based on the interpretation of single unit recordings. A least mean square (LMS) algorithm was used to de-correlate LFPs in each track, in order to remove common activity between channels and increase their spatial specificity. Subband power in the beta band (11-32 Hz) and high frequency range (200-450 Hz) were extracted from the de-correlated LFP data and used as features. A linear discriminant analysis (LDA) method was applied both for the localization of the dorsal border of STN and the prediction of the optimal track. By fusing the information from these low and high frequency bands, the dorsal border of STN was localized with a root mean square (RMS) error of 1.22 mm. The prediction accuracy for the optimal track was 80%. Individual beta band (11-32 Hz) and the range of high frequency oscillations (200-450 Hz) provided prediction accuracies of 72 and 68% respectively. The best prediction

  4. Prediction of STN-DBS Electrode Implantation Track in Parkinson's Disease by Using Local Field Potentials

    PubMed Central

    Telkes, Ilknur; Jimenez-Shahed, Joohi; Viswanathan, Ashwin; Abosch, Aviva; Ince, Nuri F.

    2016-01-01

    Optimal electrophysiological placement of the DBS electrode may lead to better long term clinical outcomes. Inter-subject anatomical variability and limitations in stereotaxic neuroimaging increase the complexity of physiological mapping performed in the operating room. Microelectrode single unit neuronal recording remains the most common intraoperative mapping technique, but requires significant expertise and is fraught by potential technical difficulties including robust measurement of the signal. In contrast, local field potentials (LFPs), owing to their oscillatory and robust nature and being more correlated with the disease symptoms, can overcome these technical issues. Therefore, we hypothesized that multiple spectral features extracted from microelectrode-recorded LFPs could be used to automate the identification of the optimal track and the STN localization. In this regard, we recorded LFPs from microelectrodes in three tracks from 22 patients during DBS electrode implantation surgery at different depths and aimed to predict the track selected by the neurosurgeon based on the interpretation of single unit recordings. A least mean square (LMS) algorithm was used to de-correlate LFPs in each track, in order to remove common activity between channels and increase their spatial specificity. Subband power in the beta band (11–32 Hz) and high frequency range (200–450 Hz) were extracted from the de-correlated LFP data and used as features. A linear discriminant analysis (LDA) method was applied both for the localization of the dorsal border of STN and the prediction of the optimal track. By fusing the information from these low and high frequency bands, the dorsal border of STN was localized with a root mean square (RMS) error of 1.22 mm. The prediction accuracy for the optimal track was 80%. Individual beta band (11–32 Hz) and the range of high frequency oscillations (200–450 Hz) provided prediction accuracies of 72 and 68% respectively. The best

  5. Missense Mutation of POU Domain Class 3 Transcription Factor 3 in Pou3f3L423P Mice Causes Reduced Nephron Number and Impaired Development of the Thick Ascending Limb of the Loop of Henle.

    PubMed

    Rieger, Alexandra; Kemter, Elisabeth; Kumar, Sudhir; Popper, Bastian; Aigner, Bernhard; Wolf, Eckhard; Wanke, Rüdiger; Blutke, Andreas

    2016-01-01

    During nephrogenesis, POU domain class 3 transcription factor 3 (POU3F3 aka BRN1) is critically involved in development of distinct nephron segments, including the thick ascending limb of the loop of Henle (TAL). Deficiency of POU3F3 in knock-out mice leads to underdevelopment of the TAL, lack of differentiation of TAL cells, and perinatal death due to renal failure. Pou3f3L423P mutant mice, which were established in the Munich ENU Mouse Mutagenesis Project, carry a recessive point mutation in the homeobox domain of POU3F3. Homozygous Pou3f3L423P mutants are viable and fertile. The present study used functional, as well as qualitative and quantitative morphological analyses to characterize the renal phenotype of juvenile (12 days) and aged (60 weeks) homo- and heterozygous Pou3f3L423P mutant mice and age-matched wild-type controls. In both age groups, homozygous mutants vs. control mice displayed significantly smaller kidney volumes, decreased nephron numbers and mean glomerular volumes, smaller TAL volumes, as well as lower volume densities of the TAL in the kidney. No histological or ultrastructural lesions of TAL cells or glomerular cells were observed in homozygous mutant mice. Aged homozygous mutants displayed increased serum urea concentrations and reduced specific urine gravity, but no evidence of glomerular dysfunction. These results confirm the role of POU3F3 in development and function of the TAL and provide new evidence for its involvement in regulation of the nephron number in the kidney. Therefore, Pou3f3L423P mutant mice represent a valuable research model for further analyses of POU3F3 functions, or for nephrological studies examining the role of congenital low nephron numbers. PMID:27420727

  6. Missense Mutation of POU Domain Class 3 Transcription Factor 3 in Pou3f3L423P Mice Causes Reduced Nephron Number and Impaired Development of the Thick Ascending Limb of the Loop of Henle

    PubMed Central

    Rieger, Alexandra; Kemter, Elisabeth; Kumar, Sudhir; Popper, Bastian; Aigner, Bernhard; Wolf, Eckhard; Wanke, Rüdiger; Blutke, Andreas

    2016-01-01

    During nephrogenesis, POU domain class 3 transcription factor 3 (POU3F3 aka BRN1) is critically involved in development of distinct nephron segments, including the thick ascending limb of the loop of Henle (TAL). Deficiency of POU3F3 in knock-out mice leads to underdevelopment of the TAL, lack of differentiation of TAL cells, and perinatal death due to renal failure. Pou3f3L423P mutant mice, which were established in the Munich ENU Mouse Mutagenesis Project, carry a recessive point mutation in the homeobox domain of POU3F3. Homozygous Pou3f3L423P mutants are viable and fertile. The present study used functional, as well as qualitative and quantitative morphological analyses to characterize the renal phenotype of juvenile (12 days) and aged (60 weeks) homo- and heterozygous Pou3f3L423P mutant mice and age-matched wild-type controls. In both age groups, homozygous mutants vs. control mice displayed significantly smaller kidney volumes, decreased nephron numbers and mean glomerular volumes, smaller TAL volumes, as well as lower volume densities of the TAL in the kidney. No histological or ultrastructural lesions of TAL cells or glomerular cells were observed in homozygous mutant mice. Aged homozygous mutants displayed increased serum urea concentrations and reduced specific urine gravity, but no evidence of glomerular dysfunction. These results confirm the role of POU3F3 in development and function of the TAL and provide new evidence for its involvement in regulation of the nephron number in the kidney. Therefore, Pou3f3L423P mutant mice represent a valuable research model for further analyses of POU3F3 functions, or for nephrological studies examining the role of congenital low nephron numbers. PMID:27420727

  7. Effect of chronic potassium loading on potassium secretion by the pars recta or descending limb of the juxtamedullary nephron in the rat.

    PubMed Central

    Battilana, C A; Dobyan, D C; Lacy, F B; Bhattacharya, J; Johnston, P A; Jamison, R L

    1978-01-01

    Recently we demonstrated potassium secretion by the pars recta or by the descending limb of the juxtamedullary nephron. The purpose of this present investigation is to study the effect of a chronic high-potassium intake on this phenomenon. Fractional reabsorption of water and sodium by the juxtamedullary proximal nephron was decreased when compared to that in normal hydropenic rats. There was a striking increase in the fraction of filtered potassium at the end of the juxtamedullary descending limb from 94+/11% to 180+/18%, which was principally a result of enhanced potassium secretion. When the concentration of potassium in the collecting tubule fluid of potassium-loaded rats was reduced after the administration of amiloride, a sharp fall was observed in the amount of potassium which reached the end of the descending limb (64+/8%). A direct correlation was observed between the fraction of filtered potassium at the descending limb and the potassium concentration in the final urine (P less than 0.001). The findings suggest that potassium, like urea, normally undergoes medullary recycling, which is enhanced by chronic potassium loading. PMID:711855

  8. Identification of human nephron progenitors capable of generation of kidney structures and functional repair of chronic renal disease

    PubMed Central

    Harari-Steinberg, Orit; Metsuyanim, Sally; Omer, Dorit; Gnatek, Yehudit; Gershon, Rotem; Pri-Chen, Sara; Ozdemir, Derya D; Lerenthal, Yaniv; Noiman, Tzahi; Ben-Hur, Herzel; Vaknin, Zvi; Schneider, David F; Aronow, Bruce J; Goldstein, Ronald S; Hohenstein, Peter; Dekel, Benjamin

    2013-01-01

    Identification of tissue-specific renal stem/progenitor cells with nephrogenic potential is a critical step in developing cell-based therapies for renal disease. In the human kidney, stem/progenitor cells are induced into the nephrogenic pathway to form nephrons until the 34 week of gestation, and no equivalent cell types can be traced in the adult kidney. Human nephron progenitor cells (hNPCs) have yet to be isolated. Here we show that growth of human foetal kidneys in serum-free defined conditions and prospective isolation of NCAM1+ cells selects for nephron lineage that includes the SIX2-positive cap mesenchyme cells identifying a mitotically active population with in vitro clonogenic and stem/progenitor properties. After transplantation in the chick embryo, these cells—but not differentiated counterparts—efficiently formed various nephron tubule types. hNPCs engrafted and integrated in diseased murine kidneys and treatment of renal failure in the 5/6 nephrectomy kidney injury model had beneficial effects on renal function halting disease progression. These findings constitute the first definition of an intrinsic nephron precursor population, with major potential for cell-based therapeutic strategies and modelling of kidney disease. PMID:23996934

  9. Measurement of Na-K-ATPase-mediated rubidium influx in single segments of rat nephron

    SciTech Connect

    Cheval, L.; Doucet, A. )

    1990-07-01

    To determine the functioning rate of Na-K-ATPase in the rat nephron, a micromethod was developed to measure the rate of rubidium uptake in single nephron segments microdissected from collagenase-treated kidneys. Because the hydrolytic activity of Na-K-ATPase displayed the same apparent affinity for K and Rb ions, whereas the Vmax elicited by K was higher than that in the presence of Rb, experiments were performed in the presence of cold Rb plus 86Rb. Before the assay, tubules were preincubated for 10 min at 37 degrees C to restore the normal transmembrane cation gradients. 86Rb uptake was measured after washing out extracellular cations by rinsing the tubules in ice-cold choline chloride solution containing Ba2+. Rb uptake increased quasi-linearly as a function of incubation time up to 30 s in the thick ascending limb, 1 min in the proximal convoluted tubule, and 5 min in the collecting tubule, and reached an equilibrium after 5-30 min. The initial rates of Rb uptake increased in a saturable fashion as Rb concentration in the medium rose from 0.25 to 5 mM. In medullary thick ascending limb, the initial rate of Rb uptake was inhibited by greater than 90% by 2.5 mM ouabain and by 10(-5) M of the metabolic inhibitor carbonyl cyanide trifluoromethoxyphenylhydrazone. Correlation of Na-K-ATPase hydrolytic activity at Vmax and initial rates of ouabain-sensitive Rb uptake in the successive segments of nephron indicates that in intact cells the pump works at approximately 20-30% of its Vmax. Increasing intracellular Na concentration by tubule preincubation in a Rb- and K-free medium increased the initial rates of Rb intake up to the Vmax of the hydrolytic activity of the pump.

  10. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron.

    PubMed

    Layton, Anita T; Vallon, Volker; Edwards, Aurélie

    2016-06-01

    Diabetes increases the reabsorption of Na(+) (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption [Formula: see text] along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising [Formula: see text] by 5-12% in the cortex and medulla. Diabetes increases overall TNa and [Formula: see text] by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers [Formula: see text] in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises [Formula: see text] in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase [Formula: see text] by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces [Formula: see text] by 33% in S3 segments, and raises [Formula: see text] by <1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical [Formula: see text] and raises medullary [Formula: see text], particularly in S3 segments. PMID:26764207

  11. Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.

    PubMed

    Canonica, Jérémie; Sergi, Chloé; Maillard, Marc; Klusonova, Petra; Odermatt, Alex; Koesters, Robert; Loffing-Cueni, Dominique; Loffing, Johannes; Rossier, Bernard; Frateschi, Simona; Hummler, Edith

    2016-05-01

    Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the "renal" form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MR(Pax8/LC1)) using a doxycycline-inducible system. Under standard diet, MR(Pax8/LC1) mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR(Pax8/LC1) mice survive but develop a severe PHA-1 phenotype with higher urinary Na(+) levels, decreased plasma Na(+), hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na(+)/Cl(-) co-transporter (NCC) protein expression and its phosphorylated form are downregulated in the MR(Pax8/LC1) knockouts, as well as the αENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na(+) and low in K(+) does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA-1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state. PMID:26762397

  12. Sodium-pump gene-expression, protein abundance and enzyme activity in isolated nephron segments of the aging rat kidney

    PubMed Central

    Scherzer, Pnina; Gal-Moscovici, Anca; Sheikh-Hamad, David; Popovtzer, Mordecai M

    2015-01-01

    Aging is associated with alteration in renal tubular functions, including sodium handling and concentrating ability. Na-K-ATPase plays a key role in driving tubular transport, and we hypothesized that decreased concentrating ability of the aging kidney is due in part to downregulation of Na-K-ATPase. In this study, we evaluated Na and K balance, aldosterone levels, and Na-K-ATPase gene expression, protein abundance, and activity in aging rat kidney. Na-K-ATPase activity (assayed microfluorometrically), mRNA (RT-PCR), and protein abundance (immunoblotting) were quantitated in the following isolated nephron segments: PCT, PST, MTAL, DCT, and CCD from 2, 8, 15, and 24 month-old-rats. In the course of aging, creatinine clearance decreased from 0.48 ± 0.02 mL/min/100 g BW to 0.28 ± 0.06 (P < 0.001) and aldosterone decreased from 23.6 ± 0.8 ng/dL to 13.2 ± 0.6 (P < 0.001). Serum Na+ and K+ increased by 4.0% and 22.5%, respectively. Na-K-ATPase activity, mRNA, and protein abundance of the α1 subunit displayed similar trends in all assayed segments; increasing in PCT and PST; decreasing in MTAL and DCT; increasing in CCD: in PCT they increased by 40%, 75%, and 250%, respectively; while in PST they increased by 80%, 50%, and 100%, respectively (P < 0.001). In MTAL they declined by 36%, 24%, and 34%, respectively, and in DCT by 38%, 59%, and 60%, respectively (P < 0.001). They were higher in CCD by 110%, 115%, and 246%, respectively (P < 0.001). Rats maintained Na/K balance; however with a steady state elevated serum K+. These results reveal quantitative changes in axial distribution of Na-K-ATPase at the level of gene expression, protein abundance, and activity in the nephrons of aging animals and may explain, in part, the pathophysiology of the senescent kidney. PMID:26056060

  13. Reduced nephron number and glomerulomegaly in Australian Aborigines: a group at high risk for renal disease and hypertension.

    PubMed

    Hoy, W E; Hughson, M D; Singh, G R; Douglas-Denton, R; Bertram, J F

    2006-07-01

    Aborigines in remote areas of Australia have much higher rates of renal disease, as well as hypertension and cardiovascular disease, than non-Aboriginal Australians. We compared kidney findings in Aboriginal and non-Aboriginal people in one remote region. Glomerular number and mean glomerular volume were estimated with the disector/fractionator combination in the right kidney of 19 Aborigines and 24 non-Aboriginal people undergoing forensic autopsy for sudden or unexpected death in the Top End of the Northern Territory. Aborigines had 30% fewer glomeruli than non-Aborigines--202,000 fewer glomeruli per kidney, or an estimated 404,000 fewer per person (P=0.036). Their mean glomerular volume was 27% larger (P=0.016). Glomerular number was significantly correlated with adult height, inferring a relationship with birthweight, which, on average, is much lower in Aboriginal than non-Aboriginal people. Aboriginal people with a history of hypertension had 30% fewer glomeruli than those without--250,000 fewer per kidney (P=0.03), or 500,000 fewer per person, and their mean glomerular volume was about 25% larger. The lower nephron number in Aboriginal people is compatible with their susceptibility to renal failure. The additional nephron deficit associated with hypertension is compatible with other reports. Lower nephron numbers are probably due in part to reduced nephron endowment, which is related to a suboptimal intrauterine environment. Compensatory glomerular hypertrophy in people with fewer nephrons, while minimizing loss of total filtering surface area, might be exacerbating nephron loss. Optimization of fetal growth should ultimately reduce the florid epidemic of renal disease, hypertension, and cardiovascular disease. PMID:16723986

  14. Subthalamic Nucleus Stimulation and Dysarthria in Parkinson's Disease: A PET Study

    ERIC Educational Resources Information Center

    Pinto, Serge; Thobois, Stephane; Costes, Nicolas; Le Bars, Didier; Benabid, Alim-Louis; Broussolle, Emmanuel; Pollak, Pierre; Gentil, Michele

    2004-01-01

    In Parkinson's disease, functional imaging studies during limb motor tasks reveal cerebral activation abnormalities that can be reversed by subthalamic nucleus (STN) stimulation. The effect of STN stimulation on parkinsonian dysarthria has not, however, been investigated using PET. The aim of the present study was to evaluate the effect of STN…

  15. The Excretion of Renal Cells Following Necrosis of the Distal Segment of the Nephron by Hexadi-Methrine Bromide

    PubMed Central

    Davies, D. J.; Kennedy, A.; Roberts, C.

    1969-01-01

    The rate of excretion of renal cells was determined in rats with necrosis of the distal convoluted tubules and broad ascending limbs of the loops of Henle caused by injection of hexadimethrine bromide. The magnitude and the duration of abnormal cell excretion were correlated both with the dose of hexadimethrine and with the degree of damage that was evident on histological examination of the kidney. In general cell excretion studies provided a satisfactory indication of the degree of renal damage but the smallest lesions did not cause a significant increase in cell excretion and occasionally a rat with a very large lesion failed to show an increase in cell excretion rate. The changes in excretion rates observed in the present experiments were less than those found previously in animals with necrosis of proximal convoluted tubules caused by mercuric chloride. This is probably due firstly to the smaller number of cells in the distal nephron and secondly to the toxin causing disintegration of many of the cells. These findings have implications for the investigation of analgesic nephrotoxicity by measurement of urinary cell excretion rates. In order to appreciate the significance of increases in renal cell excretion following administration of various substances their site of action and the type of cell damage that they cause must first be established. ImagesFigs. 1-4 PMID:5792904

  16. WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals

    PubMed Central

    Kann, Martin; Bae, Eunnyung; Lenz, Maximilian O.; Li, Liangji; Trannguyen, BaoTran; Schumacher, Valerie A.; Taglienti, Mary E.; Bordeianou, Liliana; Hartwig, Sunny; Rinschen, Markus M.; Schermer, Bernhard; Benzing, Thomas; Fan, Chen-Ming; Kreidberg, Jordan A.

    2015-01-01

    Development of the metanephric kidney depends on tightly regulated interplay between self-renewal and differentiation of a nephron progenitor cell (NPC) pool. Several key factors required for the survival of NPCs have been identified, including fibroblast growth factor (FGF) signaling and the transcription factor Wilms' tumor suppressor 1 (WT1). Here, we present evidence that WT1 modulates FGF signaling by activating the expression of growth arrest-specific 1 (Gas1), a novel WT1 target gene and novel modulator of FGF signaling. We show that WT1 directly binds to a conserved DNA binding motif within the Gas1 promoter and activates Gas1 mRNA transcription in NPCs. We confirm that WT1 is required for Gas1 expression in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. Although kidney development in Gas1 knockout mice progresses normally until E15.5, NPCs show decreased rates of proliferation at this stage and are depleted as of E17.5. Lastly, we show that Gas1 is selectively required for FGF-stimulated AKT signaling in vitro. In summary, our data suggest a model in which WT1 modulates receptor tyrosine kinase signaling in NPCs by directing the expression of Gas1. PMID:25804736

  17. Regulatory volume decrease in perfused proximal nephron: evidence for a dumping of cell K+.

    PubMed

    Kirk, K L; DiBona, D R; Schafer, J A

    1987-05-01

    We utilized the microscopic and morphometric procedures described in the preceding paper to examine the role of a swelling-activated dumping of K-salt in the reversal of hyposmotic cell swelling in the perfused proximal nephron. The rate of the regulatory volume decrease that follows cell swelling in dilute solutions was reduced by two maneuvers that attenuate the K+ chemical potential difference across the basolateral membrane; inhibiting the Na+-K+ pump (e.g., with ouabain) and raising the peritubular K+ concentration. The rate of the regulatory volume decrease was also inhibited by peritubular quinine, which blocks K channels and volume regulation for a number of mammalian cells. Additionally, exposure to hyposmotic solutions resulted in a sustained and quinine-sensitive increase in the apparent permeability of the basolateral membrane to K+ salt, which was monitored qualitatively as the rate of cell volume change that was induced by a perturbation in the peritubular K+ concentration. The simplest interpretation of these results is that the reversal of hyposmotic cell swelling in the proximal nephron is referable at least in part to a swelling-activated loss of K-salt and water from the cells. PMID:2437806

  18. Cellular interactions via conditioned media induce in vivo nephron generation from tubular epithelial cells or mesenchymal stem cells

    SciTech Connect

    Machiguchi, Toshihiko Nakamura, Tatsuo

    2013-06-07

    Highlights: •We have attempted in vivo nephron generation using conditioned media. •Vascular and tubular cells do cross-talks on cell proliferation and tubular changes. •Tubular cells suppress these changes in mesenchymal stem cells. •Tubular cells differentiate mesenchymal stem cells into tubular cells. •Nephrons can be created from implanted tubular cells or mesenchymal stem cells. -- Abstract: There are some successful reports of kidney generation by utilizing the natural course of kidney development, namely, the use of an artificially treated metanephros, blastocyst or ureteric bud. Under a novel concept of cellular interactions via conditioned media (CMs), we have attempted in vivo nephron generation from tubular epithelial cells (TECs) or mesenchymal stem cells (MSCs). Here we used 10× CMs of vascular endothelial cells (VECs) and TECs, which is the first to introduce a CM into the field of organ regeneration. We first present stimulative cross-talks induced by these CMs between VECs and TECs on cell proliferation and morphological changes. In MSCs, TEC-CM suppressed these changes, however, induced cytokeratin expression, indicating the differentiation of MSCs into TECs. As a result, glomerular and tubular structures were created following the implantation of TECs or MSCs with both CMs. Our findings suggest that the cellular interactions via CMs might induce in vivo nephron generation from TECs or MSCs. As a promoting factor, CMs could also be applied to the regeneration of other organs and tissues.

  19. [New perspective on the role of WNK1 and WNK4 in the regulation of NaCl reabsorption and K(+) secretion by the distal nephron].

    PubMed

    Rafael, Chloé; Chavez-Canales, Maria; Hadchouel, Juliette

    2016-03-01

    The study of Familial Hyperkalemic Hypertension (FHHt), a rare monogenic disease, allowed remarkable advances in the understanding of the mechanisms of regulation of NaCl reabsorption by the distal nephron. FHHt results from mutations in the genes encoding WNK1 and WNK4, two serine-threonine kinases of the WNK (With No lysine [K]) family. The clinical manifestations of FHHt are due, among others, to an increased activity of the Na(+)-Cl(-) cotransporter NCC. Several groups therefore tried to understand how WNK1 and WNK4 could regulate NCC. However, the data were often contradictory. Two of our recent studies allowed to partially explain these controversies and to propose a new model for the regulation of NCC by the WNKs. PMID:27011246

  20. A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry

    NASA Astrophysics Data System (ADS)

    Hobbs, Robert F.; Song, Hong; Huso, David L.; Sundel, Margaret H.; Sgouros, George

    2012-07-01

    Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. The S-values were calculated for the α-emitters and their descendants between the different nephron compartments for both the

  1. A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry

    PubMed Central

    Hobbs, Robert F; Song, Hong; Huso, David L; Sundel, Margaret; Sgouros, George

    2013-01-01

    Objective Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction –based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply the model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. Methods We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin go those used in the Cristy-Eckermann phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured, ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus vs. proximal tubule vs. distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. Results The S-values were calculated for the α-emitters and their descendants between the different nephron compartments

  2. Low birth weight and nephron mass and their role in the progression of chronic kidney disease: a case report on identical twins with Alport disease.

    PubMed

    Rajan, Tasleem; Barbour, Sean J; White, Colin T; Levin, Adeera

    2011-12-01

    We report the outcomes of 47-year-old monozygotic twins with Alport syndrome, who share the same maternal and genetic factors; however, in adulthood have discordant trajectories in the decline of their renal function. The twin with the more rapid progression to renal failure was born with low birth weight (LBW), suggesting congenital nephron deficiency and increased susceptibility to progressive renal disease, despite having the same genetically inherited kidney condition. This 'natural experiment' adds further credence to the hypothesis that LBW contributes to the susceptibility to chronic kidney disease. We suggest further studies and surveillance for this high-risk group of infants in order to gain additional insights into the impact of perinatal factors such as LBW. PMID:21565948

  3. Homeostasis, the milieu intérieur, and the wisdom of the nephron.

    PubMed

    Hoenig, Melanie P; Zeidel, Mark L

    2014-07-01

    The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the "internal milieu" and allow organisms the "physiologic freedom" to move into varying environments and take in varying diets and fluids. Early ingenious, albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich understanding of the nephron and the kidney's critical role in homeostasis down to the molecular level. This review summarizes those early achievements and provides a framework and introduction for the new CJASN series on renal physiology. PMID:24789550

  4. Homeostasis, the Milieu Intérieur, and the Wisdom of the Nephron

    PubMed Central

    Zeidel, Mark L.

    2014-01-01

    The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the “internal milieu” and allow organisms the “physiologic freedom” to move into varying environments and take in varying diets and fluids. Early ingenious, albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich understanding of the nephron and the kidney’s critical role in homeostasis down to the molecular level. This review summarizes those early achievements and provides a framework and introduction for the new CJASN series on renal physiology. PMID:24789550

  5. Vasopressin regulation of sodium transport in the distal nephron and collecting duct.

    PubMed

    Kortenoeven, M L A; Pedersen, N B; Rosenbaek, L L; Fenton, R A

    2015-08-15

    Arginine vasopressin (AVP) is released from the posterior pituitary gland during states of hyperosmolality or hypovolemia. AVP is a peptide hormone, with antidiuretic and antinatriuretic properties. It allows the kidneys to increase body water retention predominantly by increasing the cell surface expression of aquaporin water channels in the collecting duct alongside increasing the osmotic driving forces for water reabsorption. The antinatriuretic effects of AVP are mediated by the regulation of sodium transport throughout the distal nephron, from the thick ascending limb through to the collecting duct, which in turn partially facilitates osmotic movement of water. In this review, we will discuss the regulatory role of AVP in sodium transport and summarize the effects of AVP on various molecular targets, including the sodium-potassium-chloride cotransporter NKCC2, the thiazide-sensitive sodium-chloride cotransporter NCC, and the epithelial sodium channel ENaC. PMID:26041443

  6. Laparoscopic nephron-sparing resection of synchronous Wilms tumors in a case of hyperplasticperilobarnephroblastomatosis

    PubMed Central

    Rauth, Thomas P.; Slone, Jeremy; Crane, Gabriella; Correa, Hernan; Friedman, Debra L.; Lovvorn, Harold N.

    2011-01-01

    Diffuse hyperplasticperilobarnephroblastomatosis (DHPLN) is a rare precursor lesion of Wilms tumor (WT). Because of the increased risk to develop WT in either kidney, current management algorithms of DHPLN meritnephron-sparing strategies, beginning with chemotherapy and close radiographic monitoring into late childhood. After resolution of DHPLN, subsequent detection of a renal nodule mandates resection to exclude WT. Here, we report the case of a 4 year-old girl who developed two synchronous nodules in the right kidney more than two years after completion of therapy for DHPLN. Because of the early detection and peripheral location of these two nodules, laparoscopic nephron-sparing resection of each was performed using ultrasonic dissection. Both nodules were determined on pathology to be favorable histology WT with negative surgical margins. The child was placed onvincristine and actinomycin-D therapy for 18 weeks. PMID:21616266

  7. Intrinsic Age-Dependent Changes and Cell-Cell Contacts Regulate Nephron Progenitor Lifespan.

    PubMed

    Chen, Shuang; Brunskill, Eric W; Potter, S Steven; Dexheimer, Phillip J; Salomonis, Nathan; Aronow, Bruce J; Hong, Christian I; Zhang, Tongli; Kopan, Raphael

    2015-10-12

    During fetal development, nephrons of the metanephric kidney form from a mesenchymal progenitor population that differentiates en masse before or shortly after birth. We explored intrinsic and extrinsic mechanisms controlling progenitor lifespan in a transplantation assay that allowed us to compare engraftment of old and young progenitors into the same young niche. The progenitors displayed an age-dependent decrease in proliferation and concomitant increase in niche exit rates. Single-cell transcriptome profiling revealed progressive age-dependent changes, with heterogeneity increasing in older populations. Age-dependent elevation in mTor and reduction in Fgf20 could contribute to increased exit rates. Importantly, 30% of old progenitors remained in the niche for up to 1 week post engraftment, a net gain of 50% to their lifespan, but only if surrounded by young neighbors. We provide evidence in support of a model in which intrinsic age-dependent changes affect inter-progenitor interactions that drive cessation of nephrogenesis. PMID:26460946

  8. Dynamics of NAD in cortical nephron segments: Effect of nicotinamide and of dietary phosphate intake

    SciTech Connect

    Yusufi, A.N.K.; Kiebzak, G.M.; Kusano, E.; Werness, J.L.; Homma, S.; Dousa, T.P. )

    1987-08-01

    NAD content and the rate of NAD hydrolysis were determined in proximal convoluted tubules (PCT), proximal straight tubules (PST), and adjacent cortical nephron segments microdissected from kidneys of tyroparathyroidectomized (TPTX) rats. In the basal state, rats fed a normal phosphate diet had an NAD content higher in PCT, PST, and in cortical ascending limb (CAL) than in glomeruli. After intraperitoneal injection of nicotinamide, the NAD content increased significantly in all nephron segments except CAL. In experiments conducted on TPTX rats stabilized on a low-phosphorus diet, NAD content increased in response to a nicotinamide injection in PCT, but did not change significantly in PST. The catabolism of NAD was determined by generation of ({sup 3}H)adenosine, a major metabolite of (adenine-2,8-{sup 3}H)NAD. The rate of ({sup 3}H)adenosine generation from ({sup 3}H)NAD was significantly higher in PST than in PCT. The authors conclude that, in response to nicotinamide administration in vivo, the NAD content increases more in PCT than in PST and that this difference may be, at least partly, due to a lower rate of NAD breakdown in PCT. In a state of dietary phosphate deprivation, NAD also increases significantly in response to intraperitoneal nicotinamide in PCT, but it does not increase significantly in PST. The nicotinamide-elicited increase of NAD content in proximal tubules, mainly in PCT, may be related to inhibition of Na{sup +}-gradient-dependent inorganic phosphate (P{sub i}) reabsorption across the brush-border membrane proximal tubules and to the phosphaturic effect of nicotinamide in rats red normal-P{sub i} diet.

  9. Efficient and Specific Detection of Salmonella in Food Samples Using a stn-Based Loop-Mediated Isothermal Amplification Method

    PubMed Central

    Srisawat, Mevaree; Panbangred, Watanalai

    2015-01-01

    The Salmonella enterotoxin (stn) gene exhibits high homology among S. enterica serovars and S. bongori. A set of 6 specific primers targeting the stn gene were designed for detection of Salmonella spp. using the loop-mediated isothermal amplification (LAMP) method. The primers amplified target sequences in all 102 strains of 87 serovars of Salmonella tested and no products were detected in 57 non-Salmonella strains. The detection limit in pure cultures was 5 fg DNA/reaction when amplified at 65°C for 25 min. The LAMP assay could detect Salmonella in artificially contaminated food samples as low as 220 cells/g of food without a preenrichment step. However, the sensitivity was increased 100-fold (~2 cells/g) following 5 hr preenrichment at 35°C. The LAMP technique, with a preenrichment step for 5 and 16 hr, was shown to give 100% specificity with food samples compared to the reference culture method in which 67 out of 90 food samples gave positive results. Different food matrixes did not interfere with LAMP detection which employed a simple boiling method for DNA template preparation. The results indicate that the LAMP method, targeting the stn gene, has great potential for detection of Salmonella in food samples with both high specificity and high sensitivity. PMID:26543859

  10. Effects of Medication and Subthalamic Nucleus Deep Brain Stimulation on Tongue Movements in Speakers with Parkinson's Disease Using Electropalatography: A Pilot Study

    ERIC Educational Resources Information Center

    Hartinger, Mariam; Tripoliti, Elina; Hardcastle, William J.; Limousin, Patricia

    2011-01-01

    Parkinson's disease (PD) affects speech in the majority of patients. Subthalamic nucleus deep brain stimulation (STN-DBS) is particularly effective in reducing tremor and rigidity. However, its effect on speech is variable. The aim of this pilot study was to quantify the effects of bilateral STN-DBS and medication on articulation, using…

  11. In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron.

    PubMed

    Nesterov, Viatcheslav; Krueger, Bettina; Bertog, Marko; Dahlmann, Anke; Palmisano, Ralf; Korbmacher, Christoph

    2016-06-01

    The epithelial sodium channel (ENaC) is rate limiting for Na(+) absorption in the aldosterone-sensitive distal nephron comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT), and the entire collecting duct. Liddle syndrome (pseudohyperaldosteronism), a severe form of salt-sensitive hypertension, is caused by gain-of-function mutations of ENaC, but the precise tubular site of increased ENaC function is unknown. In the cortical collecting duct (CCD), ENaC is known to be regulated by aldosterone. In contrast, we recently reported aldosterone-independent ENaC regulation in the early part of the aldosterone-sensitive distal nephron. Here, we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice homozygous for Liddle syndrome mutation or from wild-type control mice. Whole-cell patch-clamp recordings were used to measure amiloride-sensitive ENaC currents in nephron fragments from mice maintained on different sodium diets to vary plasma aldosterone levels. Our data indicate that in mice with Liddle syndrome, the primary site of increased Na(+) reabsorption is the DCT2/CNT. In addition, increased aldosterone responsiveness of ENaC in CNT/CCD may contribute to salt-sensitive hypertension in Liddle syndrome. Single channel properties of ENaC were similar in Liddle syndrome mutation and wild-type mice, but ENaC expression at the apical membrane was increased in Liddle syndrome mutation when compared with wild-type mice, in particular, in animals maintained on a high salt diet. Our findings highlight the importance of ENaC function and regulation in the early part of the aldosterone-sensitive distal nephron for the maintenance of sodium balance and blood pressure control. PMID:27170740

  12. Eya1 Interacts with Six2 and Myc to Regulate Expansion of the Nephron Progenitor Pool during Nephrogenesis

    PubMed Central

    Xu, Jinshu; Wong, Elaine Y.M.; Cheng, Chunming; Li, Jun; Sharkar, Mohammad T.K.; Xu, Chelsea Y.; Chen, Binglai; Sun, Jianbo; Jing, Dongzhu; Xu, Pin-Xian

    2014-01-01

    SUMMARY Self-renewal and proliferation of nephron progenitor cells and the decision to initiate nephrogenesis are crucial events directing kidney development. Despite recent advancements in defining lineage and regulators for the progenitors, fundamental questions about mechanisms driving expansion of the progenitors remain unanswered. Here we show that Eya1 interacts with Six2 and Myc to control self-renewing cell activity. Cell fate tracing reveals a developmental restriction of the Eya1+ population within the intermediate mesoderm to nephron-forming cell fates and a common origin shared between caudal mesonephric and metanephric nephrons. Conditional inactivation of Eya1 leads to loss of Six2 expression and premature epithelialization of the progenitors. Six2 mediates translocation of Eya1 to the nucleus, where Eya1 uses its threonine phosphatase activity to control Myc phosphorylation/dephosphorylation and function in the progenitor cells. Our results reveal a functional link between Eya1, Six2, and Myc in driving the expansion and maintenance of the multipotent progenitors during nephrogenesis. PMID:25458011

  13. The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder

    PubMed Central

    Slatopolsky, Eduardo

    2011-01-01

    Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the ‘intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that ‘as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca2+ and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism. Vitamin D receptor, Ca2+ sensing receptor, and Klotho–fibroblast growth factor (FGF) receptor-1 complex are all significantly decreased in the parathyroid glands of patients with CKD. Duodenal instillation of phosphate rapidly decreases parathyroid hormone release without changes in calcium or calcitriol. The same procedure also rapidly increases renal phosphate excretion independently of FGF-23, suggesting the possibility of an ‘intestinal phosphatonin'. These observations suggest a possible ‘phosphate sensor' in the parathyroid glands and gastrointestinal tract, although as yet there is no proof for the existence of such a sensor. Evidence shows that phosphate has a key role in parathyroid hyperplasia by activating the transforming growth factor-α–epidermal growth factor receptor complex. Thus, control of serum phosphorus early in the course of CKD will significantly ameliorate the pathological manifestations observed during progressive deterioration of renal function. PMID:21346721

  14. Deciphering physiological role of the mechanosensitive TRPV4 channel in the distal nephron

    PubMed Central

    Mamenko, M.; Zaika, O.; Boukelmoune, N.; O'Neil, R. G.

    2014-01-01

    Long-standing experimental evidence suggests that epithelial cells in the renal tubule are able to sense osmotic and pressure gradients caused by alterations in ultrafiltrate flow by elevating intracellular Ca2+ concentration. These responses are viewed as critical regulators of a variety of processes ranging from transport of water and solutes to cellular growth and differentiation. A loss in the ability to sense mechanical stimuli has been implicated in numerous pathologies associated with systemic imbalance of electrolytes and to the development of polycystic kidney disease. The molecular mechanisms conferring mechanosensitive properties to epithelial tubular cells involve activation of transient receptor potential (TRP) channels, such as TRPV4, allowing direct Ca2+ influx to increase intracellular Ca2+ concentration. In this review, we critically analyze the current evidence about signaling determinants of TRPV4 activation by luminal flow in the distal nephron and discuss how dysfunction of this mechanism contributes to the progression of polycystic kidney disease. We also review the physiological relevance of TRPV4-based mechanosensitivity in controlling flow-dependent K+ secretion in the distal renal tubule. PMID:25503733

  15. Salt handling in the distal nephron: lessons learned from inherited human disorders.

    PubMed

    Jeck, Nikola; Schlingmann, Karl P; Reinalter, Stephan C; Kömhoff, Martin; Peters, Melanie; Waldegger, Siegfried; Seyberth, Hannsjörg W

    2005-04-01

    The molecular basis of inherited salt-losing tubular disorders with secondary hypokalemia has become much clearer in the past two decades. Two distinct segments along the nephron turned out to be affected, the thick ascending limb of Henle's loop and the distal convoluted tubule, accounting for two major clinical phenotypes, hyperprostaglandin E syndrome and Bartter-Gitelman syndrome. To date, inactivating mutations have been detected in six different genes encoding for proteins involved in renal transepithelial salt transport. Careful examination of genetically defined patients ("human knockouts") allowed us to determine the individual role of a specific protein and its contribution to the overall process of renal salt reabsorption. The recent generation of several genetically engineered mouse models that are deficient in orthologous genes further enabled us to compare the human phenotype with the animal models, revealing some unexpected interspecies differences. As the first line treatment in hyperprostaglandin E syndrome includes cyclooxygenase inhibitors, we propose some hypotheses about the mysterious role of PGE(2) in the etiology of renal salt-losing disorders. PMID:15793031

  16. Cognitive and Psychiatric Effects of STN versus GPi Deep Brain Stimulation in Parkinson's Disease: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Zhang, Xiao-Hua; Wang, Yun-Peng; Li, Ji-Ping; Li, Yong-Jie

    2016-01-01

    Background Deep brain stimulation (DBS) of either the subthalamic nucleus (STN) or the globus pallidus interna (GPi) can reduce motor symptoms in patients with Parkinson’s disease (PD) and improve their quality of life. However, the effects of STN DBS and GPi DBS on cognitive functions and their psychiatric effects remain controversial. The present meta-analysis was therefore performed to clarify these issues. Methods We searched the PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials databases. Other sources, including internet-based clinical trial registries and grey literature sources, were also searched. After searching the literature, two investigators independently performed literature screens to assess the quality of the included trials and to extract the data. The outcomes included the effects of STN DBS and GPi DBS on multiple cognitive domains, depression, anxiety, and quality of life. Results Seven articles related to four randomized controlled trials that included 521 participants were incorporated into the present meta-analysis. Compared with GPi DBS, STN DBS was associated with declines in selected cognitive domains after surgery, including attention, working memory and processing speed, phonemic fluency, learning and memory, and global cognition. However, there were no significant differences in terms of quality of life or psychiatric effects, such as depression and anxiety, between the two groups. Conclusions A selective decline in frontal-subcortical cognitive functions is observed after STN DBS in comparison with GPi DBS, which should not be ignored in the target selection for DBS treatment in PD patients. In addition, compared to GPi DBS, STN DBS does not affect depression, anxiety, and quality of life. PMID:27248139

  17. Modulatory effect of subthalamic nucleus on the development of fatigue during exhausting exercise: an in vivo electrophysiological and microdialysis study in rats.

    PubMed

    Wang, Dalei; Liu, Xiaoli; Qiao, Decai

    2012-01-01

    The purpose of the study was to investigate the modulatory effect of changes of subthalamic nucleus (STN) activity on the development of central fatigue during exhausting exercise, and reveal the possible mechanism that might affect STN activity from the perspective of neurotransmitters. Rats were randomly divided into electrophysiology and microdialysis study groups. For electrophysiological study, electrical activity in sensorimotor cortex and STN were simultaneously recorded before, during and 90min after the exhausting exercise. For microdialysis study, extracellular fluid of STN was continuously collected with a microdialysis probe and glutamate (Glu), gamma-aminobutyric acid (GABA) levels were subsequently detected with high performance liquid chromatography (HPLC). The behavioral studies showed that rats ran well initiatively with the treadmill exercise in the beginning, 45 ± 11.5min later, movement capacity reduced obviously (which was termed as 'early fatigue'). Correspondingly, STN activity increased significantly compared with rest condition (p < 0.05), while, cortex activity decreased significantly (p < 0.05). Subsequently, rats continued their exercise with minor external stimulation till exhaustion. Cortex activity reached the minimum value under exhaustion condition, while STN activity changed insignificantly (p > 0.05). For microdialysis study, the dynamic change of Glu/GABA ratio was consistent with the change of STN activity during the development of 'early fatigue' rather than the development of exhaustion. In conclusion, the present study shows that, the development of the cortex fatigue during exhausting exercise consists of two phases, 'early fatigue' and exhaustion. Our results suggest that, dynamic changes of STN activity are closely relevant to the development of 'early fatigue' rather than exhaustion, and the changes of STN activity during the development of 'early fatigue' might be partly related to the variance of Glu and GABA levels in

  18. Prostaglandin-E2 Mediated Increase in Calcium and Phosphate Excretion in a Mouse Model of Distal Nephron Salt Wasting

    PubMed Central

    Soleimani, Manoocher; Barone, Sharon; Xu, Jie; Alshahrani, Saeed; Brooks, Marybeth; McCormack, Francis X.; Smith, Roger D.; Zahedi, Kamyar

    2016-01-01

    Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and

  19. Prostaglandin-E2 Mediated Increase in Calcium and Phosphate Excretion in a Mouse Model of Distal Nephron Salt Wasting.

    PubMed

    Soleimani, Manoocher; Barone, Sharon; Xu, Jie; Alshahrani, Saeed; Brooks, Marybeth; McCormack, Francis X; Smith, Roger D; Zahedi, Kamyar

    2016-01-01

    Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and

  20. Analysis of early nephron patterning reveals a role for distal RV proliferation in fusion to the ureteric tip via a cap mesenchyme-derived connecting segment.

    PubMed

    Georgas, Kylie; Rumballe, Bree; Valerius, M Todd; Chiu, Han Sheng; Thiagarajan, Rathi D; Lesieur, Emmanuelle; Aronow, Bruce J; Brunskill, Eric W; Combes, Alexander N; Tang, Dave; Taylor, Darrin; Grimmond, Sean M; Potter, S Steven; McMahon, Andrew P; Little, Melissa H

    2009-08-15

    While nephron formation is known to be initiated by a mesenchyme-to-epithelial transition of the cap mesenchyme to form a renal vesicle (RV), the subsequent patterning of the nephron and fusion with the ureteric component of the kidney to form a patent contiguous uriniferous tubule has not been fully characterized. Using dual section in situ hybridization (SISH)/immunohistochemistry (IHC) we have revealed distinct distal/proximal patterning of Notch, BMP and Wnt pathway components within the RV stage nephron. Quantitation of mitoses and Cyclin D1 expression indicated that cell proliferation was higher in the distal RV, reflecting the differential developmental programs of the proximal and distal populations. A small number of RV genes were also expressed in the early connecting segment of the nephron. Dual ISH/IHC combined with serial section immunofluorescence and 3D reconstruction revealed that fusion occurs between the late RV and adjacent ureteric tip via a process that involves loss of the intervening ureteric epithelial basement membrane and insertion of cells expressing RV markers into the ureteric tip. Using Six2-eGFPCre x R26R-lacZ mice, we demonstrate that these cells are derived from the cap mesenchyme and not the ureteric epithelium. Hence, both nephron patterning and patency are evident at the late renal vesicle stage. PMID:19501082

  1. Epithelial cell fate in the nephron tubule is mediated by the ETS transcription factors etv5a and etv4 during zebrafish kidney development.

    PubMed

    Marra, Amanda N; Wingert, Rebecca A

    2016-03-15

    Kidney development requires the differentiation and organization of discrete nephron epithelial lineages, yet the genetic and molecular pathways involved in these events remain poorly understood. The embryonic zebrafish kidney, or pronephros, provides a simple and useful model to study nephrogenesis. The pronephros is primarily comprised of two types of epithelial cells: transportive and multiciliated cells (MCCs). Transportive cells occupy distinct tubule segments and are characterized by the expression of various solute transporters, while MCCs function in fluid propulsion and are dispersed in a "salt-and-pepper" fashion within the tubule. Epithelial cell identity is reliant on interplay between the Notch signaling pathway and retinoic acid (RA) signaling, where RA promotes MCC fate by inhibiting Notch activity in renal progenitors, while Notch acts downstream to trigger transportive cell formation and block adoption of an MCC identity. Previous research has shown that the transcription factor ets variant 5a (etv5a), and its closely related ETS family members, are required for ciliogenesis in other zebrafish tissues. Here, we mapped etv5a expression to renal progenitors that occupy domains where MCCs later emerge. Thus, we hypothesized that etv5a is required for normal development of MCCs in the nephron. etv5a loss of function caused a decline of MCC number as indicated by the reduced frequency of cells that expressed the MCC-specific markers outer dense fiber of sperm tails 3b (odf3b) and centrin 4 (cetn4), where rescue experiments partially restored MCC incidence. Interestingly, deficiency of ets variant 4 (etv4), a related gene that is broadly expressed in the posterior mesoderm during somitogenesis stages, also led to reduced MCC numbers, which were further reduced by dual etv5a/4 deficiency, suggesting that both of these ETS factors are essential for MCC formation and that they also might have redundant activities. In epistatic studies, exogenous RA

  2. Loss-of-function of OsSTN8 suppresses the photosystem II core protein phosphorylation and interferes with the photosystem II repair mechanism in rice (Oryza sativa).

    PubMed

    Nath, Krishna; Poudyal, Roshan Sharma; Eom, Joon-Seob; Park, Yu Shin; Zulfugarov, Ismayil S; Mishra, Sujata R; Tovuu, Altanzaya; Ryoo, Nayeoon; Yoon, Ho-Sung; Nam, Hong Gil; An, Gynheung; Jeon, Jong-Seong; Lee, Choon-Hwan

    2013-11-01

    STN8 kinase is involved in photosystem II (PSII) core protein phosphorylation (PCPP). To examine the role of PCPP in PSII repair during high light (HL) illumination, we characterized a T-DNA insertional knockout mutant of the rice (Oryza sativa) STN8 gene. In this osstn8 mutant, PCPP was significantly suppressed, and the grana were thin and elongated. Upon HL illumination, PSII was strongly inactivated in the mutants, but the D1 protein was degraded more slowly than in wild-type, and mobilization of the PSII supercomplexes from the grana to the stromal lamellae for repair was also suppressed. In addition, higher accumulation of reactive oxygen species and preferential oxidation of PSII reaction center core proteins in thylakoid membranes were observed in the mutants during HL illumination. Taken together, our current data show that the absence of STN8 is sufficient to abolish PCPP in osstn8 mutants and to produce all of the phenotypes observed in the double mutant of Arabidopsis, indicating the essential role of STN8-mediated PCPP in PSII repair. PMID:24103067

  3. Bicarbonate promotes BK-α/β4-mediated K excretion in the renal distal nephron

    PubMed Central

    Cornelius, Ryan J.; Wen, Donghai; Hatcher, Lori I.

    2012-01-01

    Ca-activated K channels (BK), which are stimulated by high distal nephron flow, are utilized during high-K conditions to remove excess K. Because BK predominantly reside with BK-β4 in acid/base-transporting intercalated cells (IC), we determined whether BK-β4 knockout mice (β4KO) exhibit deficient K excretion when consuming a high-K alkaline diet (HK-alk) vs. high-K chloride diet (HK-Cl). When wild type (WT) were placed on HK-alk, but not HK-Cl, renal BK-β4 expression increased (Western blot). When WT and β4KO were placed on HK-Cl, plasma K concentration ([K]) was elevated compared with control K diets; however, K excretion was not different between WT and β4KO. When HK-alk was consumed, the plasma [K] was lower and K clearance was greater in WT compared with β4KO. The urine was alkaline in mice on HK-alk; however, urinary pH was not different between WT and β4KO. Immunohistochemical analysis of pendrin and V-ATPase revealed the same increases in β-IC, comparing WT and β4KO on HK-alk. We found an amiloride-sensitive reduction in Na excretion in β4KO, compared with WT, on HK-alk, indicating enhanced Na reabsorption as a compensatory mechanism to secrete K. Treating mice with an alkaline, Na-deficient, high-K diet (LNaHK) to minimize Na reabsorption exaggerated the defective K handling of β4KO. When WT on LNaHK were given NH4Cl in the drinking water, K excretion was reduced to the magnitude of β4KO on LNaHK. These results show that WT, but not β4KO, efficiently excretes K on HK-alk but not on HK-Cl and suggest that BK-α/β4-mediated K secretion is promoted by bicarbonaturia. PMID:22993067

  4. The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson’s Disease

    PubMed Central

    2011-01-01

    T-Type Ca2+ channel inhibitors hold tremendous therapeutic potential for the treatment of pain, epilepsy, sleep disorders, essential tremor, and other neurological disorders; however, a lack of truly selective tools has hindered basic research, and selective tools from the pharmaceutical industry are potentially burdened with intellectual property (IP) constraints. Thus, an MLPCN high-throughput screen (HTS) was conducted to identify novel T-type Ca2+ channel inhibitors free from IP constraints, and freely available through the MLPCN, for use by the biomedical community to study T-type Ca2+ channels. While the HTS provided numerous hits, these compounds could not be optimized to the required level of potency to be appropriate tool compounds. Therefore, a scaffold hopping approach, guided by SurflexSim, ultimately afforded ML218 (CID 45115620), a selective T-type Ca2+ (Cav3.1, Cav3.2, Cav3.3) inhibitor (Cav3.2, IC50 = 150 nM in Ca2+ flux; Cav3.2 IC50 = 310 nM; and Cav3.3 IC50 = 270 nM, respectively in patch clamp electrophysiology) with good DMPK properties, acceptable in vivo rat PK, and excellent brain levels. Electrophysiology studies in subthalamic nucleus (STN) neurons demonstrated robust effects of ML218 on the inhibition of T-type calcium current, inhibition of low threshold spike, and rebound burst activity. Based on the basal ganglia circuitry in Parkinson’s disease (PD), the effects of ML218 in STN neurons suggest a therapeutic role for T-type Ca2+ channel inhibitors, and ML218 was found to be orally efficacious in haloperidol-induced catalepsy, a preclinical PD model, with comparable efficacy to an A2A antagonist, a clinically validated PD target. ML218 proves to be a powerful new probe to study T-type Ca2+ function in vitro and in vivo, and freely available. PMID:22368764

  5. Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease

    PubMed Central

    2014-01-01

    Background Neks, mammalian orthologs of the fungal protein kinase never-in-mitosis A, have been implicated in the pathogenesis of polycystic kidney disease. Among them, Nek1 is the primary protein inactivated in kat2J mouse models of PKD. Result We report the expression pattern of Nek1 and characterize the renal cysts that develop in kat2J mice. Nek1 is detectable in all murine tissues but its expression in wild type and kat2J heterozygous kidneys decrease as the kidneys mature, especially in tubular epithelial cells. In the embryonic kidney, Nek1 expression is most prominent in cells that will become podocytes and proximal tubules. Kidney development in kat2J homozygous mice is aberrant early, before the appearance of gross cysts: developing cortical zones are thin, populated by immature glomeruli, and characterized by excessive apoptosis of several cell types. Cysts in kat2J homozygous mice form postnatally in Bowman’s space as well as different tubular subtypes. Late in life, kat2J heterozygous mice form renal cysts and the cells lining these cysts lack staining for Nek1. The primary cilia of cells lining cysts in kat2J homozygous mice are morphologically diverse: in some cells they are unusually long and in others there are multiple cilia of varying lengths. Conclusion Our studies indicate that Nek1 deficiency leads to disordered kidney maturation, and cysts throughout the nephron. PMID:25030234

  6. Sex differences in proximal and distal nephron function contribute to the mechanism of idiopathic hypercalcuria in calcium stone formers.

    PubMed

    Ko, Benjamin; Bergsland, Kristin; Gillen, Daniel L; Evan, Andrew P; Clark, Daniel L; Baylock, Jaime; Coe, Fredric L; Worcester, Elaine M

    2015-07-01

    Idiopathic hypercalciuria (IH) is a common familial trait among patients with calcium nephrolithiasis. Previously, we have demonstrated that hypercalciuria is primarily due to reduced renal proximal and distal tubule calcium reabsorption. Here, using measurements of the clearances of sodium, calcium, and endogenous lithium taken from the General Clinical Research Center, we test the hypothesis that patterns of segmental nephron tubule calcium reabsorption differ between the sexes in IH and normal subjects. When the sexes are compared, we reconfirm the reduced proximal and distal calcium reabsorption. In IH women, distal nephron calcium reabsorption is decreased compared to normal women. In IH men, proximal tubule calcium reabsorption falls significantly, with a more modest reduction in distal calcium reabsorption compared to normal men. Additionally, we demonstrate that male IH patients have lower systolic blood pressures than normal males. We conclude that women and men differ in the way they produce the hypercalciuria of IH, with females reducing distal reabsorption and males primarily reducing proximal tubule function. PMID:25947170

  7. Phenotyping by magnetic resonance imaging nondestructively measures glomerular number and volume distribution in mice with and without nephron reduction

    PubMed Central

    Baldelomar, Edwin J.; Charlton, Jennifer R.; Beeman, Scott C.; Hann, Bradley D.; Cullen-McEwen, Luise; Pearl, Valeria M.; Bertram, John F.; Wu, Teresa; Zhang, Min; Bennett, Kevin M.

    2015-01-01

    Reduced nephron mass is strongly linked to susceptibility to chronic renal and cardiovascular diseases. There are currently no tools to identify nephropenia in clinical or preclinical diagnostics. Such new methods could uncover novel mechanisms and therapies for chronic kidney disease (CKD) and reveal how variation among traits can affect renal function and morphology. Here we used cationized ferritin (CF) enhanced-MRI (CFE-MRI) to investigate the relationship between glomerular number (Nglom) and volume (Vglom) in kidneys of healthy wild type mice and mice with oligosyndactylism (Os/+), a model of congenital nephron reduction. Mice were injected with cationic ferritin and perfused and the resected kidneys imaged with 7T MRI to detect CF-labeled glomeruli. CFE-MRI was used to measure the intrarenal distribution of individual glomerular volumes and revealed two major populations of glomeruli distinguished by size. Spatial mapping revealed that the largest glomeruli were located in the juxtamedullary region in both wild type and Os/+ mice and the smallest population located in the cortex. Os/+ mice had about a 50% reduction and 35% increase of Nglom and Vglom, respectively, in both glomerular populations compared to wild type, consistent with glomerular hypertrophy in the Os/+ mice. Thus, we provide a foundation for whole-kidney, MRI-based phenotyping of mouse renal glomerular morphology and provide new potential for quantitative human renal diagnostics. PMID:26535998

  8. New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

    PubMed Central

    Morla, Luciana; Edwards, Aurélie; Crambert, Gilles

    2016-01-01

    The renal handling of Na+ balance is a major determinant of the blood pressure (BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part (i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na+ excretion and are the target of many different regulatory processes that modulate Na+ retention more or less efficiently. G-protein coupled receptors (GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na+ absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na+ excretion, this review also highlights the complexity of these different pathways, and the connections between them. PMID:26981195

  9. Phenotyping by magnetic resonance imaging nondestructively measures glomerular number and volume distribution in mice with and without nephron reduction.

    PubMed

    Baldelomar, Edwin J; Charlton, Jennifer R; Beeman, Scott C; Hann, Bradley D; Cullen-McEwen, Luise; Pearl, Valeria M; Bertram, John F; Wu, Teresa; Zhang, Min; Bennett, Kevin M

    2016-02-01

    Reduced nephron mass is strongly linked to susceptibility to chronic renal and cardiovascular diseases. There are currently no tools to identify nephropenia in clinical or preclinical diagnostics. Such new methods could uncover novel mechanisms and therapies for chronic kidney disease (CKD) and reveal how variation among traits can affect renal function and morphology. Here we used cationized ferritin (CF)–enhanced MRI (CFE-MRI) to investigate the relationship between glomerular number (Nglom) and volume (Vglom) in kidneys of healthy wild-type mice and mice with oligosyndactylism (Os/+), a model of congenital nephron reduction. Mice were injected with CF and perfused, and the resected kidneys were imaged with 7T MRI to detect CF-labeled glomeruli. CFE-MRI was used to measure the intrarenal distribution of individual glomerular volumes and revealed two major populations of glomeruli distinguished by size. Spatial mapping revealed that the largest glomeruli were located in the juxtamedullary region in both wild-type and Os/+ mice and the smallest population located in the cortex. Os/+ mice had about a 50% reduction and 35% increase of Nglom and Vglom, respectively, in both glomerular populations compared with wild type, consistent with glomerular hypertrophy in the Os/+ mice. Thus, we provide a foundation for whole-kidney, MRI-based phenotyping of mouse renal glomerular morphology and provide new potential for quantitative human renal diagnostics. PMID:26535998

  10. Expression of TLR4 protein is reduced in chronic renal failure: evidence from an experimental model of nephron reduction.

    PubMed

    Kacsó, Ina Maria; Borza, Gabriel Mircea; Ciuce, Cătălin C; Bîrsan, Andrei; Apostu, Raluca Cristina; Dindelegan, George Călin; Bondor, Cosmina Ioana; Potra, Alina Ramona; Netea, Mihai G; Cătoi, Cornel

    2015-01-01

    Toll-like receptor 4 (TLR4) signaling is involved in various acute and chronic renal lesions and contributes to inflammation and fibrosis in several organs; the latter are important determinants to the progression of chronic kidney disease (CKD). We aimed to assess TLR4 expression in progressive CKD and relate it to severity of kidney damage, using an experimental nephron reduction model. Male Wistar rats were subjected to subtotal nephrectomy using the ligation technique, after 12 weeks of observation, serum creatinine and proteinuria were determined, animals were sacrificed, glomerulosclerosis and interstitial scarring were quantified histologically, and TLR4 expression was assessed by immunohistochemistry. Sham-operated rats served as controls. Case animals had significantly higher creatinine, proteinuria, glomerulosclerosis and tubulointerstitial involvement. TLR4 expression was prominent in proximal tubes, less staining was observed on infiltrating inflammatory cells. Percentage of TLR4-positive tubes was reduced in the subtotal nephrectomy animals, when compared to controls (0.67±0.09 versus 0.79±0.07, p=0.003). Percentage of TLR4-positive tubes correlated inversely to markers of kidney damage: to proteinuria (r=-0.55, p=0.02), serum creatinine (r=-0.53, p=0.01); percentage of glomeruli with glomerulosclerosis (r=-0.54, p=0.01) and tubulointerstitial score (r=-0.36, p=0.01). As TLR4 staining appears in tubular casts only in nephrectomy animals, shedding from damaged tubular cells is a very likely explanation for the reduced TLR4 expression in the kidneys of subjects with experimental nephron reduction. PMID:25826492

  11. Uteroplacental insufficiency causes a nephron deficit, modest renal insufficiency but no hypertension with ageing in female rats.

    PubMed

    Moritz, Karen M; Mazzuca, Marc Q; Siebel, Andrew L; Mibus, Amy; Arena, Debbie; Tare, Marianne; Owens, Julie A; Wlodek, Mary E

    2009-06-01

    In rats, uteroplacental insufficiency induced by uterine vessel ligation restricts fetal growth and impairs mammary development compromising postnatal growth. In male offspring, this results in a nephron deficit and hypertension which can be reversed by improving lactation and postnatal growth. Here, growth, blood pressure and nephron endowment in female offspring from mothers which underwent bilateral uterine vessel ligation (Restricted) on day 18 of pregnancy were examined. Sham surgery (Control) and a reduced litter group (Reduced at birth to 5, equivalent to Restricted group) were used as controls. Offspring (Control, Reduced, Restricted) were cross-fostered on postnatal day 1 onto a Control (normal lactation) or Restricted (impaired lactation) mother. Restricted-on-Restricted offspring were born small but were of similar weight to Control-on-Control by postnatal day 35. Blood pressure was not different between groups at 8, 12 or 20 weeks of age. Glomerular number was reduced in Restricted-on-Restricted offspring at 6 months without glomerular hypertrophy. Cross-fostering a Restricted pup onto a Control dam resulted in a glomerular number intermediate between Control-on-Control and Restricted-on-Restricted. Blood pressure, along with renal function, morphology and mRNA expression, was examined in Control-on-Control and Restricted-on-Restricted females at 18 months. Restricted-on-Restricted offspring did not become hypertensive but developed glomerular hypertrophy by 18 months. They had elevated plasma creatinine and alterations in renal mRNA expression of transforming growth factor-beta(1), collagen IV (alpha1) and matrix matelloproteinase-9. This suggests that perinatally growth restricted female offspring may be susceptible to onset of renal injury and renal insufficiency with ageing in the absence of concomitant hypertension. PMID:19359373

  12. Subaru Telescope Network III (STN-III): more effective, more operation-oriented, and more inexpensive solutions for the observatory's needs

    NASA Astrophysics Data System (ADS)

    Noumaru, Junichi; Kawai, Jun A.; Schubert, Kiaina; Yagi, Masafumi; Takata, Tadafumi; Winegar, Tom; Scanlon, Tim; Nishida, Takuhiro; Fox, Camron; Hayasaka, James; Forester, Jason; Uchida, Kenji; Nakamura, Isamu; Tom, Richard; Koura, Norikazu; Yamamoto, Tadahiro; Tanoue, Toshiya; Yamada, Toru

    2008-07-01

    Subaru Telescope has recently replaced most equipment of Subaru Telescope Network II with the new equipment which includes 124TB of RAID system for data archive. Switching the data storage from tape to RAID enables users to access the data faster. The STN-III dropped some important components of STN-II, such as supercomputers, development & testing subsystem for Subaru Observation Control System, or data processing subsystem. On the other hand, we invested more computers to the remote operation system. Thanks to IT innovations, our LAN as well as the network between Hilo and summit were upgraded to gigabit network at the similar or even reduced cost from the previous system. As the result of the redesigning of the computer system by more focusing on the observatory operation, we greatly reduced the total cost for computer rental, purchase and maintenance.

  13. Dual regulation of the native ClC-K2 chloride channel in the distal nephron by voltage and pH.

    PubMed

    Pinelli, Laurent; Nissant, Antoine; Edwards, Aurélie; Lourdel, Stéphane; Teulon, Jacques; Paulais, Marc

    2016-09-01

    ClC-K2, a member of the ClC family of Cl(-) channels and transporters, forms the major basolateral Cl(-) conductance in distal nephron epithelial cells and therefore plays a central role in renal Cl(-) absorption. However, its regulation remains largely unknown because of the fact that recombinant ClC-K2 has not yet been studied at the single-channel level. In the present study, we investigate the effects of voltage, pH, Cl(-), and Ca(2+) on native ClC-K2 in the basolateral membrane of intercalated cells from the mouse connecting tubule. The ∼10-pS channel shows a steep voltage dependence such that channel activity increases with membrane depolarization. Intracellular pH (pHi) and extracellular pH (pHo) differentially modulate the voltage dependence curve: alkaline pHi flattens the curve by causing an increase in activity at negative voltages, whereas alkaline pHo shifts the curve toward negative voltages. In addition, pHi, pHo, and extracellular Ca(2+) strongly increase activity, mainly because of an increase in the number of active channels with a comparatively minor effect on channel open probability. Furthermore, voltage alters both the number of active channels and their open probability, whereas intracellular Cl(-) has little influence. We propose that changes in the number of active channels correspond to them entering or leaving an inactivated state, whereas modulation of open probability corresponds to common gating by these channels. We suggest that pH, through the combined effects of pHi and pHo on ClC-K2, might be a key regulator of NaCl absorption and Cl(-)/HCO3 (-) exchange in type B intercalated cells. PMID:27574292

  14. Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a pet study

    PubMed Central

    Le Jeune, F.; Péron, J.; Biseul, I.; Fournier, S.; Sauleau, P.; Drapier, S.; Haegelen, C.; Drapier, D.; Millet, B.; Garin, E.; Herry, J.-Y.; Malbert, C.-H.

    2008-01-01

    Deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) in Parkinson's disease is thought to produce adverse events such as emotional disorders, and in a recent study, we found fear recognition to be impaired as a result. These changes have been attributed to disturbance of the STN's limbic territory and would appear to confirm that the negative emotion recognition network passes through the STN. In addition, it is now widely acknowledged that damage to the orbitofrontal cortex (OFC), especially the right side, can result in impaired recognition of facial emotions (RFE). In this context, we hypothesized that this reduced recognition of fear is correlated with modifications in the cerebral glucose metabolism of the right OFC. The objective of the present study was first, to reinforce our previous results by demonstrating reduced fear recognition in our Parkinson's disease patient group following STN DBS and, second, to correlate these emotional performances with glucose metabolism using 18FDG-PET. The 18FDG-PET and RFE tasks were both performed by a cohort of 13 Parkinson's disease patients 3 months before and 3 months after surgery for STN DBS. As predicted, we observed a significant reduction in fear recognition following surgery and obtained a positive correlation between these neuropsychological results and changes in glucose metabolism, especially in the right OFC. These results confirm the role of the STN as a key basal ganglia structure in limbic circuits. PMID:18490359

  15. Parallel down-regulation of chloride channel CLC-K1 and barttin mRNA in the thin ascending limb of the rat nephron by furosemide.

    PubMed

    Wolf, Konrad; Meier-Meitinger, Martina; Bergler, Tobias; Castrop, Hayo; Vitzthum, Helga; Riegger, Günter A J; Kurtz, Armin; Krämer, Bernhard K

    2003-09-01

    In the past few years the pivotal role of kidney Cl(-)channels (ClC-K) channels in maintaining salt and water homeostasis in the kidney has been established. The aim of the present study was to investigate the influence of the loop diuretic furosemide on the gene expression of the kidney chloride channel ClC-K1 and its recently described functional subunit barttin. Male Sprague Dawley rats received the loop diuretic furosemide (12 mg/kg/day) for 6 days. Rats had free access to 0.9% NaCl, 0.1%KCl solution to prevent volume depletion. Localisation and regulation of ClC-K1 and barttin mRNA was analysed by RNase protection and in situ hybridisation. Nephron-specific regulation was investigated by microdissection and real-time PCR quantification. In furosemide-treated rats ClC-K1 mRNA decreased to half in the inner medulla. In the renal cortex and outer medulla ClC-K1 mRNA levels were weak and did not change. Under furosemide treatment barttin mRNA was regulated in parallel with ClC-K1 mRNA. A significant mRNA decrease occurred after furosemide treatment in inner medulla (0.50 fold), whereas cortical and outer medulla levels remained unaffected. (35)S in situ hybridisation confirmed the regulation and distribution seen in the RNase protection assay experiments. Microdissection of the inner medullary collecting duct and thin limb of Henle's loop followed by real-time PCR revealed that CLC-K1 and barttin mRNA regulation in inner medulla was limited to the thin limb; mRNA levels in collecting ducts were not affected by furosemide treatment. Our findings imply that during furosemide treatment selective down-regulation of ClC-K1 and barttin mRNAs in thin limb plays a role in maintaining salt and water homeostasis. PMID:12759757

  16. The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage

    PubMed Central

    Surendran, Kameswaran; Boyle, Scott; Barak, Hila; Kim, Mijin; Stromberski, Colin; McCright, Brent; Kopan, Raphael

    2009-01-01

    We previously determined that Notch2, and not Notch1 was required for forming proximal nephron segments. The dominance of Notch2 may be conserved in humans, since Notch2 mutations occur in Alagille syndrome (ALGS) 2 patients, which includes renal complications. To test whether mutations in Notch1 could increase the severity of renal complications in ALGS, we inactivated conditional Notch1 and Notch2 alleles in mice using a Six2-GFP∷Cre. This BAC transgene is expressed mosaically in renal epithelial progenitors but uniformly in cells exiting the progenitor pool to undergo mesenchymal to epithelial transition. Although delaying Notch2 inactivation had a marginal effect on nephron numbers, it created a sensitized background in which the inactivation of Notch1 severely compromised nephron formation, function and survival. These and additional observations indicate that Notch1 in concert with Notch2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBP-J dependent manner. A significant implication is that elevating Notch1 activity could improve renal functions in ALGS2 patients. As proof of principle, we determined that conditional inactivation of Mint, an inhibitor of Notch-RBP-J interaction, resulted in a moderate rescue of Notch2 null kidneys, implying that temporal blockage of Notch signaling inhibitors downstream of receptor activation may have therapeutic benefits for ALGS patients. PMID:19914235

  17. Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells

    PubMed Central

    Muthukrishnan, Sree Deepthi; Yang, Xuehui; Friesel, Robert; Oxburgh, Leif

    2015-01-01

    Self-renewal of nephron progenitor cells (NPCs) is governed by BMP, FGF and WNT signalling. Mechanisms underlying cross-talk between these pathways at the molecular level are largely unknown. Here we delineate the pathway through which the proliferative BMP7 signal is transduced in NPCs in the mouse. BMP7 activates the MAPKs TAK1 and JNK to phosphorylate the transcription factor JUN, which in turn governs transcription of AP-1-element containing G1-phase cell cycle regulators such as Myc and Ccnd1 to promote NPC proliferation. Conditional inactivation of Tak1 or Jun in cap mesenchyme causes identical phenotypes characterized by premature depletion of NPCs. While JUN is regulated by BMP7, we find that its partner FOS is regulated by FGF9. We demonstrate that BMP7 and FGF9 coordinately regulate AP-1 transcription to promote G1-S cell cycle progression and NPC proliferation. Our findings identify a molecular mechanism explaining the important cooperation between two major NPC self-renewal pathways. PMID:26634297

  18. Increased cardiovascular and renal risk is associated with low nephron endowment in aged females: an ovine model of fetal unilateral nephrectomy.

    PubMed

    Singh, Reetu R; Jefferies, Andrew J; Lankadeva, Yugeesh R; Lombardo, Paul; Schneider-Kolsky, Michal; Hilliard, Lucinda; Denton, Kate M; Moritz, Karen M

    2012-01-01

    Previously we have shown that ovariectomised (OVX) female sheep have reduced renal function and elevated blood pressure from 6 months of age following fetal uninephrectomy (uni-x) at 100 days of gestation (term = 150 days). In the current study we examined if in intact female sheep the onset of decline in renal function and elevation in blood pressure was prevented. Studies were performed at 1 year, 2 and 5 years of age. Following fetal uni-x at 100 days, intact female sheep had ~30% reduction in glomerular filtration rate (GFR) at 1 year, which did not exacerbate with age (P(treatment) = 0.0001, P(age) = 0.7). In contrast renal blood flow was similar between the treatment groups at 1 year of age but had declined in the uni-x animals at 5 years of age (P(treatment × age) = 0.046). Interestingly, intact uni-x sheep did not develop elevations in arterial pressure until 2 years of age. Furthermore, uni-x animals had a similar capacity to respond to a cardiac challenge at 1 year and 2 years of age, however, cardiac functional reserve was significantly reduced compared to sham group at 5 years of age. Uni-x animals exhibited an increase in left ventricular dimensions at 5 years of age compared to the sham animals and compared to 2 years of age (P(treatment)<0.001, P(treatment × age)<0.001). In conclusion, the onset of renal dysfunction preceded the onset of hypertension in intact female uni-x sheep. Furthermore, this study showed that the intact females are protected from the impact of a reduced nephron endowment on cardiovascular health early in life as opposed to our findings in young male sheep and OVX uni-x female sheep. However, with ageing this protection is lost as evidenced by presence of left ventricular hypertrophy and impaired cardiac function in 5 year old uni-x female sheep. PMID:22879965

  19. Functional and oncologic outcomes after nephron-sparing surgery in a solitary kidney: 10 years of experience

    PubMed Central

    Costabel, José Ignacio; Marchiñena, Patricio García; Tirapegui, Federico; Dantur, Augusto; Jurado, Alberto; Gueglio, Guillermo

    2016-01-01

    ABSTRACT Objectives: To evaluate functional and oncologic outcomes of partial nephrectomy (PN) in patients with a solitary kidney. Materials and Methods: A retrospective analysis of patients with a solitary kidney undergoing nephron-sparing surgery between March 2003 and March 2013 was performed. GFR was recorded before the procedure and 3 months after surgery, thus establishing a change (cGFR). Several variables that may influence cGFR were analyzed. Complications are herein described, namely bleeding, fistula, acute renal failure and end-stage renal disease (ESRD). Local recurrence and margin status are also described. Survival rates were calculated using the Kaplan Meier method (2 patients with metastasis at the time of surgery were excluded from the analysis). Results: Forty-five patients were available for analysis. Median follow-up was 27.56 months (r 3-96). Mean cGFR was-7.12mL/min (SD 2.1). Variables significantly related with lower GFR after surgery were loss of renal mass (p=0.01)) and male gender (p=0.03). Four patients (8.8%) experienced hemorrhage. Nine patients (20%) developed a urinary fistula. Only one patient with bleeding required open surgery. Two patients (4.4%) needed transient dialysis. Three patients (6.6%) developed ESRD. Four patients (8.8%) had positive surgical margins (PSMs) and four patients (88%) had local recurrence (2 of these had PSMs). Five patients (11.1%) died during follow-up. Four patients (8.8%) died because of renal cancer. Estimated 2-year overall survival, disease-free survival and cancer specific survival rates were 88.4% (CI 95% 70.5-96); 87.7% (CI 95% 68.1-96) and 92.4% (CI 95% 75-98), respectively. Conclusion: Loss of renal mass and male gender were associated with lower postoperative GFR. Our outcomes were comparable with those in the World literature.

  20. Distribution of organic anion transporters NaDC3 and OAT1-3 along the human nephron.

    PubMed

    Breljak, Davorka; Ljubojević, Marija; Hagos, Yohannes; Micek, Vedran; Balen Eror, Daniela; Vrhovac Madunić, Ivana; Brzica, Hrvoje; Karaica, Dean; Radović, Nikola; Kraus, Ognjen; Anzai, Naohiko; Koepsell, Hermann; Burckhardt, Gerhard; Burckhardt, Birgitta C; Sabolić, Ivan

    2016-07-01

    The initial step in renal secretion of organic anions (OAs) is mediated by transporters in the basolateral membrane (BLM). Contributors to this process are primary active Na(+)-K(+)-ATPase (EC 3.6.3.9), secondary active Na(+)-dicarboxylate cotransporter 3 (NaDC3/SLC13A3), and tertiary active OA transporters (OATs) OAT1/SLC22A6, OAT2/SLC22A7, and OAT3/SLC22A8. In human kidneys, we analyzed the localization of these transporters by immunochemical methods in tissue cryosections and isolated membranes. The specificity of antibodies was validated with human embryonic kidney-293 cells stably transfected with functional OATs. Na(+)-K(+)-ATPase was immunolocalized to the BLM along the entire human nephron. NaDC3-related immunostaining was detected in the BLM of proximal tubules and in the BLM and/or luminal membrane of principal cells in connecting segments and collecting ducts. The thin and thick ascending limbs, macula densa, and distal tubules exhibited no reactivity with the anti-NaDC3 antibody. OAT1-OAT3-related immunostaining in human kidneys was detected only in the BLM of cortical proximal tubules; all three OATs were stained more intensely in S1/S2 segments compared with S3 segment in medullary rays, whereas the S3 segment in the outer stripe remained unstained. Expression of NaDC3, OAT1, OAT2, and OAT3 proteins exhibited considerable interindividual variability in both male and female kidneys, and sex differences in their expression could not be detected. Our experiments provide a side-by-side comparison of basolateral transporters cooperating in renal OA secretion in the human kidney. PMID:27053689

  1. SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1(Tpp1) to modulate shelterin-Stn1 interaction in fission yeast.

    PubMed

    Miyagawa, Keisuke; Low, Ross S; Santosa, Venny; Tsuji, Hiroki; Moser, Bettina A; Fujisawa, Shiho; Harland, Jennifer L; Raguimova, Olga N; Go, Andrew; Ueno, Masaru; Matsuyama, Akihisa; Yoshida, Minoru; Nakamura, Toru M; Tanaka, Katsunori

    2014-04-22

    Telomeres protect DNA ends of linear eukaryotic chromosomes from degradation and fusion, and ensure complete replication of the terminal DNA through recruitment of telomerase. The regulation of telomerase is a critical area of telomere research and includes cis regulation by the shelterin complex in mammals and fission yeast. We have identified a key component of this regulatory pathway as the SUMOylation [the covalent attachment of a small ubiquitin-like modifier (SUMO) to target proteins] of a shelterin subunit in fission yeast. SUMOylation is known to be involved in the negative regulation of telomere extension by telomerase; however, how SUMOylation limits the action of telomerase was unknown until now. We show that SUMOylation of the shelterin subunit TPP1 homolog in Schizosaccharomyces pombe (Tpz1) on lysine 242 is important for telomere length homeostasis. Furthermore, we establish that Tpz1 SUMOylation prevents telomerase accumulation at telomeres by promoting recruitment of Stn1-Ten1 to telomeres. Our findings provide major mechanistic insights into how the SUMOylation pathway collaborates with shelterin and Stn1-Ten1 complexes to regulate telomere length. PMID:24711392

  2. New percutaneous ablative modalities in nephron-sparing surgery of small renal tumors

    NASA Astrophysics Data System (ADS)

    de Riese, Werner T. W.; Nelius, Thomas; Aronoff, David R.; Mittemeyer, Bernhard T.

    2004-07-01

    Renal tumors are increasingly detected on abdominal imaging studies. Standard treatment of small renal tumors includes partial or radical nephrectomy, done either open or laparoscopically. Several in situ ablative techniques to treat small renal lesions are currently in various phases of evolution. All involve imparting destructive energy to the tumor while minimizing injury to adjacent normal tissue. Cryotherapy (CryoT), radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFUS) and high-intensity radiation (HIR) are all being evaluated as tools to ablate renal tumors. The goal with these modalities is to minimize the blood loss, tissue manipulation, and morbidity associated with excisional approaches. Animal studies have shown that large, reproducible lesions can be ablated in normal kidney tissue by these new techniques. Studies of human renal tissue response to RFA are just beginning. Ex vivo studies reveal large, reproducible controlled lesions in normal renal tissue, similar to animal studies. In vivo studies have shown no significant toxicity, while efficacy is currently under evaluation. Preliminary clinical studies in humans have revealed that renal tumors are slow to regress after treatment, but about 75% of these small renal tumors appeared well treated. Mixed responses have been observed in the remaining cases. This paper presents a concise review of efficacy, advantages and disadvantages of these new minimal invasive techniques and their possible clinical implication in the future.

  3. Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit.

    PubMed

    Perrier, Romain; Boscardin, Emilie; Malsure, Sumedha; Sergi, Chloé; Maillard, Marc P; Loffing, Johannes; Loffing-Cueni, Dominique; Sørensen, Mads Vaarby; Koesters, Robert; Rossier, Bernard C; Frateschi, Simona; Hummler, Edith

    2016-08-01

    Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal life-threatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na(+)/Cl(-) cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype. PMID:26701978

  4. Port-site metastasis as a primary complication following retroperitoneal laparoscopic radical resection of renal pelvis carcinoma or nephron-sparing surgery: A report of three cases and review of the literature

    PubMed Central

    WANG, NING; WANG, KAI; ZHONG, DACHUAN; LIU, XIA; SUN, JI; LIN, LIANXIANG; GE, LINNA; YANG, BO

    2016-01-01

    The present study reports the clinical data of two patients with renal pelvis carcinoma and one patient with renal carcinoma who developed port-site metastasis following retroperitoneal laparoscopic surgery. The current study aimed to identify the cause and prognosis of the occurrence of port-site metastasis subsequent to laparoscopic radical resection of renal pelvis carcinoma and nephron-sparing surgery. Post-operative pathology confirmed the presence of high-grade urothelial cell carcinoma in two patients and Fuhrman grade 3 renal clear cell carcinoma in one patient. Port-site metastasis was initially detected 1–7 months post-surgery. The two patients with renal pelvis carcinoma succumbed to the disease 2 and 4 months following the identification of the port-site metastasis, respectively, whereas the patient with renal carcinoma survived with no disease progression during the targeted therapy period. The occurrence of port-site metastasis may be attributed to systemic and local factors. Measures to reduce the development of this complication include strict compliance with the operating guidelines for tumor surgery, avoidance of air leakage at the port-site, complete removal of the specimen with an impermeable bag, irrigation of the laparoscopic instruments and incisional wound with povidone-iodine when necessary, and enhancement of the body's immunity. Close post-operative follow-up observation for signs of recurrence or metastasis is essential, and systemic chemotherapy may be required in patients with high-grade renal pelvis carcinoma and renal carcinoma in order to prolong life expectancy. PMID:27313720

  5. Functional improvement after subthalamic stimulation in Parkinson's disease: a non-equivalent controlled study with 12–24 month follow up

    PubMed Central

    Capecci, M; Ricciuti, R; Burini, D; Bombace, V; Provinciali, L; Iacoangeli, M; Scerrati, M; Ceravolo, M

    2005-01-01

    Objective: This study aimed to assess the effectiveness of chronic bilateral STN-S in improving the functional status of PD patients compared with patients treated with drugs alone. Methods: Controlled study of disability index changes over 12 and 24 month chronic STN stimulation. Of 39 patients with advanced PD meeting CAPSIT criteria for STN-S, 23 underwent surgery; 16 patients decided against surgery and continued on drug schedule adjustments. Functional status was measured using the Activities of Daily Living section of the Unified Parkinson's Disease Rating Scale (UPDRS-ADL), Brown's Disability Scale, and Functional Independence Measure. UPDRS motor score and subscores for selected items, levodopa equivalent daily dose, and Beck Depression Inventory scores were also monitored. Results: T12 follow up data were available for all 39 patients and T24 data for 13 STN-S and 8 control subjects. Compared with controls, STN-S patients experienced significant or highly significant improvements in all independence measures at both 12 and 24 months (time x treatment effect T12: F = 19.5, p = 0.00008; T24: F = 6.2, p = 0.005). Forward stepwise regression for independent predictors of the yearly rate of UPDRS-ADL score modification in the entire sample showed that treatment was the only factor significantly associated with functional status change (beta coefficient –0.54, t value –2.5, p = 0.02), whereas other variables—UPDRS motor score, BDI, and age at disease onset and enrolment—were not in the equation. Conclusion: STN-S is an effective therapeutic option in advanced PD. It induced a consistent improvement of functional abilities over two years to an extent that was not achieved with drug therapy alone. PMID:15897496

  6. Comparison of frequencies of non motor symptoms in Indian Parkinson’s disease patients on medical management versus deep brain stimulation: A case-control study

    PubMed Central

    Rukmini Mridula, Kandadai; Borgohain, Rupam; Jabeen, Shaik Afshan; Padmaja, Gaddamanugu; Bandaru, VCS Srinivasarao; Ankathi, Praveen; Kanikannan, Meena A; Ali Khan, Mohammed Shujath

    2015-01-01

    Background: Non motor symptoms (NMS) of idiopathic Parkinson’s disease (PD) are a major cause of disability and recognition of these symptoms and treatment is important for comprehensive health care. Deep brain stimulation of bilateral subthalamic nucleus deep brain stimulation (STN DBS) has been shown to improve motor symptoms in PD and effects on NMS are unknown. To investigate the NMS among PD patients who underwent STN DBS. Methods: We recruited prospectively 56 patients with PD, who had undergone bilateral STN DBS and 53 age and duration of illness matched PD patients on dopaminergic therapy (controls). NMS were assessed using 30 item questionnaire NMS Quest. These questions evaluated 9 domains, gastrointestinal, urinary, cardiovascular, sexual, cognition (apathy/attention/memory), anxiety/depression, hallucinations/delusions, sleep and miscellaneous. Comparison was done on individual symptoms as well as in various domains. This study was carried at Nizam’s Institution of Medical Sciences and study period was from January 2011 to December 2012. Results: Patients who underwent STN DBS had a significantly lower mean total score on NMS quest (6.7 ± 3.8) compared to controls (8.4 ± 3.7) (P < 0.00100). Symptoms in the domains of cardiovascular, gastrointestinal, sleep were significantly less frequent while sexual disturbances were significantly more frequent among patients compared to controls. On individual symptom analysis, nocturia  (P < 0.00010), unexplained pains (P < 0.00010), nausea and vomiting, constipation, lightheadedness, depression, and insomnia were less prevalent, while sexual disturbances were significantly more common in STN DBS group compared to controls. Conclusion: Bilateral STN DBS not only improves the motor symptoms but also improves many NMS in PD patients. PMID:26056553

  7. A 2D model of axial symmetry for proximal tubule of an average human nephron: indicative results of diffusion, convection and absorption processes

    NASA Astrophysics Data System (ADS)

    Insfrán, J. F.; Ubal, S.; Di Paolo, y. J.

    2016-04-01

    A simplified model of a proximal convoluted tubule of an average human nephron is presented. The model considers the 2D axisymmetric flow of the luminal solution exchanging matter with the tubule walls and the peritubular fluid by means of 0D models for the epithelial cells. The tubule radius is considered to vary along the conduit due to the trans-epithelial pressure difference. The fate of more than ten typical solutes is tracked down by the model. The Navier-Stokes and Reaction-Diffusion-Advection equations (considering the electro-neutrality principle) are solved in the lumen, giving a detailed picture of the velocity, pressure and concentration fields, along with trans-membrane fluxes and tubule deformation, via coupling with the 0D model for the tubule wall. The calculations are carried out numerically by means of the finite element method. The results obtained show good agreement with those published by other authors using models that ignore the diffusive transport and disregard a detailed calculation of velocity, pressure and concentrations. This work should be seen as a first approach towards the development of a more comprehensive model of the filtration process taking place in the kidneys, which ultimately helps in devising a device that can mimic/complement the renal function.

  8. Production of superoxide from photosystem II-light harvesting complex II supercomplex in STN8 kinase knock-out rice mutants under photoinhibitory illumination.

    PubMed

    Poudyal, Roshan Sharma; Nath, Krishna; Zulfugarov, Ismayil S; Lee, Choon-Hwan

    2016-09-01

    When phosphorylation of Photosystem (PS) II core proteins is blocked in STN8 knock-out mutants of rice (Oryza sativa) under photoinhibitory illumination, the mobilization of PSII supercomplex is prevented. We have previously proposed that more superoxide (O2(-)) is produced from PSII in the mutant (Nath et al., 2013, Plant J. 76, 675-686). Here, we clarify the type and site for the generation of reactive oxygen species (ROS). Using both histochemical and fluorescence probes, we observed that, compared with wild-type (WT) leaves, levels of ROS, including O2(-) and hydrogen peroxide (H2O2), were increased when leaves from mutant plants were illuminated with excess light. However, singlet oxygen production was not enhanced under such conditions. When superoxide dismutase was inhibited, O2(-) production was increased, indicating that it is the initial event prior to H2O2 production. In thylakoids isolated from WT leaves, kinase was active in the presence of ATP, and spectrophotometric analysis of nitrobluetetrazolium absorbance for O2(-) confirmed that PSII-driven superoxide production was greater in the mutant thylakoids than in the WT. This contrast in levels of PSII-driven superoxide production between the mutants and the WT plants was confirmed by conducting protein oxidation assays of PSII particles from osstn8 leaves under strong illumination. Those assays also demonstrated that PSII-LHCII supercomplex proteins were oxidized more in the mutant, thereby implying that PSII particles incur greater damage even though D1 degradation during PSII-supercomplex mobilization is partially blocked in the mutant. These results suggest that O2(-) is the major form of ROS produced in the mutant, and that the damaged PSII in the supercomplex is the primary source of O2(-). PMID:27390892

  9. Renal clearance studies of effect of left atrial distension in the dog.

    NASA Technical Reports Server (NTRS)

    Kinney, M. J.; Discala, V. A.

    1972-01-01

    Investigation of the water diuresis of left atrial distension in 16 dogs on the basis of clearance studies employing hydration, chronic and acute salt loading, deoxycorticosterone (DOCA) in excess, and distal tubular nephron blockade with diuretics. The diuresis was found in hydrated and salt-loaded dogs and was independent of DOCA and presumed renin depletion. It was not found in five dogs after distal tubular blockade. No significant reproducible saluresis was ever documented. The water diuresis was always stopped by exogenous vasopressin (seven dogs). Antidiuretic hormone inhibition with distal tubular nephron water permeability changes appears to be the sole mechanism of the diuresis of left atrial distension in the dog.

  10. Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.

    PubMed

    Minuth, Will W; Denk, Lucia

    2016-01-01

    Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface. Special fixation of specimens by glutaraldehyde (GA) solution including cupromeronic blue, ruthenium red, or tannic acid for electron microscopy depicts that the interface is not void but filled in extended areas by textured extracellular matrix. Surprisingly, projections of mesenchymal cells cross the interface to contact epithelial cells. At those sites the plasma membranes of a mesenchymal and an epithelial cell are connected via tunneling nanotubes. Regarding detected morphological features in combination with involved morphogens, their transport cannot longer be explained solely by diffusion. Instead, it has to be sorted according to biophysical properties of morphogens and to detected environment. Thus, the new working hypothesis is that morphogens with good solubility such as glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factors (FGFs) are transported by diffusion. Morphogens with minor solubility such as bone morphogenetic proteins (BMPs) are secreted and stored for delivery on demand in illustrated extracellular matrix. In contrast, morphogens with poor solubility such as Wnts are transported in mesenchymal cell projections along the plasma membrane or via illustrated tunneling nanotubes. However, the presence of an intercellular route between mesenchymal and epithelial stem/progenitor cells by tunneling nanotubes also makes it possible that all morphogens are transported this way. PMID:26862472

  11. Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction

    PubMed Central

    Minuth, Will W.; Denk, Lucia

    2016-01-01

    Abstract Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface. Special fixation of specimens by glutaraldehyde (GA) solution including cupromeronic blue, ruthenium red, or tannic acid for electron microscopy depicts that the interface is not void but filled in extended areas by textured extracellular matrix. Surprisingly, projections of mesenchymal cells cross the interface to contact epithelial cells. At those sites the plasma membranes of a mesenchymal and an epithelial cell are connected via tunneling nanotubes. Regarding detected morphological features in combination with involved morphogens, their transport cannot longer be explained solely by diffusion. Instead, it has to be sorted according to biophysical properties of morphogens and to detected environment. Thus, the new working hypothesis is that morphogens with good solubility such as glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factors (FGFs) are transported by diffusion. Morphogens with minor solubility such as bone morphogenetic proteins (BMPs) are secreted and stored for delivery on demand in illustrated extracellular matrix. In contrast, morphogens with poor solubility such as Wnts are transported in mesenchymal cell projections along the plasma membrane or via illustrated tunneling nanotubes. However, the presence of an intercellular route between mesenchymal and epithelial stem/progenitor cells by tunneling nanotubes also makes it possible that all morphogens are transported this way. PMID:26862472

  12. AB162. A novel “SSS+f” nephrometry score system to evaluate the technical complexity of nephron-sparing surgery

    PubMed Central

    Zhang, Shudong; Ma, Lin; Liu, Lei; Tian, Yu

    2016-01-01

    groups. Postoperative renal functional outcomes were similar among the three groups. Only mean operative time was significantly different with different group. The median warm ischemic time (WIT) was also significantly different in the low- versus high-complexity group but was similar between the moderate- and high-complexity groups. Conclusions Standardized reporting of renal tumor size, site and side is essential for decision making and effective comparisons in nephron-sparing surgery. The “SSS+f” nephrometry score is a reproducible and simple classification system that quantitates the anatomic features of renal masses. This novel approach provides a simple and easy tool for meaningful comparisons of renal masses in clinical practice.

  13. The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

    PubMed Central

    Munkley, Jennifer; Oltean, Sebastian; Vodák, Daniel; Wilson, Brian T.; Livermore, Karen E.; Zhou, Yan; Star, Eleanor; Floros, Vasileios I.; Johannessen, Bjarne; Knight, Bridget; McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Skotheim, Rolf I.; Robson, Craig N.; Leung, Hing Y.; Harries, Lorna W.; Rajan, Prabhakar; Mills, Ian G.; Elliott, David J.

    2015-01-01

    Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, being significantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression. PMID:26452038

  14. Potential role of fluctuations in the composition of renal tubular fluid through the nephron in the initiation of Randall's plugs and calcium oxalate crystalluria in a computer model of renal function.

    PubMed

    Robertson, W G

    2015-01-01

    This article describes an updated computer model which attempts to simulate known renal reabsorption and secretion activity through the nephron (NEPHROSIM) and its possible relevance to the initiation of calcium-containing renal stones. The model shows that, under certain conditions of plasma composition, de novo nucleation of both calcium oxalate (CaOx) and calcium phosphate (CaP) can take place at the end of the descending limb of the Loop of Henle (DLH), particularly in untreated, recurrent idiopathic CaOx stone-formers (RSF). The model incorporates a number of hydrodynamic factors that may influence the subsequent growth of crystals nucleated at the end of the DLH as they progress down the renal tubules. These include the fact that (a) crystals of either CaOx or CaP nucleated at the end of the DLH and travelling close to the walls of the tubule travel at slower velocities than the fluid flowing at the central axis of the tubule, (b) the transit of CaOx crystals travelling close to the tubule walls may be delayed for up to at least 25 min, during which time the crystals may continue to grow if the relative supersaturation with respect to CaOx (RSS CaOx) is high enough and (c) such CaOx crystals may stop moving or even fall back in upward-draining collecting ducts (CD) owing to the Stokes gravitational effect. The model predicts, firstly, that for small, transient increases in plasma oxalate concentration, crystallisation only takes place in the CD and leads to the formation of small crystals which are comfortably passed in the urine and, secondly, that for slightly greater increases in the filtered load of oxalate, spontaneous and/or heterogeneous nucleation of CaOx may occur both at the end of the DLH and in the CD. This latter situation leads to the passage in the final urine of a mixture of large crystals of CaOx (arising from nucleation at the end of the DLH) and small crystals of CaOx (as a result of nucleation originating in the CD). As a result of the

  15. Effect of Deep Brain Stimulation on Parkinson's Nonmotor Symptoms following Unilateral DBS: A Pilot Study

    PubMed Central

    Hwynn, Nelson; Ul Haq, Ihtsham; Malaty, Irene A.; Resnick, Andrew S.; Dai, Yunfeng; Foote, Kelly D.; Fernandez, Hubert H.; Wu, Samuel S.; Oyama, Genko; Jacobson, Charles E.; Kim, Sung K.; Okun, Michael S.

    2011-01-01

    Parkinson's disease (PD) management has traditionally focused largely on motor symptoms. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are effective treatments for motor symptoms. Nonmotor symptoms (NMSs) may also profoundly affect the quality of life. The purpose of this pilot study was to evaluate NMS changes pre- and post-DBS utilizing two recently developed questionnaires. Methods. NMS-Q (questionnaire) and NMS-S (scale) were administered to PD patients before/after unilateral DBS (STN/GPi targets). Results. Ten PD patients (9 STN implants, 1 GPi implant) were included. The three most frequent NMS symptoms identified utilizing NMS-Q in pre-surgical patients were gastrointestinal (100%), sleep (100%), and urinary (90%). NMS sleep subscore significantly decreased (−1.6 points ± 1.8, P = 0.03). The three most frequent NMS symptoms identified in pre-surgical patients using NMS-S were gastrointestinal (90%), mood (80%), and cardiovascular (80%). The largest mean decrease of NMS scores was seen in miscellaneous symptoms (pain, anosmia, weight change, and sweating) (−7 points ± 8.7), and cardiovascular/falls (−1.9, P = 0.02). Conclusion. Non-motor symptoms improved on two separate questionnaires following unilateral DBS for PD. Future studies are needed to confirm these findings and determine their clinical significance as well as to examine the strengths/weaknesses of each questionnaire/scale. PMID:22220288

  16. Aerosol-cloud interactions studied with the chemistry-climate model EMAC

    NASA Astrophysics Data System (ADS)

    Chang, D. Y.; Tost, H.; Steil, B.; Lelieveld, J.

    2014-08-01

    This study uses the EMAC atmospheric chemistry-climate model to simulate cloud properties and estimate cloud radiative effects induced by aerosols. We have tested two prognostic cloud droplet nucleation parameterizations, i.e., the standard STN (osmotic coefficient model) and hybrid (HYB, replacing the osmotic coefficient by the κ hygroscopicity parameter) schemes to calculate aerosol hygroscopicity and critical supersaturation, and consider aerosol-cloud feedbacks with a focus on warm clouds. Both prognostic schemes (STN and HYB) account for aerosol number, size and composition effects on droplet nucleation, and are tested in combination with two different cloud cover parameterizations, i.e., a relative humidity threshold and a statistical cloud cover scheme (RH-CLC and ST-CLC). The use of either STN and HYB leads to very different cloud radiative effects, particularly over the continents. The STN scheme predicts highly effective CCN activation in warm clouds and hazes/fogs near the surface. The enhanced CCN activity increases the cloud albedo effect of aerosols and cools the Earth's surface. The cooler surface enhances the hydrostatic stability of the lower continental troposphere and thereby reduces convection and convective precipitation. In contrast, the HYB simulations calculate lower, more realistic CCN activation and consequent cloud albedo effect, leading to relatively stronger convection and high cloud formation. The enhanced high clouds increase greenhouse warming and moderate the cooling effect of the low clouds. With respect to the cloud radiative effects, the statistical ST-CLC scheme shows much higher sensitivity to aerosol-cloud coupling for all continental regions than the RH-CLC threshold scheme, most pronounced for low clouds but also for high clouds. Simulations of the short wave cloud radiative effect at the top of the atmosphere in ST-CLC are a factor of 2-8 more sensitive to aerosol coupling than the RH-CLC configurations. The long wave

  17. Atherosclerotic renal artery stenosis in the post-CORAL era part 2: new directions in Transcatheter Nephron Salvage following flawed revascularization trials.

    PubMed

    Sag, Alan Alper; Sos, Thomas A; Benli, Caghan; Sal, Oguzhan; Rossignol, Patrick; Ortiz, Alberto; Solak, Yalcin; Kanbay, Mehmet

    2016-04-01

    Unlike endovascular therapeutic studies for atherosclerosis in many other vascular beds, major trials regarding endovascular renovascular revascularization have resulted in a stagnating equipoise. However, every major trial completed for this topic thus far has suffered from major methodological flaws that limit the validity and external generalizability of their results. Furthermore, certain patient populations who are known to benefit from renovascular revascularization may never be studied because they cannot be ethically withheld from life-saving treatment. Forthcoming percutaneous techniques may one day complement angioplasty and stenting in a burgeoning era of cellular modulation and endovascular-directed renal regeneration. PMID:26996432

  18. Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline*

    PubMed Central

    Ranninger, Christina; Rurik, Marc; Limonciel, Alice; Ruzek, Silke; Reischl, Roland; Wilmes, Anja; Jennings, Paul; Hewitt, Philip; Dekant, Wolfgang; Kohlbacher, Oliver; Huber, Christian G.

    2015-01-01

    Untargeted metabolomics has the potential to improve the predictivity of in vitro toxicity models and therefore may aid the replacement of expensive and laborious animal models. Here we describe a long term repeat dose nephrotoxicity study conducted on the human renal proximal tubular epithelial cell line, RPTEC/TERT1, treated with 10 and 35 μmol·liter−1 of chloroacetaldehyde, a metabolite of the anti-cancer drug ifosfamide. Our study outlines the establishment of an automated and easy to use untargeted metabolomics workflow for HPLC-high resolution mass spectrometry data. Automated data analysis workflows based on open source software (OpenMS, KNIME) enabled a comprehensive and reproducible analysis of the complex and voluminous metabolomics data produced by the profiling approach. Time- and concentration-dependent responses were clearly evident in the metabolomic profiles. To obtain a more comprehensive picture of the mode of action, transcriptomics and proteomics data were also integrated. For toxicity profiling of chloroacetaldehyde, 428 and 317 metabolite features were detectable in positive and negative modes, respectively, after stringent removal of chemical noise and unstable signals. Changes upon treatment were explored using principal component analysis, and statistically significant differences were identified using linear models for microarray assays. The analysis revealed toxic effects only for the treatment with 35 μmol·liter−1 for 3 and 14 days. The most regulated metabolites were glutathione and metabolites related to the oxidative stress response of the cells. These findings are corroborated by proteomics and transcriptomics data, which show, among other things, an activation of the Nrf2 and ATF4 pathways. PMID:26055719

  19. Comprehensive Assessment of Quality of Life and Psychosocial Adjustment in Patients with Renal Tumors Undergoing Open, Laparoscopic, and Nephron-Sparing Surgery

    PubMed Central

    Parker, Patricia A.; Swartz, Richard; Fellman, Bryan; Urbauer, Diana; Li, Yisheng; Pisters, Louis L.; Rosser, Charles J.; Wood, Christopher G.; Matin, Surena F.

    2013-01-01

    Purpose We prospectively evaluated the general and cancer-specific quality of life (QOL) and psychosocial adjustment of patients with a renal mass who underwent radical versus partial nephrectomy performed by laparoscopic or open approaches. Materials and Methods 172 patients with renal tumors completed questionnaires before surgery and again at 3 weeks, 2, 3, 6, and 12 months post-surgery. We assessed general QOL (SF-36), cancer-specific-QOL (CARES-SF), intrusive thoughts and avoidance behaviors, and fear of recurrence. We used mixed model regression analyses to compare these measures across surgery types over the course of the study and adjusted for tumor size, histology, stage and renal function. Results The physical component score of the SF-36 different significantly by surgery type over time (p = 0.04). Patients who had laparoscopy improved by month 2 whereas those who had open surgery had poorer QOL until month 3. Better cancer-specific QOL was reported in patients undergoing radical versus partial nephrectomy. Age also had significant effects on outcomes. Conclusions We report on one of the most comprehensive patient-reported prospective QOL studies in RCC patients. There were significant differences in QOL and psychosocial adjustment outcomes over the course of one year among patients who had one of four commonly accepted surgical renal procedures, and we show that these outcomes must be evaluated in the context of tumor characteristics, cancer-specific outcomes and renal function. These QOL issues may be important to consider when choosing surgical procedures for patients with renal tumors. PMID:22245327

  20. Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline.

    PubMed

    Ranninger, Christina; Rurik, Marc; Limonciel, Alice; Ruzek, Silke; Reischl, Roland; Wilmes, Anja; Jennings, Paul; Hewitt, Philip; Dekant, Wolfgang; Kohlbacher, Oliver; Huber, Christian G

    2015-07-31

    Untargeted metabolomics has the potential to improve the predictivity of in vitro toxicity models and therefore may aid the replacement of expensive and laborious animal models. Here we describe a long term repeat dose nephrotoxicity study conducted on the human renal proximal tubular epithelial cell line, RPTEC/TERT1, treated with 10 and 35 μmol·liter(-1) of chloroacetaldehyde, a metabolite of the anti-cancer drug ifosfamide. Our study outlines the establishment of an automated and easy to use untargeted metabolomics workflow for HPLC-high resolution mass spectrometry data. Automated data analysis workflows based on open source software (OpenMS, KNIME) enabled a comprehensive and reproducible analysis of the complex and voluminous metabolomics data produced by the profiling approach. Time- and concentration-dependent responses were clearly evident in the metabolomic profiles. To obtain a more comprehensive picture of the mode of action, transcriptomics and proteomics data were also integrated. For toxicity profiling of chloroacetaldehyde, 428 and 317 metabolite features were detectable in positive and negative modes, respectively, after stringent removal of chemical noise and unstable signals. Changes upon treatment were explored using principal component analysis, and statistically significant differences were identified using linear models for microarray assays. The analysis revealed toxic effects only for the treatment with 35 μmol·liter(-1) for 3 and 14 days. The most regulated metabolites were glutathione and metabolites related to the oxidative stress response of the cells. These findings are corroborated by proteomics and transcriptomics data, which show, among other things, an activation of the Nrf2 and ATF4 pathways. PMID:26055719

  1. WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron.

    PubMed

    Vidal-Petiot, Emmanuelle; Elvira-Matelot, Emilie; Mutig, Kerim; Soukaseum, Christelle; Baudrie, Véronique; Wu, Shengnan; Cheval, Lydie; Huc, Elizabeth; Cambillau, Michèle; Bachmann, Sebastian; Doucet, Alain; Jeunemaitre, Xavier; Hadchouel, Juliette

    2013-08-27

    Large deletions in the first intron of the With No lysine (K) 1 (WNK1) gene are responsible for Familial Hyperkalemic Hypertension (FHHt), a rare form of human hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis. We generated a mouse model of WNK1-associated FHHt to explore the consequences of this intronic deletion. WNK1(+/FHHt) mice display all clinical and biological signs of FHHt. This phenotype results from increased expression of long WNK1 (L-WNK1), the ubiquitous kinase isoform of WNK1, in the distal convoluted tubule, which in turn, stimulates the activity of the Na-Cl cotransporter. We also show that the activity of the epithelial sodium channel is not altered in FHHt mice, suggesting that other mechanisms are responsible for the hyperkalemia and acidosis in this model. Finally, we observe a decreased expression of the renal outer medullary potassium channel in the late distal convoluted tubule of WNK1(+/FHHt) mice, which could contribute to the hyperkalemia. In summary, our study provides insights into the in vivo mechanisms underlying the pathogenesis of WNK1-mediated FHHt and further corroborates the importance of WNK1 in ion homeostasis and blood pressure. PMID:23940364

  2. Physiological brainstem mechanisms of trigeminal nociception: An fMRI study at 3T.

    PubMed

    Schulte, Laura H; Sprenger, Christian; May, Arne

    2016-01-01

    The brainstem is a major site of processing and modulation of nociceptive input and plays a key role in the pathophysiology of various headache disorders. However, human imaging studies on brainstem function following trigeminal nociceptive stimulation are scarce as brainstem specific imaging approaches have to address multiple challenges such as magnetic field inhomogeneities and an enhanced level of physiological noise. In this study we used a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation to achieve detailed insight into physiological brainstem mechanisms of trigeminal nociception. We conducted a study of 21 healthy participants using a nociceptive ammonia stimulation of the left nasal mucosa with an optimized MR acquisition protocol for high resolution brainstem echoplanar imaging in combination with two different noise correction techniques. Significant BOLD responses to noxious ammonia stimulation were observed in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, secondary somatosensory cortex, insular cortex and cerebellum as well as in a pain modulating network including the periaqueductal gray area, hypothalamus (HT), locus coeruleus and cuneiform nucleus (CNF). Activations of the left CNF were positively correlated with pain intensity ratings. Employing psychophysiological interaction (PPI) analysis we found enhanced functional connectivity of the sTN with the contralateral sTN and HT following trigeminal nociception. We also observed enhanced functional connectivity of the CNF with the RVM during painful stimulation thus implying an important role of these two brainstem regions in central pain processing. The chosen approach to study trigeminal nociception with high-resolution fMRI offers new insight into human pain processing and might thus lead to a better understanding of headache pathophysiology. PMID:26388554

  3. Long-term Efficacy of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A 5-year Follow-up Study in China

    PubMed Central

    Jiang, Lu-Lu; Liu, Jin-Long; Fu, Xiao-Li; Xian, Wen-Biao; Gu, Jing; Liu, Yan-Mei; Ye, Jing; Chen, Jie; Qian, Hao; Xu, Shao-Hua; Pei, Zhong; Chen, Ling

    2015-01-01

    Background: Subthalamic nucleus deep brain stimulation (STN DBS) is effective against advanced Parkinson's disease (PD), allowing dramatic improvement of Parkinsonism, in addition to a significant reduction in medication. Here we aimed to investigate the long-term effect of STN DBS in Chinese PD patients, which has not been thoroughly studied in China. Methods: Ten PD patients were assessed before DBS and followed up 1, 3, and 5 years later using Unified Parkinson's Disease Rating Scale Part III (UPDRS III), Parkinson's Disease Questionnatire-39, Parkinson's Disease Sleep Scale-Chinese Version, Mini-mental State Examination, Montreal Cognitive Assessment, Hamilton Anxiety Scale and Hamilton Depression Scale. Stimulation parameters and drug dosages were recorded at each follow-up. Data were analyzed using the ANOVA for repeated measures. Results: In the “off” state (off medication), DBS improved UPDRS III scores by 35.87% in 5 years, compared with preoperative baseline (P < 0.001). In the “on” state (on medication), motor scores at 5 years were similar to the results of preoperative levodopa challenge test. The quality of life is improved by 58.18% (P < 0.001) from baseline to 3 years and gradually declined afterward. Sleep, cognition, and emotion were mostly unchanged. Levodopa equivalent daily dose was reduced from 660.4 ± 210.1 mg at baseline to 310.6 ± 158.4 mg at 5 years (by 52.96%, P < 0.001). The average pulse width, frequency and amplitude at 5 years were 75.0 ± 18.21 μs, 138.5 ± 19.34 Hz, and 2.68 ± 0.43 V, respectively. Conclusions: STN DBS is an effective intervention for PD, although associated with a slightly diminished efficacy after 5 years. Compared with other studies, patients in our study required lower voltage and medication for satisfactory symptom control. PMID:26365958

  4. Comparative evaluation of the impact of WRF/NMM and WRF/ARW meteorology on CMAQ simulations for PM2.5 and its related precursors during the 2006 TexAQS/GoMACCS study

    NASA Astrophysics Data System (ADS)

    Yu, S.; Mathur, R.; Pleim, J.; Pouliot, G.; Wong, D.; Eder, B.; Schere, K.; Gilliam, R.; Rao, S. T.

    2012-05-01

    This study presents a comparative evaluation of the impact of WRF-NMM and WRF-ARW meteorology on CMAQ simulations of PM2.5, its composition and related precursors over the eastern United States with the intensive observations obtained by aircraft (NOAA WP-3), ship and surface monitoring networks (AIRNow, IMPROVE, CASTNet and STN) during the 2006 TexAQS/GoMACCS study. The results at the AIRNow surface sites show that both ARW-CMAQ and NMM-CMAQ reproduced day-to-day variations of observed PM2.5 and captured the majority of observed PM2.5 within a factor of 2 with a NMB value of -0.4% for ARW-CMAQ and -18% for NMM-CMAQ. Both models performed much better at the urban sites than at the rural sites, with greater underpredictions at the rural sites. Both models consistently underestimated the observed PM2.5 at the rural IMPROVE sites by -1% for the ARW-CMAQ and -19% for the NMM-CMAQ. The greater underestimations of SO42-, OC and EC by the NMM-CMAQ contributed to increased underestimation of PM2.5 at the IMPROVE sites. The NMB values for PM2.5 at the STN urban sites are 15% and -16% for the ARW-CMAQ and NMM-CMAQ, respectively. The underestimation of PM2.5 at the STN sites by the NMM-CMAQ mainly results from the underestimations of the SO42-, NH4+ and TCM components, whereas the overestimation of PM2.5 at the STN sites by the ARW-CMAQ results from the overestimations of SO42-, NO3-, and NH4+. The Comparison with WP-3 aircraft measurements reveals that both ARW-CMAQ and NMM-CMAQ have very similar model performance for vertical profiles for PM2.5 chemical components (SO42-, NH4+) and related gaseous species (HNO3, SO2, NH3, isoprene, toluene, terpenes) as both models used the same chemical mechanisms and emissions. The results of ship along the coast of southeastern Texas over the Gulf of Mexico show that both models captured the temporal variations and broad synoptic change seen in the observed HCHO and acetaldehyde with the means NMB <30% most of the time but they

  5. Facilitating effects of deep brain stimulation on feedback learning in Parkinson's disease.

    PubMed

    Meissner, Sarah Nadine; Südmeyer, Martin; Keitel, Ariane; Pollok, Bettina; Bellebaum, Christian

    2016-10-15

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) provides an effective treatment for Parkinson's disease (PD) motor symptoms. However, findings of effects on cognitive function such as feedback learning remain controversial and rare. The aim of the present study was to gain a better understanding of cognitive alterations associated with STN-DBS. Therefore, we investigated effects of STN-DBS on active and observational feedback learning in PD. 18 PD patients with STN-DBS and 18 matched healthy controls completed active and observational feedback learning tasks. Patients were investigated ON and OFF STN-DBS. Tasks consisted of learning (with feedback) and test phases (without feedback). STN-DBS improved active learning during feedback trials and PD patients ON (but not OFF) STN-DBS showed comparable performance patterns as healthy controls. No STN-DBS effect was found when assessing performance during active test trials without feedback. In this case, however, STN-DBS effects were found to depend on symptom severity. While more impaired patients benefited from STN-DBS, stimulation had no facilitating effect on patients with less severe symptoms. Along similar lines, the severity of motor symptoms tended to be significantly correlated with differences in active test performance due to STN-DBS. For observational feedback learning, there was a tendency for a positive STN-DBS effect with patients reaching the performance level of healthy controls only ON STN-DBS. The present data suggest that STN-DBS facilitates active feedback learning in PD patients. Furthermore, they provide first evidence that STN-DBS might not only affect learning from own but also from observed actions and outcomes. PMID:27374161

  6. Immunocytochemical studies of the distribution of alpha and pi isoforms of glutathione S-transferase in cystic renal diseases.

    PubMed

    Hiley, C G; Otter, M; Bell, J; Strange, R C; Keeling, J W

    1994-01-01

    We describe immunohistochemical studies of the expression of alpha and pi class glutathione S-transferases (GSTs) in normal fetal kidneys. These define, in greater detail, changes in expression of alpha isoforms in the proximal tubule. At about 36 weeks of gestation expression of alpha isoforms was down-regulated in the distal tubules and collecting ducts while pi was expressed throughout the nephron. Tubular expression of alpha isoforms was restricted to the part adjacent to the glomerulus; cells farthest from the glomerulus were negative. After 40 weeks of gestation, alpha isoforms were expressed along the entire proximal tubule, while pi was restricted to the distal tubule and collecting ducts. GST expression was also studied in multicystic renal dysplasia, autosomal recessive polycystic kidney disease, and autosomal dominant polycystic kidney disease to determine whether the patterns of expression of alpha and pi isoforms allow identification of the origin of the cysts that characterize these diseases. Cysts were lined by epithelia that were strongly positive for alpha and pi isoforms. The epithelia of noncystic nephrons in renal cystic dysplasia demonstrated delayed maturity, suggesting that GST expression was dependent on the stage of development and not length of gestation. PMID:8066005

  7. COMPARISON OF DATA FROM THE STN AND IMPROVE NETWORKS

    EPA Science Inventory

    Two national chemical speciation-monitoring networks operate currently within the United States. The Interagency Monitoring of Protected Visual Environments (IMPROVE) monitoring network operates primarily in rural areas collecting aerosol and optical data to better understand th...

  8. 3-D Imaging and Simulation for Nephron Sparing Surgical Training.

    PubMed

    Ahmadi, Hamed; Liu, Jen-Jane

    2016-08-01

    Minimally invasive partial nephrectomy (MIPN) is now considered the procedure of choice for small renal masses largely based on functional advantages over traditional open surgery. Lack of haptic feedback, the need for spatial understanding of tumor borders, and advanced operative techniques to minimize ischemia time or achieve zero-ischemia PN are among factors that make MIPN a technically demanding operation with a steep learning curve for inexperienced surgeons. Surgical simulation has emerged as a useful training adjunct in residency programs to facilitate the acquisition of these complex operative skills in the setting of restricted work hours and limited operating room time and autonomy. However, the majority of available surgical simulators focus on basic surgical skills, and procedure-specific simulation is needed for optimal surgical training. Advances in 3-dimensional (3-D) imaging have also enhanced the surgeon's ability to localize tumors intraoperatively. This article focuses on recent procedure-specific simulation models for laparoscopic and robotic-assisted PN and advanced 3-D imaging techniques as part of pre- and some cases, intraoperative surgical planning. PMID:27314271

  9. Nonmotor Symptoms and Subthalamic Deep Brain Stimulation in Parkinson’s Disease

    PubMed Central

    Kim, Han-Joon; Jeon, Beom S.; Paek, Sun Ha

    2015-01-01

    Subthalamic deep brain stimulation (STN DBS) is an established treatment for the motor symptoms in patients with advanced Parkinson’s disease (PD). In addition to improvements in motor symptoms, many studies have reported changes in various nonmotor symptoms (NMSs) after STN DBS in patients with PD. Psychiatric symptoms, including depression, apathy, anxiety, and impulsivity, can worsen or improve depending on the electrical stimulation parameters, the locations of the stimulating contacts within the STN, and changes in medications after surgery. Global cognitive function is not affected by STN DBS, and there is no increase in the incidence of dementia after STN DBS compared to that after medical treatment, although clinically insignificant declines in verbal fluency have been consistently reported. Pain, especially PD-related pain, improves with STN DBS. Evidence regarding the effects of STN DBS on autonomic symptoms and sleep-related problems is limited and remains conflicting. Many symptoms of nonmotor fluctuations, which are occasionally more troublesome than motor fluctuations, improve with STN DBS. Although it is clear that NMSs are not target symptoms for STN DBS, NMSs have a strong influence on the quality of life of patients with PD, and clinicians should thus be aware of these NMSs when deciding whether to perform surgery and should pay attention to changes in these symptoms after STN DBS to ensure the optimal care for patients. PMID:26090080

  10. Primary gene structure and expression studies of rodent paracellin-1.

    PubMed

    Weber, S; Schlingmann, K P; Peters, M; Nejsum, L N; Nielsen, S; Engel, H; Grzeschik, K H; Seyberth, H W; Gröne, H J; Nüsing, R; Konrad, M

    2001-12-01

    The novel member of the claudin multigene family, paracellin-1/claudin-16, encoded by the gene PCLN1, is a renal tight junction protein that is involved in the paracellular transport of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in human PCLN1 are associated with familial hypomagnesemia with hypercalciuria and nephrocalcinosis, an autosomal recessive disease that is characterized by severe renal magnesium and calcium loss. The complete coding sequences of mouse and rat Pcln1 and the murine genomic structure are here presented. Full-length cDNAs are 939 and 1514 bp in length in mouse and rat, respectively, encoding a putative open-reading frame of 235 amino acids in both species with 99% identity. Exon-intron analysis of the human and mouse genes revealed a 100% homology of coding exon lengths and splice-site loci. By radiation hybrid mapping, the murine Pcln1 gene was assigned directly to marker D16Mit133 on mouse chromosome 16 (syntenic to a locus on human chromosome 3q27, which harbors the human PCLN1 gene). Mouse multiple-tissue Northern blot showed Pcln1 expression exclusively in the kidney. The expression profile along the nephron was analyzed by reverse transcriptase-PCR on microdissected nephron segments and immunohistochemistry of rat kidney. Paracellin-1 expression was restricted to distal tubular segments including the thick ascending limb of Henle's loop, the distal tubule, and the collecting duct. The identification and characterization of the rodent Pcln1 genes provide the basis for further studies of paracellin-1 function in suitable animal models. PMID:11729235

  11. The Subthalamic Nucleus During Decision-Making With Multiple Alternatives

    PubMed Central

    Bogacz, Rafal; Schäfer, Andreas; Neumann, Jane; Turner, Robert; Forstmann, Birte U.

    2016-01-01

    Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia. PMID:26178078

  12. The subthalamic nucleus during decision-making with multiple alternatives.

    PubMed

    Keuken, Max C; Van Maanen, Leendert; Bogacz, Rafal; Schäfer, Andreas; Neumann, Jane; Turner, Robert; Forstmann, Birte U

    2015-10-01

    Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia. PMID:26178078

  13. Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease.

    PubMed

    Marin, C; Bonastre, M; Mengod, G; Cortés, R; Rodríguez-Oroz, M C; Obeso, J A

    2013-12-01

    The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta that degenerates in Parkinson's disease. The present study aimed to investigate the role of dopaminergic denervation of STN in the origin of levodopa-induced dyskinesias. Rats were distributed in four groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the STN and in the medial forebrain bundle (MFB) as follows: a) MFB-sham plus STN-sham, b) MFB-sham plus STN-lesion, c) MFB-lesion plus STN-sham, and d) MFB-lesion plus STN-lesion. Four weeks after lesions, animals were treated with levodopa (6mg/kg with 15mg/kg benserazide i.p.) twice daily for 22 consecutive days. Abnormal involuntary movements were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin, STN cytochrome oxidase (CO) and nigral GAD67 mRNAs. STN 6-OHDA denervation did not induce dyskinesias in levodopa-treated MFB-sham animals but attenuated axial (p<0.05), limb (p<0.05) and orolingual (p<0.01) dyskinesias in rats with a concomitant lesion of the nigrostriatal pathway. The attenuation of dyskinesias was associated with a decrease in the ipsilateral STN CO mRNA levels (p<0.05). No significant differences between MFB-lesion plus STN-sham and MFB-lesion plus STN-lesion groups in the extent of STN dopaminergic denervation were observed. Moreover, intrasubthalamic microinfusion of dopamine in the MFB-lesion plus STN-lesion group triggered orolingual (p<0.01), but not axial or limb, dyskinesias. These results suggest that dopaminergic STN innervation influences the expression of levodopa-induced dyskinesias but also the existence of non dopaminergic-mediated mechanisms. STN noradrenergic depletion induced by 6-OHDA in the STN needs to be taken in account as a possible mechanism explaining the attenuation of dyskinesias in the combined lesion group. PMID:24140562

  14. Ceftriaxone prevents the neurodegeneration and decreased neurogenesis seen in a Parkinson's disease rat model: An immunohistochemical and MRI study.

    PubMed

    Weng, Jun-Cheng; Tikhonova, Maria A; Chen, Jian-Horng; Shen, Mei-Shiuan; Meng, Wan-Yun; Chang, Yen-Ting; Chen, Ke-Hsin; Liang, Keng-Chen; Hung, Ching-Sui; Amstislavskaya, Tamara G; Ho, Ying-Jui

    2016-05-15

    Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique for detecting neuronal activity in the brain of a living animal. Ceftriaxone (CEF) has been shown to have neuroprotective effects in neurodegenerative diseases. The present study was aimed at clarifying whether, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) rat model, the known CEF-induced neuronal protection was accompanied by neurogenesis and decreased loss of neuronal activity. After MPTP lesioning (day 0), the rats were treated with CEF (100mg/kg/day, i.p.) or saline for 15 days. They were then injected with MnCl2 (40mg/kg, i.p.) on day 13 and underwent a brain MRI scan on day 14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased neuronal activity and density in the nigrostriatal dopaminergic (DAergic) system and the hippocampal CA1, CA3, and dentate gyrus (DG) areas and reduced neurogenesis in the DG, but in hyperactivity in the subthalamic nucleus (STN). These neuronal changes were prevented by CEF treatment. Positive correlations between MEMRI R1 values and neuronal density in the hippocampus were evidenced. Neuronal densities in the hippocampus and SNc were positively correlated. In addition, the R1 value of the STN showed a positive correlation with its neuronal activity but showed a negative correlation with the density of DAergic neurons in the SNc. Therefore, MEMRI R1 value may serve as a good indicator for PD severity and the effect of treatment. To our knowledge, this is the first study showing that CEF prevents loss of neuronal activity and neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD. PMID:26940602

  15. The sensitivity of health effect estimates from time-series studies to fine particulate matter component sampling schedule.

    PubMed

    Kim, Sun-Young; Sheppard, Lianne; Hannigan, Michael P; Dutton, Steven J; Peel, Jennifer L; Clark, Maggie L; Vedal, Sverre

    2013-01-01

    The US Environmental Protection Agency air pollution monitoring data have been a valuable resource commonly used for investigating the associations between short-term exposures to PM2.5 chemical components and human health. However, the temporally sparse sampling on every third or sixth day may affect health effect estimation. We examined the impact of non-daily monitoring data on health effect estimates using daily data from the Denver Aerosol Sources and Health (DASH) study. Daily concentrations of four PM2.5 chemical components (elemental and organic carbon, sulfate, and nitrate) and hospital admission counts from 2003 through 2007 were used. Three every-third-day time series were created from the daily DASH monitoring data, imitating the US Speciation Trend Network (STN) monitoring schedule. A fourth, partly irregular, every-third-day time series was created by matching existing sampling days at a nearby STN monitor. Relative risks (RRs) of hospital admissions for PM2.5 components at lags 0-3 were estimated for each data set, adjusting for temperature, relative humidity, longer term temporal trends, and day of week using generalized additive models, and compared across different sampling schedules. The estimated RRs varied somewhat between the non-daily and daily sampling schedules and between the four non-daily schedules, and in some instances could lead to different conclusions. It was not evident which features of the data or analysis were responsible for the variation in effect estimates, although seeing similar variability in resampled data sets with relaxation of the every-third-day constraint suggests that limited power may have had a role. The use of non-daily monitoring data can influence interpretation of estimated effects of PM2.5 components on hospital admissions in time-series studies. PMID:23673462

  16. High-frequency electrical stimulation of the subthalamic nucleus excites target structures in a model using c-fos immunohistochemistry.

    PubMed

    Shehab, S; D'souza, C; Ljubisavljevic, M; Redgrave, P

    2014-06-13

    Deep-brain stimulation at high frequencies (HFS) directed to the subthalamic nucleus (STN) is used increasingly to treat patients with Parkinson's disease. However, the mechanism of action by which HFS of the STN achieves its therapeutic effects remains unresolved. Insofar as lesions of the STN have similar therapeutic benefit, a favored hypothesis is that HFS acts by suppressing neural activity in the STN. The purpose of the present study was to exploit prior observations that exposure to ether anesthesia in a rodent model evokes c-fos expression (a marker of neural activation) in the STN and its efferent structures, the globus pallidus, entopeduncular nucleus and substantia nigra. We showed first that exposure to ether induced a profound oscillatory pattern of neural activity in the STN and SNr, which could explain the marked induction of c-fos immunoreactivity in these structures. Secondly, inhibition of the STN by local injections of the GABA agonist, muscimol, suppressed ether-evoked c-fos expression in all target structures. This showed that excitation of target structures in the ether model originated, at least in part, from the STN. Thirdly, and contrary to expectation, HFS of the STN increased further the expression of c-fos in the STN target structures of animals treated with ether. Finally, we demonstrated, in the absence of ether treatment, that HFS and chemical stimulation of the STN with local injections of kainic acid both induced c-fos expression in the globus pallidus, entopeduncular nucleus and substantia nigra. Together these results suggest that the principal action of STN stimulation at high frequencies is to excite rather than inhibit its efferent targets. Given that Parkinsonism has been associated with increased levels of inhibitory output activity from the basal ganglia, it is unlikely that excitation of output structures revealed in this study provides a basis for deep-brain stimulation's therapeutic action. PMID:24755486

  17. Effects of neurostimulation for advanced Parkinson’s disease patients on motor symptoms: A multiple-treatments meta-analysas of randomized controlled trials

    PubMed Central

    Xie, Cheng-Long; Shao, Bei; Chen, Jie; Zhou, Yi; Lin, Shi-Yi; Wang, Wen-Wen

    2016-01-01

    Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). We aim to evaluate the efficacy of GPi (globus pallidus internus), STN (subthalamic nucleus)-DBS and medical therapy for PD. We conducted a systematic review and multiple-treatments meta-analysis to investigate the efficacy of neurostimulation and medical therapy for PD patients. Sixteen eligible studies were included in this analysis. We pooled the whole data and found obvious difference between GPi-DBS versus medical therapy and STN-DBS versus medical therapy in terms of UPDRS scores (Unified Parkinson’s Disease Rating Scale). Meanwhile, we found GPi-DBS had the similar efficacy on the UPDRS scores when compared with STN-DBS. What is more, quality of life, measured by PDQ-39 (Parkinson’s disease Questionnaire) showed greater improvement after GPi-DBS than STN-DBS. Five studies showed STN-DBS was more effective for reduction in medication than GPi-DBS. Overall, either GPi-DBS or STN-DBS was an effective technique to control PD patients’ symptoms and improved their functionality and quality of life. Meanwhile, the UPDRS scores measuring parkinsonian symptoms revealed no significant difference between GPi-DBS and STN-DBS. STN-DBS was more effective for reduction in medication than GPi-DBS. Alternatively, GPi-DBS was more effective for improving the PDQ-39 score than STN-DBS. PMID:27142183

  18. Effects of neurostimulation for advanced Parkinson's disease patients on motor symptoms: A multiple-treatments meta-analysas of randomized controlled trials.

    PubMed

    Xie, Cheng-Long; Shao, Bei; Chen, Jie; Zhou, Yi; Lin, Shi-Yi; Wang, Wen-Wen

    2016-01-01

    Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). We aim to evaluate the efficacy of GPi (globus pallidus internus), STN (subthalamic nucleus)-DBS and medical therapy for PD. We conducted a systematic review and multiple-treatments meta-analysis to investigate the efficacy of neurostimulation and medical therapy for PD patients. Sixteen eligible studies were included in this analysis. We pooled the whole data and found obvious difference between GPi-DBS versus medical therapy and STN-DBS versus medical therapy in terms of UPDRS scores (Unified Parkinson's Disease Rating Scale). Meanwhile, we found GPi-DBS had the similar efficacy on the UPDRS scores when compared with STN-DBS. What is more, quality of life, measured by PDQ-39 (Parkinson's disease Questionnaire) showed greater improvement after GPi-DBS than STN-DBS. Five studies showed STN-DBS was more effective for reduction in medication than GPi-DBS. Overall, either GPi-DBS or STN-DBS was an effective technique to control PD patients' symptoms and improved their functionality and quality of life. Meanwhile, the UPDRS scores measuring parkinsonian symptoms revealed no significant difference between GPi-DBS and STN-DBS. STN-DBS was more effective for reduction in medication than GPi-DBS. Alternatively, GPi-DBS was more effective for improving the PDQ-39 score than STN-DBS. PMID:27142183

  19. Morphology of the kidney in the West African caecilian, Geotrypetes seraphini (Amphibia, Gymnophiona, Caeciliidae).

    PubMed

    Møbjerg, N; Jespersen, A; Wilkinson, M

    2004-11-01

    This study deals with the morphology and ultrastructure of the mesonephros in adult caecilians of the species Geotrypetes seraphini. Based on serial sections in paraffin and araldite, nephrons are reconstructed and the cellular characteristics of different nephron segments described. The long and slender mesonephric kidneys of G. seraphini are broadest caudally and taper toward the front, where the organs are divided into smaller segmental divisions. Two nephron types can be distinguished on the basis of their connections to the coelom and their position within the nephric tissue: ventral nephrons connect to the coelom via a ciliated peritoneal funnel, whereas medial nephrons lack this connection. Both nephron types are composed of a filtration unit, the Malpighian corpuscle, and a renal tubule, which can be divided into six morphologically distinct segments: neck segment, proximal tubule, intermediate segment, early distal tubule, late distal tubule, and collecting tubule. Collecting tubules merge and form a branch system that opens into collecting ducts. Collecting ducts empty into the Wolffian duct. Proximal tubules of nephrons in the frontal divisions are morphologically different from the proximal tubules of more caudal kidney regions. Distal tubule subdivision is only clearly recognizable at the electron microscopic level. The length of each nephron segment is calculated from a ventral nephron with a total length of approximately 3.8 mm, and the course of the segments within the nephric tissue is reported. The number of nephrons was estimated at 1,700 units in each kidney. The segmentation and ultrastructure of the mesonephric nephrons in G. seraphini are discussed in relation to nephron descriptions from other caecilians and we further discuss the evolutionary origin of the amphibian nephron. PMID:15376276

  20. Delayed synchronization of activity in cortex and subthalamic nucleus following cortical stimulation in the rat

    PubMed Central

    Magill, Peter J; Sharott, Andrew; Bolam, J Paul; Brown, Peter

    2006-01-01

    Oscillations may play a role in the functional organization of cortico-basal ganglia-thalamocortical circuits, and it is important to understand their underlying mechanisms. The cortex often drives basal ganglia (BG) activity, and particularly, oscillatory activity in the subthalamic nucleus (STN). However, the STN may also indirectly influence cortex. The aim of this study was to characterize the delayed (>200 ms) responses of STN neurons to synchronized cortical inputs, focusing on their relationship with oscillatory cortical activity. We recorded the short-latency and delayed responses of STN units and frontal electrocorticogram (ECoG) to cortical stimulation in anaesthetized rats. Similar to previous studies, stimulation of ipsilateral frontal cortex, but not temporal cortex, evoked a short-latency triphasic response, followed by a sustained reduction or pause in firing, in rostral STN units. Caudal STN units did not show the short-latency triphasic response but often displayed a prolonged firing reduction. Oscillations in STN unit activity and ECoG were common after this sustained firing reduction, particularly between 200 and 600 ms after frontal cortical stimulation. These delayed oscillations were significantly coherent in a broad frequency band of 5–30 Hz. Coherence with ECoG at 5–15 Hz was observed throughout STN, though coherence at 15–30 Hz was largely restricted to rostral STN. Furthermore, oscillatory responses at 5–30 Hz in rostral STN predominantly led those in cortex (mean latency of 29 ms) after frontal cortical stimulation. These findings suggest that STN neurons responding to corticosubthalamic inputs may provide a delayed input to cortex, via BG output nuclei, and thence, thalamocortical pathways. PMID:16709634

  1. Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit.

    PubMed

    Hachem-Delaunay, Sabira; Fournier, Marie-Line; Cohen, Candie; Bonneau, Nicolas; Cador, Martine; Baunez, Christelle; Le Moine, Catherine

    2015-08-01

    The subthalamic nucleus (STN) is a critical component of a complex network controlling motor, associative and limbic functions. High-frequency stimulation (HFS) of the STN is an effective therapy for motor symptoms in Parkinsonian patients and can also reduce their treatment-induced addictive behaviors. Preclinical studies have shown that STN HFS decreases motivation for cocaine while increasing that for food, highlighting its influence on rewarding and motivational circuits. However, the cellular substrates of these effects remain unknown. Our objectives were to characterize the cellular consequences of STN HFS with a special focus on limbic structures and to elucidate how STN HFS may interfere with acute cocaine effects in these brain areas. Male Long-Evans rats were subjected to STN HFS (130 Hz, 60 μs, 50-150 μA) for 30 min before an acute cocaine injection (15 mg/kg) and sacrificed 10 min following the injection. Neuronal reactivity was analyzed through the expression of two immediate early genes (Arc and c-Fos) to decipher cellular responses to STN HFS and cocaine. STN HFS only activated c-Fos in the globus pallidus and the basolateral amygdala, highlighting a possible role on emotional processes via the amygdala, with a limited effect by itself in other structures. Interestingly, and despite some differential effects on Arc and c-Fos expression, STN HFS diminished the c-Fos response induced by acute cocaine in the striatum. By preventing the cellular effect of cocaine in the striatum, STN HFS might thus decrease the reinforcing properties of the drug, which is in line with the inhibitory effect of STN HFS on the rewarding and reinforcing properties of cocaine. PMID:25982833

  2. Changes in handwriting resulting from bilateral high-frequency stimulation of the subthalamic nucleus in Parkinson's disease.

    PubMed

    Siebner, H R; Ceballos-Baumann, A; Standhardt, H; Auer, C; Conrad, B; Alesch, F

    1999-11-01

    High-frequency stimulation of the subthalamic nucleus (STN) is a promising therapeutic approach in patients with severely disabling Parkinson's disease (PD). Whereas STN stimulation improves the cardinal signs of PD, little is known about the effects of STN stimulation on fine manual skills like handwriting. Therefore, the present study investigated the changes in handwriting during bilateral STN stimulation in 12 patients with advanced PD. Dopaminergic medication was discontinued at least 12 hours before the study. The patients were asked to write a standardized sentence repetitively. Five samples of the patient's script were recorded during effective bilateral STN stimulation and 1 hour after both stimulators had been switched off. The movements of the tip of the pencil were recorded using a digitizing tablet. Handwriting movements were segmented into subsequent up- and down-strokes, and a stroke-based kinematic analysis of handwriting was performed. During high-frequency STN stimulation, handwriting movements became faster and smoother indicating a partial restoration of an "open-loop" automatic performance. In addition, STN stimulation gave rise to a significant increase in the mean vertical stroke length demonstrating a stimulation-related reduction in micrographia. The present data underscores the importance of the STN in "open-loop" performance of highly skilled sequential hand movements. PMID:10584671

  3. Stimulation of the Rat Subthalamic Nucleus is Neuroprotective Following Significant Nigral Dopamine Neuron Loss

    PubMed Central

    Spieles-Engemann, A. L.; Behbehani, M. M.; Collier, T. J.; Wohlgenant, S. L.; Steece-Collier, K.; Paumier, K.; Daley, B. F.; Gombash, S.; Madhavan, L.; Mandybur, G. T.; Lipton, J.W.; Terpstra, B.T.; Sortwell, C.E.

    2010-01-01

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) is efficacious in treating the motor symptoms of Parkinson’s disease (PD). However, the impact of STN-DBS on the progression of PD is unknown. Previous preclinical studies have demonstrated that STN-DBS can attenuate the degeneration of a relatively intact nigrostriatal system from dopamine (DA)-depleting neurotoxins. The present study examined whether STN-DBS can provide neuroprotection in the face of prior significant nigral DA neuron loss similar to PD patients at the time of diagnosis. STN-DBS between two and four weeks after intrastriatal 6-hydroxydopamine (6-OHDA) provided significant sparing of DA neurons in the SN of rats. This effect was not due to inadvertent lesioning of the STN and was dependent upon proper electrode placement. Since STN-DBS appears to have significant neuroprotective properties, initiation of STN-DBS earlier in the course of PD may provide added neuroprotective benefits in addition to its ability to provide symptomatic relief. PMID:20307668

  4. The effects of subthalamic deep brain stimulation on metaphor comprehension and language abilities in Parkinson's disease.

    PubMed

    Tremblay, Christina; Macoir, Joël; Langlois, Mélanie; Cantin, Léo; Prud'homme, Michel; Monetta, Laura

    2015-02-01

    The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) on different language abilities are still controversial and its impact on high-level language abilities such as metaphor comprehension has been overlooked. The aim of this study was to determine the effects of STN electrical stimulation on metaphor comprehension and language abilities such as lexical and semantic capacities. Eight PD individuals with bilateral STN-DBS were first evaluated OFF-DBS and, at least seven weeks later, ON-DBS. Performance on metaphor comprehension, lexical decision, word association and verbal fluency tasks were compared ON and OFF-DBS in addition to motor symptoms evaluation. STN stimulation had a significant beneficial effect on motor symptoms in PD. However, this stimulation did not have any effect on metaphor comprehension or any other cognitive ability evaluated in this study. These outcomes suggest that STN stimulation may have dissociable effects on motor and language functions. PMID:25577507

  5. Deep Brain Stimulation and Medication for Parkinsonian Tremor During Secondary Tasks

    PubMed Central

    Sturman, Molly M.; Vaillancourt, David E.; Metman, Leo Verhagen; Sierens, Diane K.; Bakay, Roy A.E.; Corcos, Daniel M.

    2008-01-01

    This study examined the efficacy of subthalamic nucleus (STN), deep brain stimulation (DBS), and medication for resting tremor during performance of secondary tasks. Hand tremor was recorded using accelerometry and electromyography (EMG) from 10 patients with Parkinson’s disease (PD) and ten matched control subjects. The PD subjects were examined off treatment, on STN DBS, on medication, and on STN DBS plus medication. In the first experiment, tremor was recorded in a quiet condition and during a cognitive task designed to enhance tremor. In the second experiment, tremor was recorded in a quiet condition and during isometric finger flexion (motor task) with the contralateral limb at 5% of the maximal voluntary contraction (MVC) that was designed to suppress tremor. Results showed that: (1) STN DBS and medication reduced tremor during a cognitive task that exacerbated tremor, (2) STN DBS normalized tremor frequency in both the quiet and cognitive task conditions, whereas tremor amplitude was only normalized in the quiet condition, (3) a secondary motor task reduced tremor in a similar manner to STN DBS. These findings demonstrate that STN DBS still suppresses tremor in the presence of a cognitive task. Furthermore, a secondary motor task of the opposite limb suppresses tremor to levels comparable to STN DBS. PMID:17469210

  6. Sialyl-Tn antigen expression occurs early during human mammary carcinogenesis and is associated with high nuclear grade and aneuploidy.

    PubMed

    Cho, S H; Sahin, A; Hortobagyi, G N; Hittelman, W N; Dhingra, K

    1994-12-15

    Sialyl-Tn (STn) antigen represents an aberrant glycosylation product of cell surface mucin in adenocarcinomas. We studied its expression in 40 breast carcinomas (35 of which included in situ carcinomas) by performing immunostaining with B72.3 monoclonal antibody. STn expression was observed in 50% of cases and was equally frequent in in situ and in invasive carcinomas. Positive STn staining significantly correlated with high nuclear grade (P = 0.001), aneuploidy (P < 0.001) and high S-phase fraction (P = 0.02). No correlation was observed between STn staining and age, menopausal status, presence of invasive component, or hormone receptor positivity. STn staining may provide an objective marker of dedifferentiation of breast tumors and should be investigated further for its prognostic value in breast cancers and as a biomarker of malignant transformation of breast epithelium. PMID:7987817

  7. Does bilateral stimulation of the subthalamic nucleus aggravate apathy in Parkinson's disease?

    PubMed Central

    Czernecki, V; Pillon, B; Houeto, J; Welter, M; Mesnage, V; Agid, Y; Dubois, B

    2005-01-01

    Objective: High frequency stimulation of the subthalamic nucleus (STN) dramatically decreases motor disability in patients with Parkinson"s disease (PD), but has been reported to aggravate apathy. The aim of this study was to analyse the effect of STN stimulation on motivation and reward sensitivity in a consecutive series of PD patients. Methods: Apathy and reward sensitivity (Apathy Scale, Stimulus-Reward Learning, Reversal, Extinction, and Gambling tasks) were assessed in 18 PD patients treated by bilateral STN stimulation ("on" and "off" conditions) compared with 23 matched patients undergoing long term treatment with levodopa ("on" and "off" conditions). Results: Apathy decreased under both STN stimulation and levodopa treatment, whereas explicit and implicit stimulus reward learning was unchanged. Conclusions: Bilateral STN stimulation in PD patients does not necessarily have a negative effect on motivation and reward sensitivity and can even improve apathy provided patients have been appropriately selected for neurosurgery. PMID:15897497

  8. Stimulation of the subthalamic nucleus engages the cerebellum for motor function in parkinsonian rats.

    PubMed

    Sutton, Alexander C; O'Connor, Katherine A; Pilitsis, Julie G; Shin, Damian S

    2015-11-01

    Deep brain stimulation (DBS) is effective in managing motor symptoms of Parkinson's disease in well-selected individuals. Recently, research has shown that DBS in the basal ganglia (BG) can alter neural circuits beyond the traditional basal ganglia-thalamus-cortical (BG-TH-CX) loop. For instance, functional imaging showed alterations in cerebellar activity with DBS in the subthalamic nucleus (STN). However, these imaging studies revealed very little about how cell-specific cerebellar activity responds to STN stimulation or if these changes contribute to its efficacy. In this study, we assess whether STN-DBS provides efficacy in managing motor symptoms in Parkinson's disease by recruiting cerebellar activity. We do this by applying STN-DBS in hemiparkinsonian rats and simultaneously recording neuronal activity from the STN, brainstem and cerebellum. We found that STN neurons decreased spiking activity by 55% during DBS (P = 0.038), which coincided with a decrease in most pedunculopontine tegmental nucleus and Purkinje neurons by 29% (P < 0.001) and 28% (P = 0.003), respectively. In contrast, spike activity in the deep cerebellar nuclei increased 45% during DBS (P < 0.001), which was likely from reduced afferent activity of Purkinje cells. Then, we applied STN-DBS at sub-therapeutic current along with stimulation of the deep cerebellar nuclei and found similar improvement in forelimb akinesia as with therapeutic STN-DBS alone. This suggests that STN-DBS can engage cerebellar activity to improve parkinsonian motor symptoms. Our study is the first to describe how STN-DBS in Parkinson's disease alters cerebellar activity using electrophysiology in vivo and reveal a potential for stimulating the cerebellum to potentiate deep brain stimulation of the subthalamic nucleus. PMID:25124274

  9. Deep brain stimulation of the subthalamic nucleus increases premature responding in a rat gambling task.

    PubMed

    Aleksandrova, Lily R; Creed, Meaghan C; Fletcher, Paul J; Lobo, Daniela S S; Hamani, Clement; Nobrega, José N

    2013-05-15

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option for the motor symptoms of Parkinson's disease (PD). However, several recent studies have found an association between STN-DBS and increased impulsivity. Currently, it is not clear whether the observed increase in impulsivity results from STN-DBS per se, or whether it involves an interaction with the underlying PD neuropathology and/or intake of dopaminergic drugs. We investigated the effects of STN-DBS on performance of intact rats on two tasks measuring impulsive responding: a novel rat gambling task (rGT) and a differential reinforcement of low rate responding (DRL20s) schedule. Following initial behavioural training, animals received electrode implantation into the STN (n=24) or sham surgery (n=24), and were re-tested on their assigned behavioural task, with or without STN-DBS. Bilateral STN-DBS administered for two hours immediately prior to testing, had no effects on rGT choice behaviour or on DRL response inhibition (p>0.05). However, STN-DBS significantly increased premature responding in the rGT task (p=0.0004), an effect that took several sessions to develop and persisted in subsequent trials when no stimulation was given. Consistent with the notion of distinct facets of impulsivity with unique neurochemical underpinnings, we observed differential effects of STN-DBS in the two tasks employed. These results suggest that STN-DBS in the absence of parkinsonism may not lead to a general loss of inhibitory control, but may instead affect impulsivity under specific conditions. PMID:23434606

  10. Soil Carbon and Nitrogen Changes following Afforestation of Marginal Cropland across a Precipitation Gradient in Loess Plateau of China

    PubMed Central

    Lü, Yihe; Liu, Guohua; Fu, Bojie

    2014-01-01

    Cropland afforestation has been widely found to increase soil organic carbon (SOC) and soil total nitrogen (STN); however, the magnitudes of SOC and STN accumulation and regulating factors are less studied in dry, marginal lands, and therein the interaction between soil carbon and nitrogen is not well understood. We examined the changes in SOC and STN in younger (5–9-year-old) and older (25–30-year-old) black locust (Robinia pseudoacacia L., an N-fixing species) plantations that were established on former cropland along a precipitation gradient (380 to 650 mm) in the semi-arid Loess Plateau of China. The SOC and STN stocks of cropland and plantations increased linearly with precipitation increase, respectively, accompanying an increase in the plantation net primary productivity and the soil clay content along the increasing precipitation gradient. The SOC stock of cropland decreased in younger plantations and increased in older plantations after afforestation, and the amount of the initial loss of SOC during the younger plantations’ establishment increased with precipitation increasing. By contrast, the STN stock of cropland showed no decrease in the initial afforestation while tending to increase with plantation age, and the changes in STN were not related to precipitation. The changes in STN and SOC showed correlated and were precipitation-dependent following afforestation, displaying a higher relative gain of SOC to STN as precipitation decreased. Our results suggest that the afforestation of marginal cropland in Loess Plateau can have a significant effect on the accumulation of SOC and STN, and that precipitation has a significant effect on SOC accumulation but little effect on STN retention. The limitation effect of soil nitrogen on soil carbon accumulation is more limited in the drier area rather than in the wetter sites. PMID:24416408

  11. The Subthalamic Nucleus in Primary Dystonia: Single-Unit Discharge Characteristics

    PubMed Central

    Schrock, Lauren E.; Ostrem, Jill L.; Turner, Robert S.; Shimamoto, Shoichi A.

    2009-01-01

    Most models of dystonia pathophysiology predict alterations of activity in the basal ganglia thalamocortical motor circuit. The globus pallidus interna (GPi) shows bursting and oscillatory neuronal discharge in both human dystonia and in animal models, but it is not clear which intrinsic basal ganglia pathways are implicated in this abnormal output. The subthalamic nucleus (STN) receives prominent excitatory input directly from cortical areas implicated in dystonia pathogenesis and inhibitory input from the external globus pallidus. The goal of this study was to elucidate the role of the STN in dystonia by analyzing STN neuronal discharge in patients with idiopathic dystonia. Data were collected in awake patients undergoing microelectrode recording for implantation of STN deep brain stimulation electrodes. We recorded 62 STN neurons in 9 patients with primary dystonia. As a comparison group, we recorded 143 STN neurons in 20 patients with Parkinson's disease (PD). Single-unit activity was discriminated off-line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity. The mean STN discharge rate in dystonia patients was 26.3 Hz (SD 13.6), which was lower than that in the PD patients (35.6 Hz, SD 15.2), but higher than published values for subjects without basal ganglia dysfunction. Oscillatory activity was found in both disorders, with a higher proportion of units oscillating in the beta range in PD. Bursting discharge was a prominent feature of both dystonia and PD, whereas sensory receptive fields were expanded in PD compared with dystonia. The STN firing characteristics, in conjunction with those previously published for GPi, suggest that bursting and oscillatory discharge in basal ganglia output may be transmitted via pathways involving the STN and provide a pathophysiologic rationale for STN as a surgical target in dystonia. PMID:19846625

  12. Soil carbon and nitrogen changes following afforestation of marginal cropland across a precipitation gradient in Loess Plateau of China.

    PubMed

    Chang, Ruiying; Jin, Tiantian; Lü, Yihe; Liu, Guohua; Fu, Bojie

    2014-01-01

    Cropland afforestation has been widely found to increase soil organic carbon (SOC) and soil total nitrogen (STN); however, the magnitudes of SOC and STN accumulation and regulating factors are less studied in dry, marginal lands, and therein the interaction between soil carbon and nitrogen is not well understood. We examined the changes in SOC and STN in younger (5-9-year-old) and older (25-30-year-old) black locust (Robinia pseudoacacia L., an N-fixing species) plantations that were established on former cropland along a precipitation gradient (380 to 650 mm) in the semi-arid Loess Plateau of China. The SOC and STN stocks of cropland and plantations increased linearly with precipitation increase, respectively, accompanying an increase in the plantation net primary productivity and the soil clay content along the increasing precipitation gradient. The SOC stock of cropland decreased in younger plantations and increased in older plantations after afforestation, and the amount of the initial loss of SOC during the younger plantations' establishment increased with precipitation increasing. By contrast, the STN stock of cropland showed no decrease in the initial afforestation while tending to increase with plantation age, and the changes in STN were not related to precipitation. The changes in STN and SOC showed correlated and were precipitation-dependent following afforestation, displaying a higher relative gain of SOC to STN as precipitation decreased. Our results suggest that the afforestation of marginal cropland in Loess Plateau can have a significant effect on the accumulation of SOC and STN, and that precipitation has a significant effect on SOC accumulation but little effect on STN retention. The limitation effect of soil nitrogen on soil carbon accumulation is more limited in the drier area rather than in the wetter sites. PMID:24416408

  13. NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus

    PubMed Central

    Swanger, Sharon A.; Vance, Katie M.; Pare, Jean-François; Sotty, Florence; Fog, Karina; Smith, Yoland

    2015-01-01

    synaptic transmission in the STN has been understudied. Here, we show that GluN2B- and GluN2D-containing NMDA receptors mediate the NMDA receptor component of EPSCs in subthalamic neurons. Moreover, our results demonstrate that pharmacologic modulation of GluN2D-containing receptors alters the time course of EPSCs and controls the in vivo spike-firing rate in the STN. This study identifies GluN2D as a potential target for modulating subthalamic neuron activity. PMID:26631477

  14. Self-Reported Executive Functioning in Everyday Life in Parkinson's Disease after Three Months of Subthalamic Deep Brain Stimulation

    PubMed Central

    Pham, Uyen Ha Gia; Andersson, Stein; Toft, Mathias; Pripp, Are Hugo; Konglund, Ane Eidahl; Dietrichs, Espen; Malt, Ulrik Fredrik; Skogseid, Inger Marie; Haraldsen, Ira Ronit Hebolt; Solbakk, Anne-Kristin

    2015-01-01

    Objective. Studies on the effect of subthalamic deep brain stimulation (STN-DBS) on executive functioning in Parkinson's disease (PD) are still controversial. In this study we compared self-reported daily executive functioning in PD patients before and after three months of STN-DBS. We also examined whether executive functioning in everyday life was associated with motor symptoms, apathy, and psychiatric symptoms. Method. 40 PD patients were examined with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), the Symptom Checklist 90-Revised (SCL-90-R), and the Apathy Evaluation Scale (AES-S). Results. PD patients reported significant improvement in daily life executive functioning after 3 months of STN-DBS. Anxiety scores significantly declined, while other psychiatric symptoms remained unchanged. The improvement of self-reported executive functioning did not correlate with motor improvement after STN-DBS. Apathy scores remained unchanged after surgery. Only preoperative depressed mood had predictive value to the improvement of executive function and appears to prevent potentially favorable outcomes from STN-DBS on some aspects of executive function. Conclusion. PD patients being screened for STN-DBS surgery should be evaluated with regard to self-reported executive functioning. Depressive symptoms in presurgical PD patients should be treated. Complementary information about daily life executive functioning in PD patients might enhance further treatment planning of STN-DBS. PMID:26167329

  15. Subthalamic nucleus stimulation affects fear and sadness recognition in Parkinson's disease.

    PubMed

    Péron, Julie; Biseul, Isabelle; Leray, Emmanuelle; Vicente, Siobhan; Le Jeune, Florence; Drapier, Sophie; Drapier, Dominique; Sauleau, Paul; Haegelen, Claire; Vérin, Marc

    2010-01-01

    Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) can produce emotional disorders that have been linked to disturbance of the STN's limbic territory. The aim of this study was to confirm the impairment of the recognition of facial emotions (RFE) induced by STN DBS, not only ruling out the effect of the disease's natural progression in relation to the effect of DBS, but also assessing the influence of modifications in dopamine replacement therapy (DRT) following STN DBS. RFE was investigated in 24 PD patients who underwent STN DBS and 20 PD patients treated with apomorphine. They were assessed 3 months before and after treatment. The 2 patient groups were compared with a group of 30 healthy matched controls. The results showed that RFE for negative emotions (fear and sadness) was impaired in only the STN DBS group in the posttreatment condition and was unrelated to DRT. Results confirm the selective reduction of RFE induced by STN DBS, due neither to the disease's natural progression nor to modifications in DRT. PMID:20063943

  16. Inhibitory control and error monitoring by human subthalamic neurons

    PubMed Central

    Bastin, J; Polosan, M; Benis, D; Goetz, L; Bhattacharjee, M; Piallat, B; Krainik, A; Bougerol, T; Chabardès, S; David, O

    2014-01-01

    The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2–4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15–35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions. PMID:25203170

  17. Temperature dependence of the deformation behavior of type 316 stainless steel after low temperature neutron irradiation

    SciTech Connect

    Robertson, J.P.; Rowcliffe, A.F.; Grossbeck, M.L.; Ioka, Ikuo; Jitsukawa, Shiro

    1996-12-31

    A single heat of solution annealed 316 ss was irradiated to 7 and 18 dpa at 60, 200, 330, and 400 C. Tensile properties were studied vs dose and temperature. Large changes in yield strength, deformation mode, strain to necking (STN), and strain hardening capacity were seen. Magnitude of the changes are dependent on both irradiation temperature and neutron dose. Irradiation can more than triple the yield strength and decrease STN to <0.5% under certain conditions. A maximum increase in yield strength and a minimum in STN occur after irradiation at 330 C but failure mode remains ductile.

  18. The Subthalamic Nucleus, oscillations and conflict

    PubMed Central

    Zavala, Baltazar; Zaghloul, Kareem; Brown, Peter

    2014-01-01

    The subthalamic nucleus (STN), which is currently the most common target for deep brain stimulation for Parkinson’s disease, has received increased attention over the past few years for the roles it may play in functions beyond simple motor control. In this article we will highlight several of the theoretical, interventional, and electrophysiological studies that have implicated the STN in response inhibition. Most influential amongst this evidence has been the reported effect of STN deep brain stimulation in increasing impulsive responses in the laboratory setting. Yet, how this relates to pathological impulsivity in patient’s everyday lives remains uncertain. PMID:25688872

  19. Subthalamic Nucleus Stimulation Increases Brain Derived Neurotrophic Factor in the Nigrostriatal System and Primary Motor Cortex

    PubMed Central

    Spieles-Engemann, Anne L.; Steece-Collier, Kathy; Behbehani, Michael M.; Collier, Timothy J.; Wohlgenant, Susan L.; Kemp, Christopher J.; Cole-Strauss, Allyson; Levine, Nathan D.; Gombash, Sara E.; Thompson, Valerie B.; Lipton, Jack W.; Sortwell, Caryl E.

    2011-01-01

    The mechanisms underlying the effects of long-term deep brain stimulation of the subthalamic nucleus (STN DBS) as a therapy for Parkinson’s disease (PD) remain poorly understood. The present study examined whether functionally effective, long-term STN DBS modulates glial cell line-derived neurotrophic factor (GDNF) and/or brain-derived neurotrophic factor (BDNF) in both unlesioned and unilateral 6-hydroxydopamine lesioned rats. Lesioned rats that received two weeks of continuous unilateral STN DBS exhibited significant improvements in parkinsonian motor behaviors in tests of forelimb akinesia and rearing activity. Unilateral STN DBS did not increase GDNF in the nigrostriatal system, primary motor cortex (M1), or hippocampus of unlesioned rats. In contrast, unilateral STN DBS increased BDNF protein 2–3 fold bilaterally in the nigrostriatal system with the location (substantia nigra vs. striatum) dependent upon lesion status. Further, BDNF protein was bilaterally increased in M1 cortex by as much as 2 fold regardless of lesion status. STN DBS did not impact cortical regions that receive less input from the STN. STN DBS also was associated with bilateral increases in BDNF mRNA in the substantia nigra (SN) and internal globus pallidus (GPi). The increase observed in GPi was completely blocked by pretreatment with 5-Methyl-10,11-dihydro-5 H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), suggesting that the activation of N-methyl-D-aspartate (NMDA) receptors was involved in this phenomenon. The upregulation of BDNF associated with long term STN DBS suggest that this therapy may exert pronounced and underappreciated effects on plasticity in the basal ganglia circuitry that may play a role in the symptomatic effects of this therapy as well as support the neuroprotective effect of stimulation documented in this rat model. PMID:22328911

  20. An age-related shift of resting-state functional connectivity of the subthalamic nucleus: a potential mechanism for compensating motor performance decline in older adults

    PubMed Central

    Mathys, Christian; Hoffstaedter, Felix; Caspers, Julian; Caspers, Svenja; Südmeyer, Martin; Grefkes, Christian; Eickhoff, Simon B.; Langner, Robert

    2014-01-01

    Healthy aging is associated with decline in basic motor functioning and higher motor control. Here, we investigated age-related differences in the brain-wide functional connectivity (FC) pattern of the subthalamic nucleus (STN), which plays an important role in motor response control. As earlier studies revealed functional coupling between STN and basal ganglia, which both are known to influence the conservativeness of motor responses on a superordinate level, we tested the hypothesis that STN FC with the striatum becomes dysbalanced with age. To this end, we performed a seed-based resting-state analysis of fMRI data from 361 healthy adults (mean age: 41.8, age range: 18–85) using bilateral STN as the seed region of interest. Age was included as a covariate to identify regions showing age-related changes of FC with the STN seed. The analysis revealed positive FC of the STN with several previously described subcortical and cortical regions like the anterior cingulate and sensorimotor cortex, as well as not-yet reported regions including central and posterior insula. With increasing age, we observed reduced positive FC with caudate nucleus, thalamus, and insula as well as increased positive FC with sensorimotor cortex and putamen. Furthermore, an age-related reduction of negative FC was found with precuneus and posterior cingulate cortex. We suggest that this reduced de-coupling of brain areas involved in self-relevant but motor-unrelated cognitive processing (i.e. precuneus and posterior cingulate cortex) from the STN motor network may represent a potential mechanism behind the age-dependent decline in motor performance. At the same time, older adults appear to compensate for this decline by releasing superordinate motor control areas, in particular caudate nucleus and insula, from STN interference while increasing STN-mediated response control over lower level motor areas like sensorimotor cortex and putamen. PMID:25100995

  1. The Evaluation of PM2.5 Forecasts from Several Regional Air Quality Models Using Data from the ICARTT/NEAQS-2K4 Field Study

    NASA Astrophysics Data System (ADS)

    McKeen, S. A.; Hsie, E.; Grell, G.; Peckham, S.; Mathur, R.; Yu, S.; Gong, W.; Bouchet, V.; Menard, S.; Tang, Y.; Carmichael, G.

    2005-12-01

    Real-time air quality forecasts of aerosol PM2.5 for the Eastern U.S. and Southern Canada are currently available through a number forecast offices and research centers. This study presents results from an evaluation of six regional air quality models compared to surface data from the U.S. EPA AIRNow PM2.5 network and Speciation Trends Network (STN), as well as data collected during the ICARTT/NEAQS-2K4 field campaign from the NOAA WP-3 aircraft and Ronald H. Brown research vessel. The forecast models include two versions of the NOAA/FSL WRF/Chem model, a developmental version of the NWS/NCEP CMAQ/ETA model, the Canadian Meteorological Services CHRONOS and AURAMS models, and the University of Iowa STEM-2K3 model. Statistical evaluations of each model with the AIRNow PM2.5 network characterize the models' ability to forecast surface PM2.5 over a large region of Eastern North America for a seven-week period during the summer of 2004. The composition of aerosol PM2.5 is statistically evaluated by comparing model predicted PM2.5 sulfate, nitrate, ammonium, organic carbon and elemental carbon with aerosol compositional data from the aircraft, ship, and STN surface network. Several important conclusions have emerged from the analysis completed to date. Comparisons of model forecasts with surface AIRNow PM2.5 network data show that all models possess some skill in predicting daytime average PM2.5 levels when compared to simple persistence forecasts. An ensemble PM2.5 forecast, constructed by taking the geometric mean of the six forecasts, shows significant statistical improvement over any individual forecast. Comparisons of model forecasts with aerosol composition measurements from the W-P3 aircraft show that all models under-predict the organic carbon fraction of aerosol. SO2 oxidation rates downwind of urban centers are examined by comparing SO2/SO4 ratios between the models and WP-3 observations, and those models that include SO2 conversion to SO4 by cloud oxidation

  2. Adaptive autoregressive identification with spectral power decomposition for studying movement-related activity in scalp EEG signals and basal ganglia local field potentials

    NASA Astrophysics Data System (ADS)

    Foffani, Guglielmo; Bianchi, Anna M.; Priori, Alberto; Baselli, Giuseppe

    2004-09-01

    We propose a method that combines adaptive autoregressive (AAR) identification and spectral power decomposition for the study of movement-related spectral changes in scalp EEG signals and basal ganglia local field potentials (LFPs). This approach introduces the concept of movement-related poles, allowing one to study not only the classical event-related desynchronizations (ERD) and synchronizations (ERS), which correspond to modulations of power, but also event-related modulations of frequency. We applied the method to analyze movement-related EEG signals and LFPs contemporarily recorded from the sensorimotor cortex, the globus pallidus internus (GPi) and the subthalamic nucleus (STN) in a patient with Parkinson's disease who underwent stereotactic neurosurgery for the implant of deep brain stimulation (DBS) electrodes. In the AAR identification we compared the whale and the exponential forgetting factors, showing that the whale forgetting provides a better disturbance rejection and it is therefore more suitable to investigate movement-related brain activity. Movement-related power modulations were consistent with previous studies. In addition, movement-related frequency modulations were observed from both scalp EEG signals and basal ganglia LFPs. The method therefore represents an effective approach to the study of movement-related brain activity.

  3. Micropuncture study of hypertonic mannitol diuresis in the proximal and distal tubule of the dog kidney

    PubMed Central

    Seely, John F.; Dirks, John H.

    1969-01-01

    Fractional reabsorption of water, sodium, and potassium at proximal and distal tubular sites within the nephron was studied by recollection-micropuncture experiments on dogs undergoing hypertonic mannitol diuresis. After an initial control hydropenic phase, 16% mannitol in modified Ringer's solution was administered intravenously, resulting in marked increases in fractional excretion of water (28.7%), sodium (12.6%), and potassium (63.9%). Inulin clearance decreased significantly from 35.1 to 25.2 ml/min. Analysis of paired micropuncture data revealed a significant decrease in tubule fluid to plasma (TF:P) inulin ratios in both the proximal tubule (1.63-1.45) and distal tubule (5.38-1.94). There was also a significant decrease in proximal TF:P sodium ratios (0.99-0.93) and potassium ratios (1.05-0.98). Distal TF:P sodium ratios, in contrast, rose significantly (0.38-0.59), while TF:P potassium ratios tended towards unity whether initially greater or less than one. Fractional reabsorption of sodium and water decreased by 5% and 10% respectively in the proximal tubule, but to a lesser extent than the resulting increases in fractional urinary excretion. The nonreabsorbed fraction, however, had increased sharply at the point of distal puncture for water (32%), sodium (26%), and potassium (26%), indicating a large inhibitory effect within the loop of Henle in addition to the smaller proximal effects. PMID:5355344

  4. Advancements in Laparoscopic Partial Nephrectomy: Expanding the Feasibility of Nephron-Sparing

    PubMed Central

    Pietzak, Eugene J.; Guzzo, Thomas J.

    2012-01-01

    Partial nephrectomy (PN) offers equivalent oncologic outcomes to radical nephrectomy (RN) but has greater preservation of renal function and less risk of chronic kidney disease and cardiovascular disease. Laparoscopic PN remains underutilized likely because it is a technically challenging operation with higher rates of perioperative complications compared to open PN and laparoscopic RN. A review of the latest PN literature demonstrates that recent advancements in laparoscopic approaches, imaging modalities, ischemic mitigating strategies, renorrhaphy techniques, and hemostatic agents will likely allow greater utilization of LPN and expand its usage to increasingly more complex tumors. PMID:22645606

  5. Inhibition of K+ secretion in the distal nephron in nephrotic syndrome: possible role of albuminuria.

    PubMed

    Fila, Marc; Brideau, Gaëlle; Morla, Luciana; Cheval, Lydie; Deschênes, Georges; Doucet, Alain

    2011-07-15

    Nephrotic syndrome features massive proteinuria and retention of sodium which promotes ascite formation. In the puromycin aminonucleoside-induced rat model of nephrotic syndrome, sodium retention originates from the collecting duct where it generates a driving force for potassium secretion. However, there is no evidence for urinary potassium loss or hypokalaemia in the nephrotic syndrome. We therefore investigated the mechanism preventing urinary potassium loss in the nephrotic rats and, for comparison, in hypovolaemic rats, another model displaying increased sodium reabsorption in collecting ducts. We found that sodium retention is not associated with urinary loss of potassium in either nephrotic or hypovolaemic rats, but that different mechanisms account for potassium conservation in the two models. Collecting ducts from hypovolaemic rats displayed high expression of the potassium-secreting channel ROMK but no driving force for potassium secretion owing to low luminal sodium availability. In contrast, collecting ducts from nephrotic rats displayed a high driving force for potassium secretion but no ROMK. Down-regulation of ROMK in nephrotic rats probably stems from phosphorylation of ERK arising from the presence of proteins in the luminal fluid. In addition, nephrotic rats displayed a blunted capacity to excrete potassium when fed a potassium-rich diet, and developed hyperkalaemia. As nephrotic patients were found to display plasma potassium levels in the normal to high range, we would recommend not only a low sodium diet but also a controlled potassium diet for patients with nephrotic syndrome. PMID:21606114

  6. Distinct distribution of specific members of protein 4.1 genefamily in the mouse nephron

    SciTech Connect

    Ramez, Mohamed; Blot-Chabaud, Marcel; Cluzeaud, Francoise; Chanan, Sumita; Patterson, Michael; Walensky, Loren D.; Marfatia, Shirin; Baines, Anthony J.; Chasis, Joel A.; Conboy, John G.; Mohandas, Narla; Gascard, Philippe

    2002-12-11

    Background: Protein 4.1 is an adapter protein which linksthe actin cytoskeleton to various transmembrane proteins. 4.1 proteinsare encoded by four homologous genes, 4.1R, 4.1G, 4.1N, and 4.1B, whichundergo complex alternative splicing. Here we performed a detailedcharacterization of the expression of specific 4.1 proteins in the mousenephron. Methods: Distribution of renal 4.1 proteins was investigated bystaining of paraformaldehyde fixed mouse kidney sections with antibodieshighly specific for each 4.1 protein. Major 4.1 splice forms, amplifiedfrom mouse kidney marathon cDNA, were expressed in transfected COS-7cells in order to assign species of known exon composition to proteinsdetected in kidney. Results: A 105kDa4.1R splice form, initiating atATG-2 translation initiation site and lacking exon 16, but including exon17B, was restricted to thick ascending limb of Henle's loop. A 95kDa 4.1Nspliceform,lacking exons 15 and 17D, was expressed in either descendingor ascending thin limb of Henle'sloop, distal convoluted tubule and allregions of the collecting duct system. A major 108kDa 4.1B spliceform,initiating at a newly characterized ATG translation initiation site, andlacking exons 15, 17B, and 21, was present only in Bowman's capsule andproximal convoluted tubule (PCT). There was no expression of 4.1G inkidney. Conclusion: Distinct distribution of 4.1 proteins along thenephron suggests their involvement in targeting of selected transmembraneproteins in kidney epithelium andtherefore in regulation of specifickidney functions.

  7. Expression of the human nephron differentiation molecules in renal cell carcinomas.

    PubMed Central

    Droz, D.; Zachar, D.; Charbit, L.; Gogusev, J.; Chrétein, Y.; Iris, L.

    1990-01-01

    The authors tested frozen sections from 28 renal cell carcinomas (RCC)--21 clear, 1 eosinophilic, 4 basophilic, and 2 spindle-shaped cell type--with monoclonal antibodies (MAb) reacting against cytokeratin, vimentin, CD24, CALLA/CD10, villin, CD26, and HLA class I and class II molecules. These molecules are markers of specific segments of the mature kidney, and their loss or acquisition reflects the different steps of human nephrogenesis. KI67 MAb was used to evaluate cell-proliferating activity. All RCC cases expressed cytokeratin. Coexpression of vimentin was observed in 21 of 28 cases. Whether of clear or chromophilic type, all tumoral cells strongly expressed CD24 molecule, present on primitive blastema cells. All clear-type RCCs expressed CALLA/CD10 and 60% were also villin positive; some were faintly positive for CD26. CALLA, villin, and CD26 were not detected in basophilic cell type. HLA class I molecules were variably expressed in almost all cases, but HLA class II were never detected on tumoral cells. Except for the spindle-shaped population, cell-proliferating activity was low. These results favor the hypothesis that RCCs derive from cells that have 'recovered' the different options of metanephric differentiation. Clear cells show evidence of maturation toward proximal type, while basophilic cells do not. It would be of interest to evaluate the usefulness of serum measurements of villin and/or CALLA as markers in clear cell-type RCC. Images Figure 1 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:1699423

  8. Specialized expression of simple O-glycans along the rat kidney nephron.

    PubMed

    Toma, V; Zuber, C; Sata, T; Roth, J

    1999-11-01

    Glycosyltransferases can exhibit tissue-specific expression. By histochemistry glycosyltransferases and their products can be localized to specific cell types in organs of complex cellular composition. We have applied the lectin Amaranthin, having a nominal specificity for Galbeta1,3GalNAcR and Neu5Ac2,3Galbeta1, 3GalNAcalpha-R, and a monoclonal antibody raised against Galbeta1, 3GalNAcalphaR to examine the distribution of these simple O-glycans in adult rat kidney. The monoclonal antibody stained ascending thin limbs of Henle, distal convoluted tubules, and collecting ducts of cortex and outer medulla. Remarkably, the ascending thick limb of Henle, located between ascending thin limb and distal convoluted tubules, was unreactive. However, Amaranthin staining was detectable in ascending thick limbs of Henle, in addition to the structures positive with the monoclonal antibody. In kidney extracts, two bands of approximately 160 kDa and >210 kDa were reactive with both Amaranthin and the monoclonal antibody. One band at approximately 200 kDa, and a smear at approximately 100 kDa, were reactive only with Amaranthin. Our data show that in rat kidney simple O-linked glycans are expressed in a highly specialized manner along the renal tubule and can be detected only on a few glycoproteins. This may reflect a cell-type-specific expression of the corresponding glycosyltransferases. PMID:10536035

  9. Contemporary Issues Surrounding Small Renal Masses: Evaluation, Diagnostic Biopsy, Nephron Sparing, and Novel Treatment Modalities.

    PubMed

    Leone, Andrew R; Diorio, Gregory J; Spiess, Philippe E; Gilbert, Scott M

    2016-06-01

    Incidental identification of small renal masses (SRMs) has become increasingly common with widespread adoption of cross-sectional imaging. To date, early detection of SRMs has not translated to a substantial improvement in cancer-specific survival. Guidelines on the management of SRMs are evolving to reflect recent developments in treatment. The major approaches to managing SRMs include active surveillance, partial/radical nephrectomy, and ablative therapies, such as radiofrequency ablation with cryoablation. The goal of treatment is to optimize oncologic and renal function outcomes while avoiding overtreatment and associated morbidity. In this review, we summarize the diagnosis of SRMs, the role of renal mass biopsy, different treatment strategies, and future directions, including emerging molecular biomarkers. PMID:27323710

  10. Anaesthesia for autotransplantation after extracorporeal nephron sparing surgery for bilateral giant renal angiomyolipoma.

    PubMed

    Rajmohan, Nisha; Neeta, S; Das, Hk

    2014-01-01

    Extracorporeal 'work bench surgery' with subsequent autotransplantation is a challenge from both anaesthetic and surgical point of view when performed bilaterally or in a solitary kidney. A 28-year-old female with bilateral giant angiomyolipoma of kidneys was taken up for renal autotransplantation. Patient had a huge tumour, which was the largest reported exophytic tumour to be excised by this technique. Both kidneys were operated at an interval of 1 month, under combined general and epidural anaesthesia. Anaesthetic challenges faced during the procedure were maintenance of adequate perfusion of the grafted kidneys, containment of massive blood loss and coagulopathy during the perioperative period. Patient recovered in due course with functioning autotransplanted kidney. A careful pre-operative preparation with intraoperative maintenance of adequate blood volume and blood pressure is the key for graft survival. PMID:24700904

  11. Anaesthesia for autotransplantation after extracorporeal nephron sparing surgery for bilateral giant renal angiomyolipoma

    PubMed Central

    Rajmohan, Nisha; Neeta, S; Das, HK

    2014-01-01

    Extracorporeal ‘work bench surgery’ with subsequent autotransplantation is a challenge from both anaesthetic and surgical point of view when performed bilaterally or in a solitary kidney. A 28-year-old female with bilateral giant angiomyolipoma of kidneys was taken up for renal autotransplantation. Patient had a huge tumour, which was the largest reported exophytic tumour to be excised by this technique. Both kidneys were operated at an interval of 1 month, under combined general and epidural anaesthesia. Anaesthetic challenges faced during the procedure were maintenance of adequate perfusion of the grafted kidneys, containment of massive blood loss and coagulopathy during the perioperative period. Patient recovered in due course with functioning autotransplanted kidney. A careful pre-operative preparation with intraoperative maintenance of adequate blood volume and blood pressure is the key for graft survival. PMID:24700904

  12. Evaluation of real-time PM2.5 forecasts and process analysis for PM2.5 formation over the eastern United States using the Eta-CMAQ forecast model during the 2004 ICARTT study

    NASA Astrophysics Data System (ADS)

    Yu, Shaocai; Mathur, Rohit; Schere, Kenneth; Kang, Daiwen; Pleim, Jonathan; Young, Jeffrey; Tong, Daniel; Pouliot, George; McKeen, Stuart A.; Rao, S. T.

    2008-03-01

    The performance of the Eta-Community Multiscale Air Quality (CMAQ) modeling system in forecasting PM2.5 and chemical species is assessed over the eastern United States with the observations obtained by aircraft (NOAA P-3 and NASA DC-8) and four surface monitoring networks (AIRNOW, IMPROVE, CASTNet and STN) during the 2004 International Consortium for Atmospheric Research on Transport and Transformation (ICARTT) study. The results of the statistical analysis at the AIRNOW sites show that the model was able to reproduce the day-to-day and spatial variations of observed PM2.5 and captured a majority (73%) of PM2.5 observations within a factor of 2, with normalized mean bias of -21%. The consistent underestimations in regional PM2.5 forecast at other networks (IMPROVE and STN) were mainly due to the underestimation of total carbonaceous aerosols at both urban and rural sites. The significant underestimation of the "other" category, which predominantly is composed of primary emitted trace elements in the current model configuration, is also one of the reasons leading to the underestimation of PM2.5 at rural sites. The systematic overestimations of SO42- both at the surface sites and aloft, in part, suggest too much SO2 cloud oxidation due to the overestimation of SO2 and H2O2 in the model. The underestimation of NH4+ at the rural sites and aloft may be attributed to the exclusion of some sources of NH3 in the emission inventory. The systematic underestimations of NO3- may result from the general overestimations of SO42-. Note that there are compensating errors among the underestimation of PM2.5 species (such as total carbonaceous aerosols) and overestimation of PM2.5 species (such as SO42-), leading to generally better performance of PM2.5 mass. The systematic underestimation of biogenic isoprene (by ˜30%) and terpene (by a factor of 4) suggests that their biogenic emissions may have been biased low, whereas the consistent overestimations of toluene by the model under

  13. Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study.

    PubMed

    Stefurak, Taresa; Mikulis, David; Mayberg, Helen; Lang, Anthony E; Hevenor, Stephanie; Pahapill, Peter; Saint-Cyr, Jean; Lozano, Andres

    2003-12-01

    Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinson's disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36-year-old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High-frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level-dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmann's area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico-basal ganglionic systems that may converge in close proximity

  14. Neuropsychological functioning following bilateral subthalamic nucleus stimulation in Parkinson's disease.

    PubMed

    Morrison, C E; Borod, J C; Perrine, K; Beric, A; Brin, M F; Rezai, A; Kelly, P; Sterio, D; Germano, I; Weisz, D; Olanow, C W

    2004-03-01

    The cognitive effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) have been examined. However, there are no reported studies that evaluate, by incorporating a disease control group, whether neuropsychological performance in surgical patients changes beyond the variability of the assessment measures. To examine this issue, 17 PD patients were tested before and after bilateral STN stimulator implantation, both on and off stimulation. Eleven matched PD controls were administered the same repeatable neuropsychological test battery twice. Relative to changes seen in the controls, the surgery for electrode placement mildly adversely affected attention and language functions. STN stimulation, per se, had little effect on cognition. The STN DBS procedure as a whole resulted in a mild decline in delayed verbal recall and language functions. There were no surgery, stimulation, or procedure effects on depression scale scores. In contrast to these group findings, one DBS patient demonstrated significant cognitive decline following surgery. PMID:15010083

  15. The Urinary Phosphate to Serum Fibroblast Growth Factor 23 Ratio Is a Useful Marker of Atherosclerosis in Early-Stage Chronic Kidney Disease

    PubMed Central

    Yamada, Hodaka; Kuro-o, Makoto; Hara, Kazuo; Ueda, Yuichiro; Kusaka, Ikuyo; Kakei, Masafumi; Ishikawa, San-e

    2016-01-01

    Background Fibroblast growth factor 23 (FGF23) regulates mineral homeostasis. In developed renal dysfunction, FGF23 levels increase to maintain the phosphate excretion capacity. However, in diabetic patients with early-stage renal impairment, the FGF23 elevation is not very sensitive. We hypothesized that urinary phosphate (U-P)/serum FGF23 ratio would theoretically be an index that reflects the number of nephrons (nephron index). In this study, we determined whether the nephron index would be associated with renal function and vascular diseases in diabetic patients. Methods In total, 142 patients with diabetes mellitus were enrolled. The nephron index was calculated using the following formula: U-P (mg/day)/ serum FGF23 (pg/ml). Results The mean age was 63 ± 11 years and eGFR levels were 79.5 ± 25.4 ml/min/1.73 m2, respectively. Thirty patients had a medical history of macroangiopathy. The Nephron index was significantly decreased in subjects with macroangiopathy compared with those without macroangiopathy. A multivariate analysis of risk factors for macroangiopathy revealed that duration of diabetes, eGFR, and nephron index were significantly associated with a higher frequency of arteriosclerotic disease. Conclusion These findings suggest that a decrease in nephron index reflects early-stage renal impairment and is an independent risk factor of macroangiopathy in diabetic patients. PMID:27504998

  16. Depression and intelligence in patients with Parkinson's disease and deep-brain stimulation.

    PubMed

    Schadt, Courtney R; Cox, Katie L; Tramontana, Michael G; Byrne, Daniel W; Davis, Thomas L; Fang, John Y; Konrad, Peter E; Padaliya, Bhavna; Mutter, Robert W; Gill, Chandler E; Richardson, Caralee R; Charles, P David

    2006-07-01

    The goal of this study is to examine the association of depression with intelligence and education in patients with Parkinson's disease treated with bilateral subthalamic nucleus stimulation (STN-DBS). The literature has been contradictory concerning depression in Parkinson's disease patients. Some studies have shown less depression in Parkinson's disease patients with more education not treated with STN-DBS. Other recently published studies indicate that STN-DBS improves the depression associated with Parkinson's disease. No studies have examined the correlation of these factors with depression in Parkinson's disease patients treated with STN-DBS. We administered the Beck Depression Inventory (BDI) pre- and postoperatively to 21 Parkinson's disease patients (seven women, 14 men, ages 49-75) who underwent STN-DBS. The postoperative scores of the lower 50th percentile (n=8) of the Verbal Comprehensive Index of the Wechsler Adult Intelligence Scale (WAIS-III) decreased significantly (P=0.036), while the upper 50th percentile (n=13) remained nearly constant (P=0.802). Furthermore, as the education increased from highschool to graduate level, patients demonstrated less improvement in depressive symptoms postoperatively. These findings suggest that Parkinson's disease patients with lower intelligence test scores and less education benefit more with regards to depressive symptomatology after STN-DBS than patients with higher scores and education. PMID:16895282

  17. Submyelin potassium accumulation may functionally block subsets of local axons during deep brain stimulation: a modeling study

    NASA Astrophysics Data System (ADS)

    Bellinger, S. C.; Miyazawa, G.; Steinmetz, P. N.

    2008-09-01

    Deep brain stimulation has been used for over a decade to relieve the symptoms of Parkinson's disease, although its mechanism of action remains poorly understood. To better understand the direct effects of DBS on central neurons, a computational model of a myelinated axon has been constructed which includes the effects of K+ accumulation within the peri-axonal space. Using best estimates of anatomic and electrogenic model parameters for in vivo STN axons, the model predicts a functional block along the axon due to K+ accumulation in the submyelin space. The functional block occurs for a range of model parameters: high stimulation frequencies (>130 Hz); high extracellular K+ concentrations (>3 × 10-3 M); low maximum Na+/K+ ATPase current densities (<0.026 A m-2); low diffusion coefficients for K+ diffusion out of the submyelin space (<2.4 × 10-9 m2 s-1); small periaxonal space widths of the myelin attachment sections (<2.7 × 10-9 m) and perinodal/internodal sections (<8.4 × 10-9 m). These results suggest that therapeutic DBS of the STN likely results in a functional block for many STN axons, although a subset of STN axons may also be activated at the stimulating frequency.

  18. The subthalamic nucleus. Part I: development, cytology, topography and connections.

    PubMed

    Marani, Enrico; Heida, Tjitske; Lakke, Egbert A J F; Usunoff, Kamen G

    2008-01-01

    This monograph (Part I of two volumes) on the subthalamic nucleus (STN) accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections. The light and electron microscopical cytology focuses on the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses enzymes, NO, glial fibrillary acidic protein (GFAP), calcium binding proteins, and receptors (dopamine, cannabinoid, opioid, glutamate, gamma-aminobutyric acid (GABA), serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is also reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historical point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections. Part II of the two volumes (volume 199) on the subthalamic nucleus (STN) starts with a systemic model of the basal ganglia to evaluate the position of the STN in the direct, indirect and hyperdirect pathways. A summary of in vitro studies is given, describing STN spontaneous activity as well as responses to depolarizing and hyperpolarizing inputs and high-frequency stimulation. STN bursting activity and the underlying ionic mechanisms are investigated. Deep brain stimulation used for symptomatic treatment of Parkinson's disease is discussed in terms of the elements that are influenced and its hypothesized mechanisms. This part of the monograph explores the pedunculopontine-subthalamic connections and summarizes attempts to mimic neurotransmitter actions of the pedunculopontine nucleus in cell cultures and high-frequency stimulation on cultured dissociated rat subthalamic neurons. STN cell models--single- and multi-compartment models and system-level models are discussed in relation to subthalamic function and dysfunction. Parts I and II are compared. PMID:18727483

  19. The subthalamic nucleus part II: modelling and simulation of activity.

    PubMed

    Heida, Tjitske; Marani, Enrico; Usunoff, Kamen G

    2008-01-01

    Part I of The Subthalamic Nucleus (volume 198) (STN) accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections.The light and electron microscopical cytology focuses on the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses enzymes, NO, glial fibrillary acidic protein (GFAP), calcium binding proteins, and receptors (dopamine, cannabinoid, opioid, glutamate, gamma-aminobutyric acid (GABA), serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is also reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historical point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections. This monograph (Part II of the two volumes) on the subthalamic nucleus (STN) starts with a systemic model of the basal ganglia to evaluate the position of the STN in the direct, indirect and hyperdirect pathways. A summary of in vitro studies is given, describing STN spontaneous activity as well as responses to depolarizing and hyperpolarizing inputs and high-frequency stimulation. STN bursting activity and the underlying ionic mechanisms are investigated. Deep brain stimulation used for symptomatic treatment of Parkinson's disease is discussed in terms of the elements that are influenced and its hypothesized mechanisms. This part of the monograph explores the pedunculopontine-subthalamic connections and summarizes attempts to mimic neurotransmitter actions of the pedunculopontine nucleus in cell cultures and high-frequency stimulation on cultured dissociated rat subthalamic neurons. STN cell models - single- and multi-compartment models and system-level models are discussed in relation to subthalamic function and dysfunction. Parts I and II are compared. PMID:18727495

  20. Metanephric kidney development in the chicken embryo: Glomerular numbers, characteristics and perfusion.

    PubMed

    Bolin, Greta; Burggren, Warren W

    2013-10-01

    The developing metanephric kidneys and chorioallantoic membrane (CAM) work in unison to ensure ion and water homeostasis in the avian embryo within its egg. This study focused on how avian renal structure and glomerular perfusion change in concert during development, as well as on changes in body fluid compartment osmolalities. White leghorn chicken eggs were incubated at 37.5°C and 55-60% relative humidity and were examined during days (D) 10-18 of development. Alcian blue, a stain that forms solid aggregations in actively perfused glomeruli of the metanephric kidney, was used to identify the proportion of glomeruli actually perfused. Total nephron number increased from 4705±1599 nephrons/kidney on day 12 to 39,825±3051 nephrons/kidney on day 18. Actively perfused nephrons increased ~23-fold from 761±481 nephrons/kidney on day 12 (~16% of total nephrons) to 17,313±2750 nephrons/kidney on 18 (~43% of total nephrons). Glomerular volume increased from days 12 to 14, remaining constant thereafter. Blood and cloacal fluid osmolality ranged from 270 to 280 mOsm/L. Amniotic fluid osmolality changed in a complex fashion during development but was comparable to blood on days 10 and 18. Allantoic fluid had the lowest osmolalities (175-215 mOsm/L) across development. Uric acid increased steadily within the allantoic fluid compartment, from 36±1mmol/L to 63±4mmol/L. The avian metanephric kidney thus shows a dramatic increase in both recruitment of nephrons and potential filtering capacity during the last half of incubation, in preparation for the degeneration of the allantoic membranes prior to internal piping and subsequent hatching. PMID:23850715

  1. Uranium microdistribution in renal cortex of rats after chronic exposure: a study by secondary ion mass spectrometry microscopy.

    PubMed

    Tessier, Christine; Suhard, David; Rebière, François; Souidi, Maâmar; Dublineau, Isabelle; Agarande, Michelle

    2012-02-01

    For a few years, the biological effects on ecosystems and the public of the bioaccumulation of radionuclides in situations of chronic exposures have been studied. This work, in keeping with the ENVIRHOM French research program, presents the uranium microdistribution by secondary ion mass spectrometry (SIMS) technique in the renal cortex of rats following chronic exposure to this low level element in the drinking water (40 mg/L) as a function to exposure duration (6, 9, 12, and 18 months). The SIMS mass spectra and 238U+ ion images produced with a SIMS CAMECA 4F-E7 show the kinetic of uranium accumulation in the different structures of the kidney. For the rats contaminated up to 12 months, the radioelement is mainly fixed in the proximal tubules; then after 18 exposure months, uranium is detected in all the segments of the nephron. This work has also shown that ion microscopy is an analytical method to detect trace elements and give elemental cartography at the micrometer scale. PMID:22217926

  2. Identification of (2S,3S)-β-Methyltryptophan as the Real Biosynthetic Intermediate of Antitumor Agent Streptonigrin

    PubMed Central

    Kong, Dekun; Zou, Yi; Zhang, Zhang; Xu, Fei; Brock, Nelson L.; Zhang, Liping; Deng, Zixin; Lin, Shuangjun

    2016-01-01

    Streptonigrin is a potent antitumor antibiotic, active against a wide range of mammalian tumor cells. It was reported that its biosynthesis relies on (2S,3R)-β-methyltryptophan as an intermediate. In this study, the biosynthesis of (2S,3R)-β-methyltryptophan and its isomer (2S,3S)-β-methyltryptophan by enzymes from the streptonigrin biosynthetic pathway is demonstrated. StnR is a pyridoxal 5′-phosphate (PLP)-dependent aminotransferase that catalyzes a transamination between L-tryptophan and β-methyl indolepyruvate. StnQ1 is an S-adenosylmethionine (SAM)-dependent C-methyltransferase and catalyzes β-methylation of indolepyruvate to generate (R)-β-methyl indolepyruvate. Although StnR exhibited a significant preference for (S)-β-methyl indolepyruvate over the (R)-epimer, StnQ1 and StnR together catalyze (2S,3R)-β-methyltryptophan formation from L-tryptophan. StnK3 is a cupin superfamily protein responsible for conversion of (R)-β-methyl indolepyruvate to its (S)-epimer and enables (2S,3S)-β-methyltryptophan biosynthesis from L-tryptophan when combined with StnQ1 and StnR. Most importantly, (2S,3S)-β-methyltryptophan was established as the biosynthetic intermediate of the streptonigrin pathway by feeding experiments with a knockout mutant, contradicting the previous proposal that stated (2S,3R)-β-methyltryptophan as the intermediate. These data set the stage for the complete elucidation of the streptonigrin biosynthetic pathway, which would unlock the potential of creating new streptonigrin analogues by genetic manipulation of the biosynthetic machinery. PMID:26847951

  3. Mismatch negativity-like potential (MMN-like) in the subthalamic nuclei in Parkinson's disease patients.

    PubMed

    Minks, Eduard; Jurák, Pavel; Chládek, Jan; Chrastina, Jan; Halámek, Josef; Shaw, Daniel J; Bareš, Martin

    2014-12-01

    An infrequent change to an otherwise repetitive sequence of stimuli leads to the generation of mismatch negativity (MMN), even in the absence of attention. This evoked negative response occurs in the scalp-recorded electroencephalogram (EEG) over the temporal and frontal cortices, 100-250 ms after onset of the deviant stimulus. The MMN is used to detect sensory information processing. The aim of our study was to investigate whether MMN can be recorded in the subthalamic nuclei (STN) as evidence of auditory information processing on an unconscious level within this structure. To our knowledge, MMN has never been recorded in the human STN. We recorded intracerebral EEG using a MMN paradigm in five patients with Parkinson's disease (PD) who were implanted with depth electrodes in the subthalamic nuclei (STN). We found far-field MMN when intracerebral contacts were connected to an extracranial reference electrode. In all five PD patients (and nine of ten intracerebral electrodes), we also found near-field MMN-like potentials when intracerebral contacts were referenced to one another, and in some electrodes, we observed phase reversals in these potentials. The mean time-to-peak latency of the intracerebral MMN-like potentials was 214 ± 38 ms (median 219 ms). We reveal MMN-like potentials in bilateral STN. This finding provides evidence that STN receives sensory (auditory) information from other structures. The question for further research is whether STN receives such signals through a previously described hyperdirect pathway between STN and frontal cortex (a known generator of the MMN potential) and if the STN contributes to sensorimotor integration. PMID:24809684

  4. Continuous bilateral infusion of vigabatrin into the subthalamic nucleus: Effects on seizure threshold and GABA metabolism in two rat models.

    PubMed

    Gey, Laura; Gernert, Manuela; Löscher, Wolfgang

    2016-07-01

    The subthalamic nucleus (STN) plays a crucial role as a regulator of basal ganglia outflow but also influences the activity of cortical and limbic structures, so that it is widely used as a therapeutic target in different brain diseases, including epilepsy. In addition to electrical stimulation of the STN, targeted delivery of anti-seizure drugs to the STN may constitute an alternative treatment approach in patients with pharmacoresistant epilepsy. In the present experimental study, we investigated the anti-seizure and adverse effects of chronic infusion of vigabatrin into the STN of rats. Vigabatrin is a clinically approved anti-seizure drug, which acts by increasing brain GABA levels by irreversibly inhibiting GABA-aminotransferase (GABA-T). Based on functional and neurochemical effects of acute STN microinjection, doses for continuous infusion were calculated and administered, using an innovative drug infusion technology. Bilateral infusion of only 10μg/day vigabatrin over 3weeks into the STN resulted in an almost complete inhibition of GABA-T and 4-fold increase in GABA in the target region, which was associated with a significant increase in seizure threshold, determined once weekly by i.v. infusion of pentylenetetrazole (PTZ). Lower doses or unilateral infusion were less effective, both on PTZ seizures and on kindled seizures. Bilateral infusion into substantia nigra pars reticulata was less effective and more toxic than STN infusion. In part of the rats, tolerance to the anti-seizure effect developed. The data demonstrate that chronic administration of very low, nontoxic doses of vigabatrin into STN is an effective means of increasing local GABA concentrations and seizure threshold. PMID:26976738

  5. Effects of Deep Brain Stimulation and Medication on Strength, Bradykinesia, and Electromyographic Patterns of the Ankle Joint in Parkinson’s Disease

    PubMed Central

    Vaillancourt, David E.; Prodoehl, Janey; Sturman, Molly M.; Bakay, Roy A.E.; Metman, Leo Verhagen; Corcos, Daniel M.

    2008-01-01

    We investigated the control of movement in 12 patients with Parkinson’s disease (PD) after they received surgically implanted high-frequency stimulating electrodes in the subthalamic nucleus (STN). The experiment studied ankle strength, movement velocity, and the associated electromyographic patterns in PD patients, six of whom had tremor at the ankle. The patients were studied off treatment, ON STN deep brain stimulation (DBS), on medication, and on medication plus STN DBS. Twelve matched control subjects were also examined. Medication alone and STN DBS alone increased patients’ ankle strength, ankle velocity, agonist muscle burst amplitude, and agonist burst duration, while reducing the number of agonist bursts during movement. These findings were similar for PD patients with and without tremor. The combination of medication plus STN DBS normalized maximal strength at the ankle joint, but ankle movement velocity and electromyographic patterns were not normalized. The findings are the first to demonstrate that STN DBS and medication increase strength and movement velocity at the ankle joint. PMID:16124011

  6. Effects of Deep Brain Stimulation on Pausing During Spontaneous Speech in Parkinson’s Disease

    PubMed Central

    Ahn, Ji Sook; Van Lancker Sidtis, Diana; Sidtis, John J.

    2016-01-01

    The present study examined pausing patterns in spontaneous speech as a measure of the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on parkinsonian speech. Pauses reflect various aspects of speech and language processes, including motor initiation and linguistic planning. Relatively little attention has been given to pauses in determining the effect of STN-DBS. An examination of pausing may be helpful to understanding how this form of therapy affects these behaviors. Seven individuals with Parkinson’s disease who received surgery for bilateral STN-DBS participated. Spontaneous speech samples were elicited in both the ON and OFF STN-DBS condition. Findings indicated that long pauses (250–3000 ms) in spontaneous speech were significantly shorter and more frequent in the STN-DBS ON condition. Furthermore, the proportion of nonlinguistic boundary pauses was significantly greater with stimulation. The findings support previous studies suggesting that speech motor control and lexical retrieval may be affected by STN-DBS. PMID:26848252

  7. Neuropsychology Review Submission

    PubMed Central

    Rossi, P. Justin; Okun, Michael S.

    2016-01-01

    It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson’s disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN. PMID:26577509

  8. The Subthalamic Nucleus, Limbic Function, and Impulse Control.

    PubMed

    Rossi, P Justin; Gunduz, Aysegul; Okun, Michael S

    2015-12-01

    It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson's disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN. PMID:26577509

  9. Influence of propofol and fentanyl on deep brain stimulation of the subthalamic nucleus.

    PubMed

    Kim, Wonki; Song, In Ho; Lim, Yong Hoon; Kim, Mi-Ryoung; Kim, Young Eun; Hwang, Jae Ha; Kim, In Keyoung; Song, Sang Woo; Kim, Jin Wook; Lee, Woong-Woo; Kim, Han-Joon; Kim, Cheolyoung; Kim, Hee Chan; Kim, In Young; Park, Hee Pyoung; Kim, Dong Gyu; Jeon, Beom Seok; Paek, Sun Ha

    2014-09-01

    We investigated the effect of propofol and fentanyl on microelectrode recording (MER) and its clinical applicability during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. We analyzed 8 patients with Parkinson's disease, underwent bilateral STN DBS with MER. Their left sides were done under awake and then their right sides were done with a continuous infusion of propofol and fentanyl under local anesthesia. The electrode position was evaluated by preoperative MRI and postoperative CT. The clinical outcomes were assessed at six months after surgery. We isolated single unit activities from the left and the right side MERs. There was no significant difference in the mean firing rate between the left side MERs (38.7 ± 16.8 spikes/sec, n=78) and the right side MERs (35.5 ± 17.2 spikes/sec, n=66). The bursting pattern of spikes was more frequently observed in the right STN than in the left STN. All the electrode positions were within the STNs on both sides and the off-time Unified Parkinson's Disease Rating Scale part III scores at six months after surgery decreased by 67% of the preoperative level. In this study, a continuous infusion of propofol and fentanyl did not significantly interfere with the MER signals from the STN. The results of this study suggest that propofol and fentanyl can be used for STN DBS in patients with advanced Parkinson's disease improving the overall experience of the patients. PMID:25246748

  10. Three-dimensional SPACE fluid-attenuated inversion recovery at 3 T to improve subthalamic nucleus lead placement for deep brain stimulation in Parkinson's disease: from preclinical to clinical studies.

    PubMed

    Senova, Suhan; Hosomi, Koichi; Gurruchaga, Jean-Marc; Gouello, Gaëtane; Ouerchefani, Naoufel; Beaugendre, Yara; Lepetit, Hélène; Lefaucheur, Jean-Pascal; Badin, Romina Aron; Dauguet, Julien; Jan, Caroline; Hantraye, Philippe; Brugières, Pierre; Palfi, Stéphane

    2016-08-01

    OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established therapy for motor symptoms in patients with pharmacoresistant Parkinson's disease (PD). However, the procedure, which requires multimodal perioperative exploration such as imaging, electrophysiology, or clinical examination during macrostimulation to secure lead positioning, remains challenging because the STN cannot be reliably visualized using the gold standard, T2-weighted imaging (T2WI) at 1.5 T. Thus, there is a need to improve imaging tools to better visualize the STN, optimize DBS lead implantation, and enlarge DBS diffusion. METHODS Gradient-echo sequences such as those used in T2WI suffer from higher distortions at higher magnetic fields than spin-echo sequences. First, a spin-echo 3D SPACE (sampling perfection with application-optimized contrasts using different flip angle evolutions) FLAIR sequence at 3 T was designed, validated histologically in 2 nonhuman primates, and applied to 10 patients with PD; their data were clinically compared in a double-blind manner with those of a control group of 10 other patients with PD in whom STN targeting was performed using T2WI. RESULTS Overlap between the nonhuman primate STNs segmented on 3D-histological and on 3D-SPACE-FLAIR volumes was high for the 3 most anterior quarters (mean [± SD] Dice scores 0.73 ± 0.11, 0.74 ± 0.06, and 0.60 ± 0.09). STN limits determined by the 3D-SPACE-FLAIR sequence were more consistent with electrophysiological edges than those determined by T2WI (0.9 vs 1.4 mm, respectively). The imaging contrast of the STN on the 3D-SPACE-FLAIR sequence was 4 times higher (p < 0.05). Improvement in the Unified Parkinson's Disease Rating Scale Part III score (off medication, on stimulation) 12 months after the operation was higher for patients who underwent 3D-SPACE-FLAIR-guided implantation than for those in whom T2WI was used (62.2% vs 43.6%, respectively; p < 0.05). The total electrical energy

  11. Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson's disease.

    PubMed

    Serranová, Tereza; Jech, Robert; Dušek, Petr; Sieger, Tomáš; Růžička, Filip; Urgošík, Dušan; Růžička, Evžen

    2011-10-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty-four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS-related sensitivity to food reward stimuli cues might drive DBS-treated patients to higher food intake and subsequent weight gain. PMID:21780183

  12. 2NH and 3OH are crucial structural requirements in sphingomyelin for sticholysin II binding and pore formation in bilayer membranes.

    PubMed

    Maula, Terhi; Isaksson, Y Jenny E; García-Linares, Sara; Niinivehmas, Sanna; Pentikäinen, Olli T; Kurita, Mayuko; Yamaguchi, Shou; Yamamoto, Tetsuya; Katsumura, Shigeo; Gavilanes, José G; Martínez-del-Pozo, Alvaro; Slotte, J Peter

    2013-05-01

    Sticholysin II (StnII) is a pore-forming toxin from the sea anemone Stichodactyla heliantus which belongs to the large actinoporin family. The toxin binds to sphingomyelin (SM) containing membranes, and shows high binding specificity for this lipid. In this study, we have examined the role of the hydrogen bonding groups of the SM long-chain base (i.e., the 2NH and the 3OH) for StnII recognition. We prepared methylated SM-analogs which had reduced hydrogen bonding capability from 2NH and 3OH. Both surface plasmon resonance experiments, and isothermal titration calorimetry measurements indicated that StnII failed to bind to bilayers containing methylated SM-analogs, whereas clear binding was seen to SM-containing bilayers. StnII also failed to induce calcein release (i.e., pore formation) from vesicles made to contain methylated SM-analogs, but readily induced calcein release from SM-containing vesicles. Molecular modeling of SM docked to the phosphocholine binding site of StnII indicated that the 2NH and 3OH groups were likely to form a hydrogen bond with Tyr135. In addition, it appeared that Tyr111 and Tyr136 could donate hydrogen bonds to phosphate oxygen, thus stabilizing SM binding to the toxin. We conclude that the interfacial hydrogen bonding properties of SM, in addition to the phosphocholine head group, are crucial for high-affinity SM/StnII-interaction. PMID:23376330

  13. Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson's disease

    PubMed Central

    Ludwig, Janne; Remien, Piet; Guballa, Christoph; Binder, Andreas; Binder, Sabine; Schattschneider, Jörn; Herzog, Jan; Volkmann, Jens; Deuschl, Günther; Wasner, Gunnar; Baron, Ralf

    2007-01-01

    Dysfunctions of the autonomic nervous system (ANS) are common in Parkinson's disease (PD). Regarding motor disability, deep brain stimulation of the subthalamic nucleus (STN) is an effective treatment option in long lasting PD. The aims of this study were to examine whether STN stimulation has an influence on functions of the ANS and to compare these effects to those induced by levodopa. Blood pressure (BP) and heart rate (HR) during rest and orthostatic conditions, HR variability (HRV) and breathing‐induced cutaneous sympathetic vasoconstriction (CVC) were tested in 14 PD patients treated with STN stimulation during “ON” and “OFF” condition of the stimulator. The effects of a single dose of levodopa on ANS were tested in 15 PD patients without DBS. STN stimulation had no influence on cardiovascular ANS functions, whereas CVC was significantly increased. In contrast, levodopa significantly lowered BP and HR at rest and enhanced orthostatic hypotension. Further, HRV, skin perfusion and temperature increased after administration of levodopa. Our results suggest that in contrast to levodopa, STN stimulation has only minor effects on autonomic functions. Since less pharmacotherapy is needed after STN stimulation, reduced levodopa intake results in relative improvement of autonomic function in deep brain stimulated PD patients. PMID:17371906

  14. Evaluation of MODIS surrogates for meteorological humidity data in east Africa.

    PubMed

    Lin, Shengpan; Moore, Nathan J; Messina, Joseph P; Wu, Jiaping

    2013-01-01

    Satellite remote sensing technology has shown promising results in characterizing the environment in which plants and animals thrive. Remote sensing scientists, biologists, and epidemiologists are adopting remotely sensed imagery to compensate for the paucity of weather information measured by weather stations. With measured humidity from three stations as baselines, our study reveals that Normalised Difference Vegetation Index (NDVI) and atmosphere saturation deficits at the 780 hPa pressure level (D MODIS), both of which were derived from the MODerate-resolution Imaging Spectroradiometer (MODIS) sensor, were significantly correlated with station saturation deficits (D stn)(ȣrȣ = 0.42-0.63, p < 0.001). These metrics have the potential to estimate saturation deficits over east Africa. Four to nine days of lags were found in the NDVI responding to D stn. For the daily estimations of D stn, D MODIS had a better performance than the NDVI. However, both of them poorly explained the variances in daily D stn using simple regression models (adj. R (2) = 0.17-0.39). When the estimation temporal scale was changed to 16-day, their performances were similar, and both were better than daily estimations. For D stn estimations at coarser geographic scales, given that many factors such as soil, vegetation, slope, aspect, and wind speed might complicate the NDVI response lags and model construction, D MODIS is more favourable as a proxy of the saturation deficit over ground due to its simple relationship with D stn. PMID:23956475

  15. Whole-genome association study identifies STK39 as a hypertension susceptibility gene

    PubMed Central

    Wang, Ying; O'Connell, Jeffrey R.; McArdle, Patrick F.; Wade, James B.; Dorff, Sarah E.; Shah, Sanjiv J.; Shi, Xiaolian; Pan, Lin; Rampersaud, Evadnie; Shen, Haiqing; Kim, James D.; Subramanya, Arohan R.; Steinle, Nanette I.; Parsa, Afshin; Ober, Carole C.; Welling, Paul A.; Chakravarti, Aravinda; Weder, Alan B.; Cooper, Richard S.; Mitchell, Braxton D.; Shuldiner, Alan R.; Chang, Yen-Pei C.

    2009-01-01

    Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39. We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n = 7,125, P < 10−6). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cell-based functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na+ excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway. PMID:19114657

  16. The effects of high frequency subthalamic stimulation on balance performance and fear of falling in patients with Parkinson's disease

    PubMed Central

    Nilsson, Maria H; Fransson, Per-Anders; Jarnlo, Gun-Britt; Magnusson, Måns; Rehncrona, Stig

    2009-01-01

    Background Balance impairment is one of the most distressing symptoms in Parkinson's disease (PD) even with pharmacological treatment (levodopa). A complementary treatment is high frequency stimulation in the subthalamic nucleus (STN). Whether STN stimulation improves postural control is under debate. The aim of this study was to explore the effects of STN stimulation alone on balance performance as assessed with clinical performance tests, subjective ratings of fear of falling and posturography. Methods Ten patients (median age 66, range 59–69 years) with bilateral STN stimulation for a minimum of one year, had their anti-PD medications withdrawn overnight. Assessments were done both with the STN stimulation turned OFF and ON (start randomized). In both test conditions, the following were assessed: motor symptoms (descriptive purposes), clinical performance tests, fear of falling ratings, and posturography with and without vibratory proprioceptive disturbance. Results STN stimulation alone significantly (p = 0.002) increased the scores of the Berg balance scale, and the median increase was 6 points. The results of all timed performance tests, except for sharpened Romberg, were significantly (p ≤ 0.016) improved. The patients rated their fear of falling as less severe, and the total score of the Falls-Efficacy Scale(S) increased (p = 0.002) in median with 54 points. All patients completed posturography when the STN stimulation was turned ON, but three patients were unable to do so when it was turned OFF. The seven patients with complete data showed no statistical significant difference (p values ≥ 0.109) in torque variance values when comparing the two test situations. This applied both during quiet stance and during the periods with vibratory stimulation, and it was irrespective of visual input and sway direction. Conclusion In this sample, STN stimulation alone significantly improved the results of the clinical performance tests that mimic activities in

  17. Genomics of chromophobe renal cell carcinoma: implications from a rare tumor for pan-cancer studies

    PubMed Central

    Rathmell, Kimryn W.; Chen, Fengju; Creighton, Chad J.

    2015-01-01

    Chromophobe Renal Cell Carcinoma (ChRCC) is a rare subtype of the renal cell carcinomas, a heterogenous group of cancers arising from the nephron. Recently, The Cancer Genome Atlas (TCGA) profiled this understudied disease using multiple data platforms, including whole exome sequencing, whole genome sequencing (WGS), and mitochondrial DNA (mtDNA) sequencing. The insights gained from this study would have implications for other types of kidney cancer as well as for cancer biology in general. Global molecular patterns in ChRCC provided clues as to this cancer's cell of origin, which is distinct from that of the other renal cell carcinomas, illustrating an approach that might be applied towards elucidating the cell of origin of other cancer types. MtDNA sequencing revealed loss-of-function mutations in NADH dehydrogenase subunits, highlighting the role of deregulated metabolism in this and other cancers. Analysis of WGS data led to the discovery of recurrent genomic rearrangements involving TERT promoter region, which were associated with very high expression levels of TERT, pointing to a potential mechanism for TERT deregulation that might be found in other cancers. WGS data, generated by large scale efforts such as TCGA and the International Cancer Genomics Consortium (ICGC), could be more extensively mined across various cancer types, to uncover structural variants, mtDNA mutations, themes of tumor metabolic properties, as well as noncoding point mutations. TCGA's data on ChRCC should continue to serve as a resource for future pan-cancer as well as kidney cancer studies, and highlight the value of investigations into rare tumor types to globally inform principals of cancer biology. PMID:25859550

  18. Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors.

    PubMed

    Sagarduy, A; Llorente, J; Miguelez, C; Morera-Herreras, T; Ruiz-Ortega, J A; Ugedo, L

    2016-03-01

    The most effective treatment for Parkinson's disease (PD), l-DOPA, induces dyskinesia after prolonged use. We have previously shown that in 6-hydroxydopamine (6-OHDA) lesioned rats rendered dyskinetic by prolonged l-DOPA administration, lesion of the subthalamic nucleus (STN) reduces not only dyskinesias but also buspirone antidyskinetic effect. This study examined the effect of buspirone on STN neuron activity. Cell-attached recordings in parasagittal slices from naïve rats showed that whilst serotonin excited the majority of STN neurons, buspirone showed an inhibitory main effect but only in 27% of the studied cells which was prevented by the 5-HT1A receptor selective antagonist WAY-100635. Conversely, single-unit extracellular recordings were performed in vivo on STN neurons from four different groups, i.e., control, chronically treated with l-DOPA, 6-OHDA lesioned and lesioned treated with l-DOPA (dyskinetic) rats. In control animals, systemic-buspirone administration decreased the firing rate in a dose-dependent manner in every cell studied. This effect, prevented by WAY-100635, was absent in 6-OHDA lesioned rats and was not modified by prolonged l-DOPA administration. Altogether, buspirone in vivo reduces consistently the firing rate of the STN neurons through 5-HT1A receptors whereas ex vivo buspirone seems to affect only a small population of STN neurons. Furthermore, the lack of effect of buspirone in 6-OHDA lesioned rats, suggests the requirement of not only the activation of 5-HT1A receptors but also an intact nigrostriatal pathway for buspirone to inhibit the STN activity. PMID:26687972

  19. Cognition and Depression Following Deep Brain Stimulation of the Subthalamic Nucleus and Globus Pallidus Pars Internus in Parkinson's Disease: A Meta-Analysis.

    PubMed

    Combs, Hannah L; Folley, Bradley S; Berry, David T R; Segerstrom, Suzanne C; Han, Dong Y; Anderson-Mooney, Amelia J; Walls, Brittany D; van Horne, Craig

    2015-12-01

    Parkinson's disease (PD) is a common, degenerative disorder of the central nervous system. Individuals experience predominantly extrapyramidal symptoms including resting tremor, rigidity, bradykinesia, gait abnormalities, cognitive impairment, depression, and neurobehavioral concerns. Cognitive impairments associated with PD are diverse, including difficulty with attention, processing speed, executive functioning, memory recall, visuospatial functions, word-retrieval, and naming. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is FDA approved and has been shown to be effective in reducing motor symptoms of PD. Studies have found that stimulating STN and GPi are equally effective at improving motor symptoms and dyskinesias; however, there has been discrepancy as to whether the cognitive, behavioral, and mood symptoms are affected differently between the two targets. The present study used random-effects meta-analytic models along with a novel p-curve analytic procedure to compare the potential cognitive and emotional impairments associated with STN-DBS in the current literature to those associated with GPi-DBS. Forty-one articles were reviewed with an aggregated sample size of 1622 patients. Following STN-DBS, small declines were found in psychomotor speed, memory, attention, executive functions, and overall cognition; and moderate declines were found in both semantic and phonemic fluency. However, GPi-DBS resulted in fewer neurocognitive declines than STN-DBS (small declines in attention and small-moderate declines in verbal fluency). With regards to its effect on depression symptomatology, both GPi-DBS and STN-DBS resulted in lower levels of depressive symptoms post-surgery. From a neurocognitive standpoint, both GPi-DBS and STN-DBS produce subtle cognitive declines but appears to be relatively well tolerated. PMID:26459361

  20. No Effect of Subthalamic Deep Brain Stimulation on Intertemporal Decision-Making in Parkinson Patients123

    PubMed Central

    Wojtecki, Lars; Storzer, Lena; Schnitzler, Alfons

    2016-01-01

    Abstract Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for the motor symptoms of Parkinson’s disease (PD). DBS or pharmacological treatment is believed to modulate the tendency to, or reverse, impulse control disorders. Several brain areas involved in impulsivity and reward valuation, such as the prefrontal cortex and striatum, are linked to the STN, and activity in these areas might be affected by STN-DBS. To investigate the effect of STN-DBS on one type of impulsive decision-making—delay discounting (i.e., the devaluation of reward with increasing delay until its receipt)—we tested 40 human PD patients receiving STN-DBS treatment and medication for at least 3 months. Patients were pseudo-randomly assigned to one of four groups to test the effects of DBS on/off states as well as medication on/off states on delay discounting. The delay-discounting task consisted of a series of choices among a smaller. sooner or a larger, later monetary reward. Despite considerable effects of DBS on motor performance, patients receiving STN-DBS did not choose more or less impulsively compared with those in the off-DBS group, as well as when controlling for risk attitude. Although null results have to be interpreted with caution, our findings are of significance to other researchers studying the effects of PD treatment on impulsive decision-making, and they are of clinical relevance for determining the therapeutic benefits of using STN-DBS. PMID:27257622

  1. A novel lead design enables selective deep brain stimulation of neural populations in the subthalamic region

    NASA Astrophysics Data System (ADS)

    van Dijk, Kees J.; Verhagen, Rens; Chaturvedi, Ashutosh; McIntyre, Cameron C.; Bour, Lo J.; Heida, Ciska; Veltink, Peter H.

    2015-08-01

    Objective. The clinical effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) as a treatment for Parkinson’s disease are sensitive to the location of the DBS lead within the STN. New high density (HD) lead designs have been created which are hypothesized to provide additional degrees of freedom in shaping the stimulating electric field. The objective of this study is to compare the performances of a new HD lead with a conventional cylindrical contact (CC) lead. Approach. A computational model, consisting of a finite element electric field model combined with multi-compartment neuron and axon models representing different neural populations in the subthalamic region, was used to evaluate the two leads. We compared ring-mode and steering-mode stimulation with the HD lead to single contact stimulation with the CC lead. These stimulation modes were tested for the lead: (1) positioned in the centroid of the STN, (2) shifted 1 mm towards the internal capsule (IC), and (3) shifted 2 mm towards the IC. Under these conditions, we quantified the number of STN neurons that were activated without activating IC fibers, which are known to cause side-effects. Main results. The modeling results show that the HD lead is able to mimic the stimulation effect of the CC lead. Additionally, in steering-mode stimulation there was a significant increase of activated STN neurons compared to the CC mode. Significance. From the model simulations we conclude that the HD lead in steering-mode with optimized stimulation parameter selection can stimulate more STN cells. Next, the clinical impact of the increased number of activated STN cells should be tested and balanced across the increased complexity of identifying the optimized stimulation parameter settings for the HD lead.

  2. No Effect of Subthalamic Deep Brain Stimulation on Intertemporal Decision-Making in Parkinson Patients.

    PubMed

    Seinstra, Maayke; Wojtecki, Lars; Storzer, Lena; Schnitzler, Alfons; Kalenscher, Tobias

    2016-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for the motor symptoms of Parkinson's disease (PD). DBS or pharmacological treatment is believed to modulate the tendency to, or reverse, impulse control disorders. Several brain areas involved in impulsivity and reward valuation, such as the prefrontal cortex and striatum, are linked to the STN, and activity in these areas might be affected by STN-DBS. To investigate the effect of STN-DBS on one type of impulsive decision-making-delay discounting (i.e., the devaluation of reward with increasing delay until its receipt)-we tested 40 human PD patients receiving STN-DBS treatment and medication for at least 3 months. Patients were pseudo-randomly assigned to one of four groups to test the effects of DBS on/off states as well as medication on/off states on delay discounting. The delay-discounting task consisted of a series of choices among a smaller. sooner or a larger, later monetary reward. Despite considerable effects of DBS on motor performance, patients receiving STN-DBS did not choose more or less impulsively compared with those in the off-DBS group, as well as when controlling for risk attitude. Although null results have to be interpreted with caution, our findings are of significance to other researchers studying the effects of PD treatment on impulsive decision-making, and they are of clinical relevance for determining the therapeutic benefits of using STN-DBS. PMID:27257622

  3. Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks.

    PubMed

    Delaville, Claire; McCoy, Alex J; Gerber, Colin M; Cruz, Ana V; Walters, Judith R

    2015-04-29

    Oscillatory activity in both beta and gamma ranges has been recorded in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients and linked to motor function, with beta activity considered antikinetic, and gamma activity, prokinetic. However, the extent to which nonmotor networks contribute to this activity is unclear. This study uses hemiparkinsonian rats performing a treadmill walking task to compare synchronized STN local field potential (LFP) activity with activity in motor cortex (MCx) and medial prefrontal cortex (mPFC), areas involved in motor and cognitive processes, respectively. Data show increases in STN and MCx 29-36 Hz LFP spectral power and coherence after dopamine depletion, which are reduced by apomorphine and levodopa treatments. In contrast, recordings from mPFC 3 weeks after dopamine depletion failed to show peaks in 29-36 Hz LFP power. However, mPFC and STN both showed peaks in the 45-55 Hz frequency range in LFP power and coherence during walking before and 21 days after dopamine depletion. Interestingly, power in this low gamma range was transiently reduced in both mPFC and STN after dopamine depletion but recovered by day 21. In contrast to the 45-55 Hz activity, the amplitude of the exaggerated 29-36 Hz rhythm in the STN was modulated by paw movement. Furthermore, as in PD patients, after dopamine treatment a third band (high gamma) emerged in the lesioned hemisphere. The results suggest that STN integrates activity from both motor and cognitive networks in a manner that varies with frequency, behavioral state, and the integrity of the dopamine system. PMID:25926466

  4. Subthalamic Nucleus Activity in the Awake Hemiparkinsonian Rat: Relationships with Motor and Cognitive Networks

    PubMed Central

    Delaville, Claire; McCoy, Alex J.; Gerber, Colin M.; Cruz, Ana V.

    2015-01-01

    Oscillatory activity in both beta and gamma ranges has been recorded in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients and linked to motor function, with beta activity considered antikinetic, and gamma activity, prokinetic. However, the extent to which nonmotor networks contribute to this activity is unclear. This study uses hemiparkinsonian rats performing a treadmill walking task to compare synchronized STN local field potential (LFP) activity with activity in motor cortex (MCx) and medial prefrontal cortex (mPFC), areas involved in motor and cognitive processes, respectively. Data show increases in STN and MCx 29–36 Hz LFP spectral power and coherence after dopamine depletion, which are reduced by apomorphine and levodopa treatments. In contrast, recordings from mPFC 3 weeks after dopamine depletion failed to show peaks in 29–36 Hz LFP power. However, mPFC and STN both showed peaks in the 45–55 Hz frequency range in LFP power and coherence during walking before and 21 days after dopamine depletion. Interestingly, power in this low gamma range was transiently reduced in both mPFC and STN after dopamine depletion but recovered by day 21. In contrast to the 45–55 Hz activity, the amplitude of the exaggerated 29–36 Hz rhythm in the STN was modulated by paw movement. Furthermore, as in PD patients, after dopamine treatment a third band (high gamma) emerged in the lesioned hemisphere. The results suggest that STN integrates activity from both motor and cognitive networks in a manner that varies with frequency, behavioral state, and the integrity of the dopamine system. PMID:25926466

  5. Globus pallidus neurons dynamically regulate the activity pattern of subthalamic nucleus neurons through the frequency-dependent activation of postsynaptic GABAA and GABAB receptors.

    PubMed

    Hallworth, Nicholas E; Bevan, Mark D

    2005-07-01

    Reciprocally connected GABAergic neurons of the globus pallidus (GP) and glutamatergic neurons of the subthalamic nucleus (STN) are a putative generator of pathological rhythmic burst firing in Parkinson's disease (PD). Burst firing of STN neurons may be driven by rebound depolarization after barrages of GABA(A) receptor (GABA(A)R)-mediated IPSPs arising from pallidal fibers. To determine the conditions under which pallidosubthalamic transmission activates these and other postsynaptic GABARs, a parasagittal mouse brain slice preparation was developed in which pallidosubthalamic connections were preserved. Intact connectivity was first confirmed through the injection of a neuronal tracer into the GP. Voltage-clamp and gramicidin-based perforated-patch current-clamp recordings were then used to study the relative influences of GABA(A)R- and GABA(B)R-mediated pallidosubthalamic transmission on STN neurons. Spontaneous phasic, but not tonic, activation of postsynaptic GABA(A)Rs reduced the frequency and disrupted the rhythmicity of autonomous firing in STN neurons. However, postsynaptic GABA(B)Rs were only sufficiently activated to impact STN firing when pallidosubthalamic transmission was elevated or pallidal fibers were synchronously activated by electrical stimulation. In a subset of neurons, rebound burst depolarizations followed high-frequency, synchronous stimulation of pallidosubthalamic fibers. Although GABA(B)R-mediated hyperpolarization was itself sufficient to generate rebound bursts, coincident activation of postsynaptic GABA(A)Rs produced longer and more intense burst firing. These findings elucidate a novel route through which burst activity can be generated in the STN, and suggest that GABARs on STN neurons could act in a synergistic manner to generate abnormal burst activity in PD. PMID:16000620

  6. Maximal subthalamic beta hypersynchrony of the local field potential in Parkinson's disease is located in the central region of the nucleus.

    PubMed

    de Solages, Camille; Hill, Bruce C; Yu, Hong; Henderson, Jaimie M; Bronte-Stewart, Helen

    2011-12-01

    A pathological marker of Parkinson's disease is the existence of abnormal synchrony of neuronal activity within the beta frequency range (13-35 Hz) in the subthalamic nucleus (STN). Recent studies examining the topography of this rhythm have located beta hypersynchrony in the most dorsal part of the STN. In contrast, this study of the topography of the local field potential beta oscillations in 18 STNs with a 1 mm spatial resolution revealed that the point of maximal beta hypersynchrony was located at 53 ± 24% of the trajectory span from the dorsal to the ventral borders of the STN (corresponding to a 3.0 ± 1.6 mm depth for a 5.9 ± 0.75 mm STN span). This suggests that maximal beta hypersynchrony is located in the central region of the nucleus and that further investigation should be done before using STN spectral profiles as an indicator for guiding placement of deep brain stimulation leads. PMID:21205981

  7. A Non-Invasive Imaging Approach to Understanding Speech Changes following Deep Brain Stimulation in Parkinson’s Disease

    PubMed Central

    Narayana, Shalini; Jacks, Adam; Robin, Donald A.; Poizner, Howard; Zhang, Wei; Franklin, Crystal; Liotti, Mario; Vogel, Deanie; Fox, Peter T.

    2009-01-01

    Purpose To explore the use of non-invasive functional imaging and “virtual” lesion techniques to study the neural mechanisms underlying motor speech disorders in Parkinson’s disease. Here, we report the use of Positron Emission Tomography (PET) and transcranial magnetic stimulation (TMS) to explain exacerbated speech impairment following subthalamic nucleus deep brain stimulation (STN-DBS) in a patient with Parkinson’s disease. Method Perceptual and acoustic speech measures as well as cerebral blood flow (CBF) during speech as measured by PET were obtained with STN-DBS on and off. TMS was applied to a region in the speech motor network found to be abnormally active during DBS. Speech disruption by TMS was compared both perceptually and acoustically with that resulting from DBS on. Results Speech production was perceptually inferior and acoustically less contrastive during left STN stimulation compared to no stimulation. Increased neural activity in left dorsal premotor cortex (PMd) was observed during DBS on. “Virtual” lesioning of this region resulted in speech characterized by decreased speech segment duration, increased pause duration, and decreased intelligibility. Conclusions This case report provides evidence that impaired speech production accompanying STN-DBS may be resulting from unintended activation of PMd. Clinical application of functional imaging and TMS may lead to optimizing the delivery of STN-DBS to improve outcomes for speech production as well as general motor abilities. PMID:19029533

  8. Continuous High-Frequency Stimulation of the Subthalamic Nucleus Improves Cell Survival and Functional Recovery Following Dopaminergic Cell Transplantation in Rodents.

    PubMed

    Furlanetti, Luciano L; Cordeiro, Joacir Graciolli; Cordeiro, Karina Kohn; García, Joanna A; Winkler, Christian; Lepski, Guilherme A; Coenen, Volker A; Nikkhah, Guido; Döbrössy, Máté D

    2015-01-01

    Subthalamic nucleus (STN) high-frequency stimulation (HFS) is a routine treatment in Parkinson's disease (PD), with confirmed long-term benefits. An alternative, but still experimental, treatment is cell replacement and restorative therapy based on transplanted dopaminergic neurons. The current experiment evaluated the potential synergy between neuromodulation and grafting by studying the effect of continuous STN-HFS on the survival, integration, and functional efficacy of ventral mesencephalic dopaminergic precursors transplanted into a unilateral 6-hydroxydopamine medial forebrain bundle lesioned rodent PD model. One group received continuous HFS of the ipsilateral STN starting a week prior to intrastriatal dopaminergic neuron transplantation, whereas the sham-stimulated group did not receive STN-HFS but only dopaminergic grafts. A control group was neither lesioned nor transplanted. Over the following 7 weeks, the animals were probed on a series of behavioral tasks to evaluate possible graft and/or stimulation-induced functional effects. Behavioral and histological data suggest that STN-HFS significantly increased graft cell survival, graft-host integration, and functional recovery. These findings might open an unexplored road toward combining neuromodulative and neuroregenerative strategies to treat severe neurologic conditions. PMID:25857428

  9. The influence of subthalamic nucleus stimulation on pragmatic language production in Parkinson's disease.

    PubMed

    Van Lier, Sam; Batens, Katja; Santens, Patrick; Van Roost, Dirk; Van Herreweghe, Mieke; De Letter, Miet

    2016-06-01

    While the influence of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on the comprehension of pragmatic language in Parkinson's disease (PD) has been the focus of studies, its impact on production, however, has yet to be elucidated. (1) Investigating the inf luence of DBS STN on pragmatic language production in spontaneous speech by comparing different stimulation conditions and (2) evaluating the effect of asymmetric dopaminergic denervation. This paper included 18 patients with advanced idiopathic PD with STN DBS. [Ten PD patients with predominantly left hemispheric dopamine denervation (PD-left) and eight PD patients with predominantly right-hemispheric dopamine denervation (PD-right).] The pragmatic components 'communicative functions' and 'conversational skills' were evaluated by analysing the spontaneous language production in four stimulation conditions. STN stimulation did not appear to influence the pragmatic production skills. Only when asymmetric dopamine depletion was taken into account the parameter 'giving an explanation' interaction was detectable. STN DBS appears to have some influence on the production of pragmatic language depending on asymmetric dopaminergic denervation. Suggestions are made for further research of pragmatic production in Parkinson's disease. PMID:26442686

  10. A study of renal blood flow regulation using the discrete wavelet transform

    NASA Astrophysics Data System (ADS)

    Pavlov, Alexey N.; Pavlova, Olga N.; Mosekilde, Erik; Sosnovtseva, Olga V.

    2010-02-01

    In this paper we provide a way to distinguish features of renal blood flow autoregulation mechanisms in normotensive and hypertensive rats based on the discrete wavelet transform. Using the variability of the wavelet coefficients we show distinctions that occur between the normal and pathological states. A reduction of this variability in hypertension is observed on the microscopic level of the blood flow in efferent arteriole of single nephrons. This reduction is probably associated with higher flexibility of healthy cardiovascular system.

  11. Is surgeon intuition equivalent to models of operative complexity in determining the surgical approach for nephron sparing surgery?

    PubMed Central

    Sharma, Pranav; McCormick, Barrett Z.; Zargar-Shoshtari, Kamran; Sexton, Wade J.

    2016-01-01

    Introduction: The choice of approach for partial nephrectomy often depends on surgical complexity. We aimed to determine if surgeon intuition was equivalent to markers of operative complexity, such as RENAL nephrometry and Mayo adhesive probability (MAP) score, in determining the surgical approach for partial nephrectomy (PN). Materials and Methods: We retrospectively identified 119 masses removed for suspected renal cell carcinoma from January 2012 to September 2014 by a single surgeon who intuitively chose treatment with one of three surgical approaches: Open PN (OPN), robotic-assisted transperitoneal PN (RATPN), or robotic-assisted retroperitoneal PN (RARPN). Clinicodemographic characteristics, pathological features, and postoperative outcomes were compared for each approach. Logistic regression was performed to identify independent predictors of open surgical resection, our primary endpoint. Results: Fifty-four tumors (45%) were resected via OPN, 40 (34%) via RATPN, and 25 (21%) via RARPN. OPN was performed in patients with more comorbidities (P = 0.02), lower baseline renal function (P < 0.01), more solitary kidneys (P < 0.01), and more multifocal disease (P < 0.01). Patients undergoing OPN had higher median nephrometry scores compared to RATPN and RARPN patients (8 vs. 7 vs. 7, respectively; P = 0.03), but MAP scores were no different among all three groups (P = 0.36). On multivariate analysis, higher nephrometry scores (odds ratio: 1.41, 95% confidence interval: 1.10-1.81; P = 0.007) were independently associated with open surgical resection. Nephrometry score was predictive of OPN (area under curve = 0.64, P = 0.01) with a score of 6.5 having the highest sensitivity and specificity (76% and 42%, respectively). Conclusions: RENAL nephrometry score was associated with surgical approach intuitively chosen by an experienced surgeon, but the presence of adherent perinephric fat did not correlate with decision-making. PMID:27127355

  12. Increased extracellular dopamine and 5-hydroxytryptamine levels contribute to enhanced subthalamic nucleus neural activity during exhausting exercise.

    PubMed

    Hu, Y; Liu, X; Qiao, D

    2015-09-01

    The purpose of the study was to explore the mechanism underlying the enhanced subthalamic nucleus (STN) neural activity during exhausting exercise from the perspective of monoamine neurotransmitters and changes of their corresponding receptors. Rats were randomly divided into microdialysis and immunohistochemistry study groups. For microdialysis study, extracellular fluid of the STN was continuously collected with a microdialysis probe before, during and 90 min after one bout of exhausting exercise. Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels were subsequently detected with high-performance liquid chromatography (HPLC). For immunohistochemistry study, the expression of DRD2 and HT2C receptors in the STN, before, immediately after and 90 min after exhaustion was detected through immunohistochemistry technique. Microdialysis study results showed that the extracellular DA and 5-HT neurotransmitters increased significantly throughout the procedure of exhausting exercise and the recovery period (P<0.05 or P<0.01). Immunohistochemistry study results showed that the expression levels of DRD2 and HT2C in the rat STN immediately after exhausting exercise and at the time point of 90 min after exhaustion were both higher than those of the rest condition, but the difference was not significant (P>0.05). Our results suggest that the increased extracellular DA and 5-HT in the STN might be one important factor leading to the enhanced STN neural activity and the development of fatigue during exhausting exercise. This study may essentially offer useful evidence for better understanding of the mechanism of the central type of exercise-induced fatigue. PMID:26424920

  13. A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission.

    PubMed

    O'Cearbhaill, Roisin E; Ragupathi, Govind; Zhu, Jianglong; Wan, Qian; Mironov, Svetlana; Yang, Guangbin; Spassova, Maria K; Iasonos, Alexia; Kravetz, Sara; Ouerfelli, Ouathek; Spriggs, David R; Danishefsky, Samuel J; Sabbatini, Paul J

    2016-01-01

    We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011-Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient's pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36-68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2-39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability. PMID:27110823

  14. A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission

    PubMed Central

    O’Cearbhaill, Roisin E.; Ragupathi, Govind; Zhu, Jianglong; Wan, Qian; Mironov, Svetlana; Yang, Guangbin; Spassova, Maria K.; Iasonos, Alexia; Kravetz, Sara; Ouerfelli, Ouathek; Spriggs, David R.; Danishefsky, Samuel J.; Sabbatini, Paul J.

    2016-01-01

    We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability. PMID:27110823

  15. Older Candidates for Subthalamic Deep Brain Stimulation in Parkinson's Disease Have a Higher Incidence of Psychiatric Serious Adverse Events

    PubMed Central

    Cozac, Vitalii V.; Ehrensperger, Michael M.; Gschwandtner, Ute; Hatz, Florian; Meyer, Antonia; Monsch, Andreas U.; Schuepbach, Michael; Taub, Ethan; Fuhr, Peter

    2016-01-01

    Objective: To investigate the incidence of serious adverse events (SAE) of subthalamic deep brain stimulation (STN-DBS) in elderly patients with Parkinson's disease (PD). Methods: We investigated a group of 26 patients with PD who underwent STN-DBS at mean age 63.2 ± 3.3 years. The operated patients from the EARLYSTIM study (mean age 52.9 ± 6.6) were used as a comparison group. Incidences of SAE were compared between these groups. Results: A higher incidence of psychosis and hallucinations was found in these elderly patients compared to the younger patients in the EARLYSTIM study (p < 0.01). Conclusions: The higher incidence of STN-DBS-related psychiatric complications underscores the need for comprehensive psychiatric pre- and postoperative assessment in older DBS candidates. However, these psychiatric SAE were transient, and the benefits of DBS clearly outweighed its adverse effects. PMID:27375478

  16. Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation on gait kinematics in Parkinson's disease: a randomized, blinded study.

    PubMed

    Lizarraga, Karlo J; Jagid, Jonathan R; Luca, Corneliu C

    2016-08-01

    Gait dysfunction in Parkinson's disease (PD) does not always respond to bilateral subthalamic nucleus deep brain stimulation (STN-DBS). Since right hemisphere motor networks may be dominant for gait control, identical stimulation of asymmetric circuits could account for gait dysfunction. We compared the effects of bilateral and unilateral STN-DBS on gait kinematics in PD patients who developed gait impairment after STN-DBS. Twenty-two PD patients with >50 % improvement in motor scores, but dopamine-resistant gait dysfunction 6-12 months after bilateral STN-DBS were blindly tested off dopaminergic effects in four randomly assigned DBS conditions: bilateral, right-sided, left-sided and off stimulation. Motor scores (MDS-UPDRS III), gait scores (MDS-UPRDS 2.11-2.13 + 3.9-3.13), turning time (seconds), stride length (meters) and velocity (meters/second) were measured 1 h after DBS changes. Motor and gait scores significantly improved with bilateral versus unilateral STN-DBS. Stride length and velocity (0.95 ± 0.06, 0.84 ± 0.07) significantly improved with bilateral (1.09 ± 0.04, 0.95 ± 0.05), right-sided (1.06 ± 0.04, 0.92 ± 0.05) and left-sided stimulation (1.01 ± 0.05, 0.90 ± 0.05) (p < 0.05). Stride length significantly improved with right-sided versus left-sided (0.05 ± 0.02) and bilateral versus left-sided stimulation (0.07 ± 0.02) (p < 0.05). Turning time (4.89 ± 0.6) tended to improve with bilateral (4.13 ± 0.5) (p = 0.15) and right-sided (4.27 ± 0.6) (p = 0.2) more than with left STN-DBS (4.69 ± 0.5) (p = 0.5). Bilateral STN-DBS yields greater improvement in motor and gait scores in PD patients. Yet, unilateral stimulation has similar effects on gait kinematics. Particularly, right-sided stimulation might produce slightly greater improvements. Although the clinical relevance of differential programming of right versus left-sided STN-DBS is unclear, this approach could be considered in the management of

  17. Subthalamic Stimulation Reduces Vowel Space at the Initiation of Sustained Production: Implications for Articulatory Motor Control in Parkinson’s Disease

    PubMed Central

    Sidtis, John J.; Alken, Amy G.; Tagliati, Michele; Alterman, Ron; Van Lancker Sidtis, Diana

    2016-01-01

    Background: Stimulation of the subthalamic nuclei (STN) is an effective treatment for Parkinson’s disease, but complaints of speech difficulties after surgery have been difficult to quantify. Speech measures do not convincingly account for such reports. Objective: This study examined STN stimulation effects on vowel production, in order to probe whether DBS affects articulatory posturing. The objective was to compare positioning during the initiation phase with the steady prolongation phase by measuring vowel spaces for three “corner” vowels at these two time frames. Methods: Vowel space was measured over the initial 0.25 sec of sustained productions of high front (/i/), high back (/u/) and low vowels (/a/), and again during a 2 sec segment at the midpoint. Eight right-handed male subjects with bilateral STN stimulation and seven age-matched male controls were studied based on their participation in a larger study that included functional imaging. Mean values: age = 57±4.6 yrs; PD duration = 12.3±2.7 yrs; duration of DBS = 25.6±21.2 mos, and UPDRS III speech score = 1.6±0.7. STN subjects were studied off medication at their therapeutic DBS settings and again with their stimulators off, counter-balanced order. Results: Vowel space was larger in the initiation phase compared to the midpoint for both the control and the STN subjects off stimulation. With stimulation on, however, the initial vowel space was significantly reduced to the area measured at the mid-point. For the three vowels, the acoustics were differentially affected, in accordance with expected effects of front versus back position in the vocal tract. Conclusions: STN stimulation appears to constrain initial articulatory gestures for vowel production, raising the possibility that articulatory positions normally used in speech are similarly constrained. PMID:27003219

  18. The Evolution of the Society of Trauma Nurses' Leadership Institute.

    PubMed

    Krichten, Amy; Kyle, Amber

    2015-01-01

    The Society of Trauma Nurses (STN) understands the increasing complexity of trauma care and the vital leadership role nurses play. In 2009, the STN took the initiative to form a Leadership Committee tasked with researching the possibility of developing a mechanism to offer trauma leaders opportunities in leadership development. Investigation and collaboration among the committee members, with input from the Board of Directors and the organization's executive director, resulted in the STN Leadership Institute. The Leadership Institute design is to equip trauma nurses with the tools needed to effectively lead from the bedside to the boardroom and beyond through web-based modules. Operationalization of the plan took intense focus and dedicated leadership. Following a pilot study, the initial cohort ran the first quarter of 2015. Because of the positive feedback and identified opportunities for improvement, the program will continue to be offered with further expansion planning underway. PMID:26574939

  19. High-Frequency Stimulation at the Subthalamic Nucleus Suppresses Excessive Self-Grooming in Autism-Like Mouse Models.

    PubMed

    Chang, Andrew D; Berges, Victoria A; Chung, Sunho J; Fridman, Gene Y; Baraban, Jay M; Reti, Irving M

    2016-06-01

    Approximately one quarter of individuals with an autism spectrum disorder (ASD) display self-injurious behavior (SIB) ranging from head banging to self-directed biting and punching. Sometimes, these behaviors are extreme and unresponsive to pharmacological and behavioral therapies. We have found electroconvulsive therapy (ECT) can produce life-changing results, with more than 90% suppression of SIB frequency. However, these patients typically require frequent maintenance ECT (mECT), as often as every 5 days, to sustain the improvement gained during the acute course. Long-term consequences of such frequent mECT started as early as childhood in some cases are unknown. Accordingly, there is a need for alternative forms of chronic stimulation for these patients. To explore the feasibility of deep brain stimulation (DBS) for intractable SIB seen in some patients with an ASD, we utilized two genetically distinct mouse models demonstrating excessive self-grooming, namely the Viaat-Mecp2(-/y) and Shank3B(-/-) lines, and administered high-frequency stimulation (HFS) via implanted electrodes at the subthalamic nucleus (STN-HFS). We found that STN-HFS significantly suppressed excessive self-grooming in both genetic lines. Suppression occurs both acutely when stimulation is switched on, and persists for several days after HFS is stopped. This effect was not explained by a change in locomotor activity, which was unaffected by STN-HFS. Likewise, social interaction deficits were not corrected by STN-HFS. Our data show STN-HFS suppresses excessive self-grooming in two autism-like mouse models, raising the possibility DBS might be used to treat intractable SIB associated with ASDs. Further studies are required to explore the circuitry engaged by STN-HFS, as well as other potential stimulation sites. Such studies might also yield clues about pathways, which could be modulated by non-invasive stimulatory techniques. PMID:26606849

  20. Innervation of the renal proximal convoluted tubule of the rat

    SciTech Connect

    Barajas, L.; Powers, K. )

    1989-12-01

    Experimental data suggest the proximal tubule as a major site of neurogenic influence on tubular function. The functional and anatomical axial heterogeneity of the proximal tubule prompted this study of the distribution of innervation sites along the early, mid, and late proximal convoluted tubule (PCT) of the rat. Serial section autoradiograms, with tritiated norepinephrine serving as a marker for monoaminergic nerves, were used in this study. Freehand clay models and graphic reconstructions of proximal tubules permitted a rough estimation of the location of the innervation sites along the PCT. In the subcapsular nephrons, the early PCT (first third) was devoid of innervation sites with most of the innervation occurring in the mid (middle third) and in the late (last third) PCT. Innervation sites were found in the early PCT in nephrons located deeper in the cortex. In juxtamedullary nephrons, innervation sites could be observed on the PCT as it left the glomerulus. This gradient of PCT innervation can be explained by the different tubulovascular relationships of nephrons at different levels of the cortex. The absence of innervation sites in the early PCT of subcapsular nephrons suggests that any influence of the renal nerves on the early PCT might be due to an effect of neurotransmitter released from renal nerves reaching the early PCT via the interstitium and/or capillaries.

  1. Kidney organogenesis in the zebrafish: insights into vertebrate nephrogenesis and regeneration

    PubMed Central

    Gerlach, Gary F.; Wingert, Rebecca A.

    2012-01-01

    Vertebrates form a progressive series of up to three kidney organs during development—the pronephros, mesonephros, and metanephros. Each kidney derives from the intermediate mesoderm and is comprised of conserved excretory units called nephrons. The zebrafish is a powerful model for vertebrate developmental genetics, and recent studies have illustrated that zebrafish and mammals share numerous similarities in nephron composition and physiology. The zebrafish embryo forms an architecturally simple pronephros that has two nephrons, and these eventually become a scaffold onto which a mesonephros of several hundred nephrons is constructed during larval stages. In adult zebrafish, the mesonephros exhibits ongoing nephrogenesis, generating new nephrons from a local pool of renal progenitors during periods of growth or following kidney injury. The characteristics of the zebrafish pronephros and mesonephros make them genetically tractable kidney systems in which to study the functions of renal genes and address outstanding questions about the mechanisms of nephrogenesis. Here, we provide an overview of the formation and composition of these zebrafish kidney organs, and discuss how various zebrafish mutants, gene knockdowns, and transgenic models have created frameworks in which to further delineate nephrogenesis pathways. PMID:24014448

  2. Motor behaviors in the sheep evoked by electrical stimulation of the subthalamic nucleus.

    PubMed

    Lentz, Linnea; Zhao, Yan; Kelly, Matthew T; Schindeldecker, William; Goetz, Steven; Nelson, Dwight E; Raike, Robert S

    2015-11-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is used to treat movement disorders, including advanced Parkinson's disease (PD). The pathogenesis of PD and the therapeutic mechanisms of DBS are not well understood. Large animal models are essential for investigating the mechanisms of PD and DBS. The purpose of this study was to develop a novel sheep model of STN DBS and quantify the stimulation-evoked motor behaviors. To do so, a large sample of animals was chronically-implanted with commercial DBS systems. Neuroimaging and histology revealed that the DBS leads were implanted accurately relative to the neurosurgical plan and also precisely relative to the STN. It was also possible to repeatedly conduct controlled evaluations of stimulation-evoked motor behavior in the awake-state. The evoked motor responses depended on the neuroanatomical location of the electrode contact selected for stimulation, as contacts proximal to the STN evoked movements at significantly lower voltages. Tissue stimulation modeling demonstrated that selecting any of the contacts stimulated the STN, whereas selecting the relatively distal contacts often also stimulated thalamus but only the distal-most contact stimulated internal capsule. The types of evoked motor behaviors were specific to the stimulation frequency, as low but not high frequencies consistently evoked movements resembling human tremor or dyskinesia. Electromyography confirmed that the muscle activity underlying the tremor-like movements in the sheep was consistent with human tremor. Overall, this work establishes that the sheep is a viable a large-animal platform for controlled testing of STN DBS with objective motor outcomes. Moreover, the results support the hypothesis that exaggerated low-frequency activity within individual nodes of the motor network can drive symptoms of human movement disorders, including tremor and dyskinesia. PMID:26231574

  3. Effects of focused ion beam milling on electron backscatter diffraction patterns in strontium titanate and stabilized zirconia.

    PubMed

    Saowadee, N; Agersted, K; Bowen, J R

    2012-06-01

    This study investigates the effect of focused ion beam (FIB) current and accelerating voltage on electron backscatter diffraction pattern quality of yttria-stabilized zirconia (YSZ) and Nb-doped strontium titanate (STN) to optimize data quality and acquisition time for 3D-EBSD experiments by FIB serial sectioning. Band contrast and band slope were used to describe the pattern quality. The FIB probe currents investigated ranged from 100 to 5000 pA and the accelerating voltage was either 30 or 5 kV. The results show that 30 kV FIB milling induced a significant reduction of the pattern quality of STN samples compared to a mechanically polished surface but yielded a high pattern quality on YSZ. The difference between STN and YSZ pattern quality is thought to be caused by difference in the degree of ion damage as their backscatter coefficients and ion penetration depths are virtually identical. Reducing the FIB probe current from 5000 to 100 pA improved the pattern quality by 20% for STN but only showed a marginal improvement for YSZ. On STN, a conductive coating can help to improve the pattern quality and 5 kV polishing can lead to a 100% improvement of the pattern quality relatively to 30 kV FIB milling. For 3D-EBSD experiments of a material such as STN, it is recommended to combine a high kV FIB milling and low kV polishing for each slice in order to optimize the data quality and acquisition time. PMID:22582798

  4. Organization of the pronephric kidney revealed by large-scale gene expression mapping

    PubMed Central

    Raciti, Daniela; Reggiani, Luca; Geffers, Lars; Jiang, Qiuhong; Bacchion, Francesca; Subrizi, Astrid E; Clements, Dave; Tindal, Christopher; Davidson, Duncan R; Kaissling, Brigitte; Brändli, André W

    2008-01-01

    Background The pronephros, the simplest form of a vertebrate excretory organ, has recently become an important model of vertebrate kidney organogenesis. Here, we elucidated the nephron organization of the Xenopus pronephros and determined the similarities in segmentation with the metanephros, the adult kidney of mammals. Results We performed large-scale gene expression mapping of terminal differentiation markers to identify gene expression patterns that define distinct domains of the pronephric kidney. We analyzed the expression of over 240 genes, which included members of the solute carrier, claudin, and aquaporin gene families, as well as selected ion channels. The obtained expression patterns were deposited in the searchable European Renal Genome Project Xenopus Gene Expression Database. We found that 112 genes exhibited highly regionalized expression patterns that were adequate to define the segmental organization of the pronephric nephron. Eight functionally distinct domains were discovered that shared significant analogies in gene expression with the mammalian metanephric nephron. We therefore propose a new nomenclature, which is in line with the mammalian one. The Xenopus pronephric nephron is composed of four basic domains: proximal tubule, intermediate tubule, distal tubule, and connecting tubule. Each tubule may be further subdivided into distinct segments. Finally, we also provide compelling evidence that the expression of key genes underlying inherited renal diseases in humans has been evolutionarily conserved down to the level of the pronephric kidney. Conclusion The present study validates the Xenopus pronephros as a genuine model that may be used to elucidate the molecular basis of nephron segmentation and human renal disease. PMID:18492243

  5. Initial pathological events in renal dysplasia with urinary tract obstruction in utero.

    PubMed

    Shibata, S; Shigeta, M; Shu, Y; Watanabe, T; Nagata, M

    2001-10-01

    Multicystic dysplastic kidneys (MCDK) and obstructive renal dysplasia (ORD) are two different phenotypes of dysplasia commonly associated with urinary tract obstruction. However, the mechanisms whereby obstruction in the developing kidney leads to each dysplasia are unknown. In the present study, 16 fetal MCDKs and 3 fetal ORDs (18-35 weeks of gestation) were analyzed with light microscopy, point-counting morphometry, immunohistochemistry with a podocyte marker, and scanning electron microscopy. Additionally, reconstructions of dysplastic nephrons were done via serial section analysis. Early stages of MCDK and ORD similarly revealed numerous cyst formations, predominantly in the subcapsular nephrogenic zone. Occasionally, glomerular tuft remnants with mature podocyte phenotypes were observed in cysts, suggesting the acquisition of filtration. Three dimensionally, basic nephron structures were installed in the cystic nephrons, namely the macula densa with a primary loop structure. Cysts developed in the once-induced nephrons due to fluid retention in both MCDK and ORD. In utero urinary tract obstruction may cause urine retention in functioning nephrons and lead to glomerular cysts in the nephrogenic zone. These findings were common to MCDK and ORD, albeit at different sites of obstruction. Expansion of glomerular cysts with tubular dilatation (cysts) disturbs the subsequent nephrogenesis and may contribute to the misdevelopment of fetal kidneys. PMID:11710644

  6. Glomerular hemodynamics in established glycerol-induced acute renal failure in the rat.

    PubMed Central

    Wolfert, A I; Oken, D E

    1989-01-01

    The glomerular dynamic correlates of failed filtration were studied in volume replete rats with established glycerol-induced acute renal failure (ARF). Over one-half of all nephrons formed virtually no filtrate, while the single nephron glomerular filtration rate (SNGFR) of fluid-filled nephrons, measured at the glomerulotubular junction to preclude the possibility of covert tubular leakage, averaged one-sixth of control (P less than 0.001). Even that low mean value was elevated by a few nephrons with a near normal SNGFR. Renal failure thus reflected both total filtration failure in the majority of nephrons and massively reduced filtration in most of the remainder. Glomerular capillary pressure (Pg) averaged some 14 mmHg below control (P less than 0.001), whereas the arterial colloid osmotic and Bowman's space pressures were not significantly altered. Renocortical and whole kidney blood flow were also unchanged. Marked internephron functional heterogeneity precluded estimates of the ultrafiltration coefficient. However, the fall in SNGFR correlated well with the markedly depressed Pg and afferent net filtration pressure (delta PnetA, P less than 0.001), which in turn were caused by increased preglomerular resistance and a reciprocal fall in efferent arteriolar resistance. This complex change in intrarenal resistances was largely, if not entirely, responsible for failed filtration in this ARF model. PMID:2592568

  7. Roles of Iroquois Transcription Factors in Kidney Development

    PubMed Central

    Marra, Amanda N.; Wingert, Rebecca A.

    2014-01-01

    Congenital anomalies of the kidney and urinary tract (CAKUT) affect 1/500 live births. CAKUT lead to end stage renal failure in children, and are associated with high morbidity rates. Understanding the mechanisms of kidney development, and that of other associated urogenital tissues, is crucial to the prevention and treatment of CAKUT. The kidney arises from self-renewing mesenchymal renal stem cells that produce nephrons, which are the principal functional units of the organ. To date, the genetic and cellular mechanisms that control nephrogenesis have remained poorly understood. In recent years, developmental studies using amphibians and zebrafish have revealed that their simple embryonic kidney, known as the pronephros, is a useful paradigm for comparative studies of nephron ontogeny. Here, we discuss the new found roles for Iroquois transcription factors in pronephric nephron patterning, and explore the relevance of these findings for kidney development in humans. PMID:24855634

  8. Cognitive Changes following Bilateral Deep Brain Stimulation of Subthalamic Nucleus in Parkinson's Disease: A Meta-Analysis

    PubMed Central

    Meng, Xiangyu; Xiao, Jinsong; Zhang, Junjian

    2016-01-01

    Background. Nowadays, it has been largely acknowledged that deep brain stimulation of subthalamic nucleus (STN DBS) can alleviate motor symptoms of Parkinson's disease, but its effects on cognitive function remain unclear, which are not given enough attention by many clinical doctors and researchers. To date, 3 existing meta-analyses focusing on this issue included self-control studies and have not drawn consistent conclusions. The present study is the first to compare effect sizes of primary studies that include control groups, hoping to reveal the net cognitive outcomes after STN DBS and the clinical significance. Methods. A structured literature search was conducted using strict criteria. Only studies with control group could be included. Data on age, duration of disease, levodopa equivalent dosage (LED), and multiple cognitive scales were collected and pooled. Results. Of 172 articles identified, 10 studies (including 3 randomized controlled trials and 7 nonrandomized controlled studies) were eligible for inclusion. The results suggest that STN DBS results in decreased global cognition, memory, verbal fluency, and executive function compared with control group. No significant difference is found in other cognitive domains. Conclusions. STN DBS seems relatively safe with respect to cognitive function, and further studies should focus on the exact mechanisms of possible verbal deterioration after surgery in the future. PMID:27314016

  9. Ouabain protects against adverse developmental programming of the kidney.

    PubMed

    Li, Juan; Khodus, Georgiy R; Kruusmägi, Markus; Kamali-Zare, Padideh; Liu, Xiao-Li; Eklöf, Ann-Christine; Zelenin, Sergey; Brismar, Hjalmar; Aperia, Anita

    2010-01-01

    The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards the formation of functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that ouabain, the Na,K-ATPase ligand, triggers a calcium-nuclear factor-κB signal, which protects kidney development from adverse effects of malnutrition. To mimic malnutrition, kidneys were serum deprived for 24 h. This resulted in severe retardation of nephron formation and a robust increase in apoptosis. In ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given a low-protein diet and treated with ouabain or vehicle throughout pregnancy. Thus, we have identified a survival signal and a feasible therapeutic tool to prevent adverse programming of kidney development. PMID:20975704

  10. Development of the Mammalian Kidney.

    PubMed

    McMahon, Andrew P

    2016-01-01

    The basic unit of kidney function is the nephron. In the mouse, around 14,000 nephrons form in a 10-day period extending into early neonatal life, while the human fetus forms the adult complement of nephrons in a 32-week period completed prior to birth. This review discusses our current understanding of mammalian nephrogenesis: the contributing cell types and the regulatory processes at play. A conceptual developmental framework has emerged for the mouse kidney. This framework is now guiding studies of human kidney development enabled in part by in vitro systems of pluripotent stem cell-seeded nephrogenesis. A near future goal will be to translate our developmental knowledge-base to the productive engineering of new kidney structures for regenerative medicine. PMID:26969971

  11. Thermal oscillations in rat kidneys: an infrared imaging study

    PubMed Central

    Gorbach, Alexander M.; Wang, Hengliang; Elster, Eric

    2008-01-01

    A high-resolution infrared (IR) camera was used to assess rhythmicity in localized renal blood flow, including the extent of regions containing nephrons with spontaneous oscillations in their individual blood flow. The IR imaging was able to follow changes in rat renal perfusion during baseline conditions, during occlusion of the main renal artery and during the administration of either saline or papaverine. Concurrent recordings were made of tubular pressure in superficial nephrons. Spontaneous vascular oscillations centred around 0.02–0.05 Hz and approximately 0.01 Hz could be detected reproducibly by IR imaging. Their spectral characteristics and their response to papaverine were in line with tubular pressure measurements. The intensity of and synchrony between thermal signals from different local areas of the kidney may allow, after surgical exposure, non-invasive imaging of functional clusters involved in renal cortical blood flow. Through visualization of the spatial extent of thermal oscillations, IR imaging holds promise in assessing kidney autoregulatory mechanisms. PMID:18650199

  12. A study of the intrarenal recycling of urea in the rat with chronic experimental pyelonephritis.

    PubMed Central

    Gilbert, R M; Weber, H; Turchin, L; Fine, L G; Bourgoignie, J J; Bricker, N S

    1976-01-01

    The concentrating ability of the kidney was studied by clearance and micropuncture techniques and tissue slice analyses in normal rats with two intact kidneys (intact controls), normal rats with a solitary kidney (uninephrectomized controls), and uremic rats with a single pyelonephritic kidney. Urinary osmolality after water deprivation for 24 h and administration of antidiuretic hormone was 2,501+/-217 and 2,874+/-392 mosmol/kg H2O in intact and uninephrectomized control rats, respectively, and 929+/-130 mosmol/kg H2O in pyelonephritic rats (P less than 0.001 compared to each control group). Fractional water reabsorption and concentrating ability were significantly decreased in the pyelonephritic group, and, to achieve an equivalent fractional excretion of urea, a greater fractional excretion of water was required in the pyelonephritic rats than in the control rats. Whole animal glomerular filtration rate was 1.57+/-0.19 ml/min and 1.39+/-0.18 ml/min in intact and in uninephrectomized controls, respectively, and 0.30+/-0.07 ml/min in pyelonephritic rats (P less than 0.001 compared to each control group). Single nephron glomerular filtration rate was 35.6+/-3.8 nl/min in intact control rats and was significantly increased (P less than 0.05) in both uninephrectomized (88.0+/-10.8 nl/min) and pyelonephritic rats (71.5+/-14.4 nl/min). In all groups fractional water delivery and fractional sodium delivery were closely comparable at the end of the proximal convoluted tubule and at the beginning of the distal convoluted tubule. In contrast, fractional urea delivery out of the proximal tubule was greater in the intact control group (73+/-8%) than in either the uninephrectomized (52+/-2%) or the pyelonephritic group (53+/-3%) (P less than 0.005). Fractional urea delivery at the early part of the distal tubule increased significantly to 137+/-11% and 93+/-6% of the filtered load in intact control and uninephrectomized control rats, respectively (P less than 0.001 compared

  13. Subthalamic Nucleus Deep Brain Stimulation Modulate Catecholamine Levels with Significant Relations to Clinical Outcome after Surgery in Patients with Parkinson’s Disease

    PubMed Central

    Yamamoto, Tatsuya; Uchiyama, Tomoyuki; Higuchi, Yoshinori; Asahina, Masato; Hirano, Shigeki; Yamanaka, Yoshitaka; Kuwabara, Satoshi

    2015-01-01

    postoperative UPDRS- III score in off phase three months after STN-DBS. The preoperative cerebrospinal fluid (CSF) 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) levels had significantly negative correlations with postoperative UPDRS- III score in off phase one year after STN-DBS and the preoperative CSF homovanilic acid (HVA) levels had significant negative correlations with postoperative UPDRS- III score in on phase three months after STN-DBS. In PDQ-39 SI (summary index), preoperative plasma dopamine (DA) level had significantly negative correlations with postoperative PDQ-39 SI one year after STN-DBS suggesting that higher preoperative plasma DA level resulted in better quality of life (QOL) one year after STN-DBS. The stepwise multiple linear regression study revealed that higher preoperative plasma HVA levels had negative influence on the postoperative motor symptoms (i.e., increase in the score of UPDRS), whereas higher preoperative CSF L-DOPA levels had positive influence on the postoperative motor symptoms and QOL (decrease in the score of UPDRS and PDQ-39 SI) The catecholamine levels were not significantly reduced postoperatively in 11 patients despite the significant reduction in levodopa equivalent doses. Unexpectedly, CSF HVA levels significantly increased from 0.00089±0.0003 ng/μl to 0.002±0.0008 ng/μl after STN-DBS. Conclusion The preoperative catecholamine levels might affect the postoperative motor symptoms and quality of life. The catecholamine levels were not significantly reduced postoperatively despite the significant reduction in levodopa equivalent doses. PMID:26394059

  14. Effects of Stimulation of the Subthalamic Nucleus on Naming and Reading Nouns and Verbs in Parkinson's Disease

    ERIC Educational Resources Information Center

    Silveri, Maria Caterina; Ciccarelli, Nicoletta; Baldonero, Eleonora; Piano, Carla; Zinno, Massimiliano; Soleti, Francesco; Bentivoglio, Anna Rita; Albanese, Alberto; Daniele, Antonio

    2012-01-01

    An impairment for verbs has been described in patients with Parkinson's disease (PD), suggesting that a disruption of frontal-subcortical circuits may result in dysfunction of the neural systems involved in action-verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation…

  15. Pitch Variability in Patients with Parkinson's Disease: Effects of Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus

    ERIC Educational Resources Information Center

    Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; van Doorn, Jan

    2013-01-01

    Purpose: The purpose of the present study was to examine the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) pitch characteristics of connected speech in patients with Parkinson's disease (PD). Method: The authors evaluated 16 patients preoperatively and 12 months after DBS surgery. Eight…

  16. Intensive Voice Treatment (LSVT[R]LOUD) for Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus

    ERIC Educational Resources Information Center

    Spielman, Jennifer; Mahler, Leslie; Halpern, Angela; Gilley, Phllip; Klepitskaya, Olga; Ramig, Lorraine

    2011-01-01

    Purpose: Intensive voice therapy (LSVT[R]LOUD) can effectively manage voice and speech symptoms associated with idiopathic Parkinson disease (PD). This small-group study evaluated voice and speech in individuals with and without deep brain stimulation of the subthalamic nucleus (STN-DBS) before and after LSVT LOUD, to determine whether outcomes…

  17. Articulatory Closure Proficiency in Patients with Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus and Caudal Zona Incerta

    ERIC Educational Resources Information Center

    Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; Nordh, Erik; van Doorn, Jan

    2014-01-01

    Purpose: The present study aimed at comparing the effects of deep brain stimulation (DBS) treatment of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) on the proficiency in achieving oral closure and release during plosive production of people with Parkinson's disease. Method: Nineteen patients participated preoperatively and…

  18. Two cycles of recurrent maternal half-sib selection reduce foliar late blight in a diploid hybrid Solanum phureja-S. stenotomum population by two-thirds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Foliar late blight, caused by Phytophthora infestans, is an important disease problem worldwide. Foliar resistance to late blight was found in a hybrid population of the cultivated diploid species Solanum phureja-S. stenotomum (phu-stn). The objective of this study was to determine if resistance t...

  19. Bilateral Deep Brain Stimulation of the Subthalamic Nucleus under Sedation with Propofol and Fentanyl

    PubMed Central

    Lee, Woong-Woo; Ehm, Gwanhee; Yang, Hui-Jun; Song, In Ho; Lim, Yong Hoon; Kim, Mi-Ryoung; Kim, Young Eun; Hwang, Jae Ha; Park, Hye Ran; Lee, Jae Min; Kim, Jin Wook; Kim, Han-Joon; Kim, Cheolyoung; Kim, Hee Chan; Park, Eunkyoung; Kim, In Young; Kim, Dong Gyu

    2016-01-01

    Awakening during deep brain stimulation (DBS) surgery may be stressful to patients. The aim of the current study was to evaluate the effect on MER signals and their applicability to subthalmic nucleus (STN) DBS surgery for patients with Parkinson’s disease (PD) under sedation with propofol and fentanyl. Sixteen consecutive patients with PD underwent STN-DBS surgery with propofol and fentanyl. Their MER signals were achieved during the surgery. To identify the microelectrodes positions, the preoperative MRI and postoperative CT were used. Clinical profiles were also collected at the baseline and at 6 months after surgery. All the signals were slightly attenuated and contained only bursting patterns, compared with our previous report. All electrodes were mostly located in the middle one third part of the STN on both sides of the brain in the fused images. Six months later, the patients were improved significantly in the medication-off state and they met with less dyskinesia and less off-duration. Our study revealed that the sedation with propofol and fentanyl was applicable to STN-DBS surgery. There were no significant problems in precise positioning of bilateral electrodes. The surgery also improved significantly clinical outcomes in 6-month follow-up. PMID:27018855

  20. Bilateral Deep Brain Stimulation of the Subthalamic Nucleus under Sedation with Propofol and Fentanyl.

    PubMed

    Lee, Woong-Woo; Ehm, Gwanhee; Yang, Hui-Jun; Song, In Ho; Lim, Yong Hoon; Kim, Mi-Ryoung; Kim, Young Eun; Hwang, Jae Ha; Park, Hye Ran; Lee, Jae Min; Kim, Jin Wook; Kim, Han-Joon; Kim, Cheolyoung; Kim, Hee Chan; Park, Eunkyoung; Kim, In Young; Kim, Dong Gyu; Jeon, Beomseok; Paek, Sun Ha

    2016-01-01

    Awakening during deep brain stimulation (DBS) surgery may be stressful to patients. The aim of the current study was to evaluate the effect on MER signals and their applicability to subthalmic nucleus (STN) DBS surgery for patients with Parkinson's disease (PD) under sedation with propofol and fentanyl. Sixteen consecutive patients with PD underwent STN-DBS surgery with propofol and fentanyl. Their MER signals were achieved during the surgery. To identify the microelectrodes positions, the preoperative MRI and postoperative CT were used. Clinical profiles were also collected at the baseline and at 6 months after surgery. All the signals were slightly attenuated and contained only bursting patterns, compared with our previous report. All electrodes were mostly located in the middle one third part of the STN on both sides of the brain in the fused images. Six months later, the patients were improved significantly in the medication-off state and they met with less dyskinesia and less off-duration. Our study revealed that the sedation with propofol and fentanyl was applicable to STN-DBS surgery. There were no significant problems in precise positioning of bilateral electrodes. The surgery also improved significantly clinical outcomes in 6-month follow-up. PMID:27018855

  1. Anatomo-clinical atlases correlate clinical data and electrode contact coordinates: application to subthalamic deep brain stimulation.

    PubMed

    Lalys, Florent; Haegelen, Claire; Mehri, Maroua; Drapier, Sophie; Vérin, Marc; Jannin, Pierre

    2013-01-30

    For patients suffering from Parkinson's disease with severe movement disorders, functional surgery may be required when medical therapy is not effective. In Deep Brain Stimulation (DBS), electrodes are implanted within the brain to stimulate deep structures such as SubThalamic Nucleus (STN). The quality of patient surgical outcome is generally related to the accuracy of nucleus targeting during surgery. In this paper, we focused on identifying optimum sites for STN DBS by studying symptomatic motor improvement along with neuropsychological side effects. We described successive steps for constructing digital atlases gathering patient's location of electrode contacts automatically segmented from postoperative images, and clinical scores. Three motor and five neuropsychological scores were included in the study. Correlations with active contact locations were carried out using an adapted hierarchical ascendant classification. Such analysis enabled the extraction of representative clusters to determine the optimum site for therapeutic STN DBS. For each clinical score, we built an anatomo-clinical atlas representing its improvement or deterioration in relation with the anatomical location of electrodes and from a population of implanted patients. To the best of our knowledge, we reported for the first time a discrepancy between a very good motor improvement by targeting the postero-superior region of the STN and an inevitable deterioration of the categorical and phonemic fluency in the same region. Such atlases and associated analysis may help better understanding of functional mapping in deep structures and may help pre-operative decision-making process and especially targeting. PMID:23147008

  2. Conflict-dependent dynamic of subthalamic nucleus oscillations during moral decisions.

    PubMed

    Fumagalli, Manuela; Giannicola, Gaia; Rosa, Manuela; Marceglia, Sara; Lucchiari, Claudio; Mrakic-Sposta, Simona; Servello, Domenico; Pacchetti, Claudio; Porta, Mauro; Sassi, Marco; Zangaglia, Roberta; Franzini, Angelo; Albanese, Alberto; Romito, Luigi; Piacentini, Sylvie; Zago, Stefano; Pravettoni, Gabriella; Barbieri, Sergio; Priori, Alberto

    2011-01-01

    Although lesional, neuroimaging, and brain stimulation studies have provided an insight into the neural mechanisms of judgement and decision-making, all these works focused on the cerebral cortex, without investigating the role of subcortical structures such as the basal ganglia. Besides being an effective therapeutic tool, deep brain stimulation (DBS) allows local field potential (LFP) recordings through the stimulation electrodes thus providing a physiological "window" on human subcortical structures. In this study we assessed whether subthalamic nucleus LFP oscillations are modulated by processing of moral conflictual, moral nonconflictual, and neutral statements. To do so, in 16 patients with Parkinson's disease (8 men) bilaterally implanted with subthalamic nucleus (STN) electrodes for DBS, we recorded STN LFPs 4 days after surgery during a moral decision task. During the task, recordings from the STN showed changes in LFP oscillations. Whereas the 14--30 Hz band (beta) changed during the movement executed to perform the task, the 5--13 Hz band (low-frequency) changed when subjects evaluated the content of statements. Low-frequency band power increased significantly more during conflictual than during nonconflictual or neutral sentences. We conclude that STN responds specifically to conflictual moral stimuli, and could be involved in conflictual decisions of all kinds, not only those for moral judgment. LFP oscillations provide novel direct evidence that the neural processing of conflictual decision-making spreads beyond the cortex to the basal ganglia and encompasses a specific subcortical conflict-dependent component. PMID:21061226

  3. Confirmation of functional zones within the human subthalamic nucleus: Patterns of connectivity and sub-parcellation using diffusion weighted imaging

    PubMed Central

    Lambert, Christian; Zrinzo, Ludvic; Nagy, Zoltan; Lutti, Antoine; Hariz, Marwan; Foltynie, Thomas; Draganski, Bogdan; Ashburner, John; Frackowiak, Richard

    2012-01-01

    The subthalamic nucleus (STN) is a small, glutamatergic nucleus situated in the diencephalon. A critical component of normal motor function, it has become a key target for deep brain stimulation in the treatment of Parkinson's disease. Animal studies have demonstrated the existence of three functional sub-zones but these have never been shown conclusively in humans. In this work, a data driven method with diffusion weighted imaging demonstrated that three distinct clusters exist within the human STN based on brain connectivity profiles. The STN was successfully sub-parcellated into these regions, demonstrating good correspondence with that described in the animal literature. The local connectivity of each sub-region supported the hypothesis of bilateral limbic, associative and motor regions occupying the anterior, mid and posterior portions of the nucleus respectively. This study is the first to achieve in-vivo, non-invasive anatomical parcellation of the human STN into three anatomical zones within normal diagnostic scan times, which has important future implications for deep brain stimulation surgery. PMID:22173294

  4. Blockade of mGluR glutamate receptors in the subthalamic nucleus ameliorates motor asymmetry in an animal model of Parkinson's disease.

    PubMed

    Phillips, Janice M; Lam, Hoa A; Ackerson, Larry C; Maidment, Nigel T

    2006-01-01

    It has been suggested that Group I metabotropic glutamate receptor antagonists could have potential therapeutic value in the treatment of Parkinson's disease. There is evidence that when given systemically, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a metabotropic glutamate receptor type 5 (mGluR5) antagonist, produces anti-parkinsonian effects in animal models, but the site of action has not been directly established. In the present study, we examined whether the subthalamic nucleus (STN) and its output structures may mediate such an effect using a unilateral rat model of Parkinson's disease. A battery of simple behavioral tests, reliably sensitive to dopamine depletion, was applied consecutively: (i) prior to surgery; (ii) 3 weeks following a unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta; (iii) at 1 h, 24 h and 4 days following a microinjection of MPEP, via an indwelling cannula, into the STN, entopeduncular nucleus (EP) or substantia nigra zona reticulata. Unilaterally dopamine-depleted animals typically had severe motor and sensorimotor asymmetries 3 weeks following surgery. Microinjection of 25 nmol MPEP into the STN of these animals significantly attenuated these asymmetries relative to vehicle. Further microinjections of lower doses (5 and 10 nmol) revealed a dose-response effect. Microinjection of MPEP into either the EP or substantia nigra zona reticulata was without effect. These data suggest that MPEP may act at the level of the STN to reduce glutamatergic overactivity and thereby induce anti-parkinsonian effects. PMID:16420425

  5. [Parkinson's disease and cortico-Basal Ganglia circuits].

    PubMed

    Pan, Ming-Kai; Tai, Chun-Hwei; Kuo, Chung-Chin

    2010-09-01

    Cortico-basal ganglia circuit model has been studied extensively after it was first proposed by Alexander and Crutcher in 1990. This model accurately predicted the hyperactivity of indirect pathway and subthalamic nucleus(STN) in the dopamine deficiency state of Parkinson's disease (PD), prompting the experimental approaches of lesioning STN in parkinsonian primates. Application of these successful experiences with STN lesions in the reversal of parkinsonian symptoms to human PD patients facilitates the development of STN deep brain stimulation (DBS), which has become one of the most important therapies for PD in recent years. Although the classical model of the cortico-basal ganglia circuits by Alexander and Crutcher has provided many important insights into the basal ganglia function, the functional role of cortico-subthalamic "hyperdirect" pathway in the circuits has been relatively neglected. The first part of this article summarizes recent development concerning the cortico-basal ganglia circuits, especially emphasizing the importance of the hyperdirect pathway. In the second part of this article, we would describe the analyses of gross corticobasal ganglia circuit electrophysiological findings, especially emphasizing the coherence between two oscillating signals. We would also discuss the correlation between these parameters and the motor dysfunction, and its pathophysiological implications in PD. PMID:20824544

  6. Near-infrared stimulation on globus pallidus and subthalamus

    NASA Astrophysics Data System (ADS)

    Yoo, Minsu; Koo, Ho; Kim, Minsun; Kim, Hyoung-Ihl; Kim, Sohee

    2013-12-01

    Near-infrared stimulation (NIS) is an emerging technique used to evoke action potentials in nervous systems. Its efficacy of evoking action potentials has been demonstrated in different nerve tissues. However, few studies have been performed using NIS to stimulate the deep brain structures, such as globus pallidus (GP) and subthalamic nucleus (STN). Male Sprague-Dawley rats were randomly divided into GP stimulation group (n=11) and STN stimulation group (n=6). After introducing optrodes stereotaxically into the GP or STN, we stimulated neural tissue for 2 min with continuous near-infrared light of 808 nm while varying the radiant exposure from 40 to 10 mW. The effects were investigated with extracellular recordings and the temperature rises at the stimulation site were also measured. NIS was found to elicit excitatory responses in eight out of 11 cases (73%) and inhibitory responses in three cases in the GP stimulation group, whereas it predominantly evoked inhibitory responses in seven out of eight cases (87.5%) and an excitatory response in one case in STN stimulation group. Only radiation above 20 mW, accompanying temperature increases of more than 2°C, elicited a statistically significant neural response (p<0.05). The responsiveness to NIS was linearly dependent on the power of radiation exposure.

  7. FACS array profiling identifies Ecto-5' nucleotidase as a striatopallidal neuron-specific gene involved in striatal-dependent learning.

    PubMed

    Ena, Sabrina L; De Backer, Jean-François; Schiffmann, Serge N; de Kerchove d'Exaerde, Alban

    2013-05-15

    The striatopallidal (STP) and striatonigral (STN) neurons constitute the main neuronal populations of the striatum. Despite the increasing knowledge concerning their involvement in multiple tasks associated with the striatum, it is still challenging to understand the precise differential functions of these two neuronal populations and to identify and study new genes involved in these functions. Here, we describe a reliable approach, applied on adult mouse brain, to generate specific STP and STN neuron gene profiles. STP and STN neurons were identified in the same animal using the transgenic Adora2A-Cre × Z/EG mouse model combined with retrograde labeling, respectively. Gene profiling was generated from FACS-purified neurons leading to the identification of new STP and STN neuron-specific genes. Knock-down models based on Cre-dependent lentiviral vector were developed to investigate their function either in striatal or in STP neurons. Thereby, we demonstrate that ecto-5'-nucleotidase (NT5e) is specifically expressed in STP neurons and is at the origin of most of the extracellular adenosine produced in the striatum. Behavioral analysis of striatal and STP neuron knock-down mouse models as well as NT5e knock-out mice demonstrates the implication of this STP neuron enzyme in motor learning. PMID:23678122

  8. Underlying neurobiology and clinical correlates of mania status after subthalamic nucleus deep brain stimulation in Parkinson's disease: a review of the literature.

    PubMed

    Chopra, Amit; Tye, Susannah J; Lee, Kendall H; Sampson, Shirlene; Matsumoto, Joseph; Adams, Andrea; Klassen, Bryan; Stead, Matt; Fields, Julie A; Frye, Mark A

    2012-01-01

    Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson's disease (PD). The authors review the current literature to identify the clinical correlates associated with subthalamic nucleus (STN) DBS-induced hypomania/mania in PD patients. Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male sex, and/or early-onset PD. STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanisms of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight toward development of future DBS mood-stabilization therapies. PMID:22450620

  9. Recognition of emotional prosody is altered after subthalamic nucleus deep brain stimulation in Parkinson's disease.

    PubMed

    Péron, Julie; Grandjean, Didier; Le Jeune, Florence; Sauleau, Paul; Haegelen, Claire; Drapier, Dominique; Rouaud, Tiphaine; Drapier, Sophie; Vérin, Marc

    2010-03-01

    The recognition of facial emotions is impaired following subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD). These changes have been linked to a disturbance in the STN's limbic territory, which is thought to be involved in emotional processing. This was confirmed by a recent PET study where these emotional modifications were correlated with changes in glucose metabolism in different brain regions, including the amygdala and the orbitofrontal regions that are well known for their involvement in emotional processing. Nevertheless, the question as to whether these emotional changes induced by STN DBS in PD are modality-specific has yet to be answered. The objective of this study was therefore to examine the effects of STN DBS in PD on the recognition of emotional prosody. An original emotional prosody paradigm was administered to twenty-one post-operative PD patients, twenty-one pre-operative PD patients and twenty-one matched controls. Results showed that both the pre- and post-operative groups differed from the healthy controls. There was also a significant difference between the pre and post groups. More specifically, an analysis of their continuous judgments revealed that the performance of the post-operative group compared with that of the other two groups was characterized by a systematic emotional bias whereby they perceived emotions more strongly. These results suggest that the impaired recognition of emotions may not be specific to the visual modality but may also be present when emotions are expressed through the human voice, implying the involvement of the STN in the brain network underlying the recognition of emotional prosody. PMID:20005239

  10. Dopamine Release in the Nonhuman Primate Caudate and Putamen Depends upon Site of Stimulation in the Subthalamic Nucleus

    PubMed Central

    Min, Hoon-Ki; Ross, Erika K.; Jo, Hang Joon; Cho, Shinho; Settell, Megan L.; Jeong, Ju Ho; Duffy, Penelope S.; Chang, Su-Youne; Bennet, Kevin E.; Blaha, Charles D.

    2016-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for medically refractory Parkinson's disease. Although DBS has recognized clinical utility, its biologic mechanisms are not fully understood, and whether dopamine release is a potential factor in those mechanisms is in dispute. We tested the hypothesis that STN DBS-evoked dopamine release depends on the precise location of the stimulation site in the STN and the site of recording in the caudate and putamen. We conducted DBS with miniature, scaled-to-animal size, multicontact electrodes and used functional magnetic resonance imaging to identify the best dopamine recording site in the brains of nonhuman primates (rhesus macaques), which are highly representative of human brain anatomy and circuitry. Real-time stimulation-evoked dopamine release was monitored using in vivo fast-scan cyclic voltammetry. This study demonstrates that STN DBS-evoked dopamine release can be reduced or increased by redirecting STN stimulation to a slightly different site. SIGNIFICANCE STATEMENT Electrical stimulation of deep structures of the brain, or deep brain stimulation (DBS), is used to modulate pathological brain activity. However, technological limitations and incomplete understanding of the therapeutic mechanisms of DBS prevent personalization of this therapy and may contribute to less-than-optimal outcomes. We have demonstrated that DBS coincides with changes in dopamine neurotransmitter release in the basal ganglia. Here we mapped relationships between DBS and changes in neurochemical activity. Importantly, this study shows that DBS-evoked dopamine release can be reduced or increased by refocusing the DBS on a slightly different stimulation site. PMID:27251623

  11. The combined depletion of monoamines alters the effectiveness of subthalamic deep brain stimulation.

    PubMed

    Faggiani, Emilie; Delaville, Claire; Benazzouz, Abdelhamid

    2015-10-01

    Non-motor symptoms of Parkinson's disease are under-studied and therefore not well treated. Here, we investigated the role of combined depletions of dopamine, norepinephrine and/or serotonin in the manifestation of motor and non-motor deficits in the rat. Then, we studied the impact of these depletions on the efficacy of deep brain stimulation of the subthalamic nucleus (STN-DBS). We performed selective depletions of dopamine, norepinephrine and serotonin, and the behavioral effects of different combined depletions were investigated using the open field, the elevated plus maze and the forced swim test. Bilateral dopamine depletion alone induced locomotor deficits associated with anxiety and mild "depressive-like" behaviors. Although additional depletions of norepinephrine and/or serotonin did not potentiate locomotor and anxiety disorders, combined depletions of the three monoamines dramatically exacerbated "depressive-like" behavior. STN-DBS markedly reversed locomotor deficits and anxiety behavior in animals with bilateral dopamine depletion alone. However, these improvements were reduced or lost by the additional depletion of norepinephrine and/or serotonin, indicating that the depletion of these monoamines may interfere with the antiparkinsonian efficacy of STN-DBS. Furthermore, our results showed that acute STN-DBS improved "depressive-like" disorder in animals with bilateral depletion of dopamine and also in animals with combined depletions of the three monoamines, which induced severe immobility in the forced swim test. Our data highlight the key role of monoamine depletions in the pathophysiology of anxiety and depressive-like disorders and provide the first evidence of their negative consequences on the efficacy of STN-DBS upon the motor and anxiety disorders in the context of Parkinson's disease. PMID:26206409

  12. Weight Gain following Pallidal Deep Brain Stimulation: A PET Study.

    PubMed

    Sauleau, Paul; Drapier, Sophie; Duprez, Joan; Houvenaghel, Jean-François; Dondaine, Thibaut; Haegelen, Claire; Drapier, Dominique; Jannin, Pierre; Robert, Gabriel; Le Jeune, Florence; Vérin, Marc

    2016-01-01

    The mechanisms behind weight gain following deep brain stimulation (DBS) surgery seem to be multifactorial and suspected depending on the target, either the subthalamic nucleus (STN) or the globus pallidus internus (GPi). Decreased energy expenditure following motor improvement and behavioral and/or metabolic changes are possible explanations. Focusing on GPi target, our objective was to analyze correlations between changes in brain metabolism (measured with PET) and weight gain following GPi-DBS in patients with Parkinson's disease (PD). Body mass index was calculated and brain activity prospectively measured using 2-deoxy-2[18F]fluoro-D-glucose PET four months before and four months after the start of GPi-DBS in 19 PD patients. Dopaminergic medication was included in the analysis to control for its possible influence on brain metabolism. Body mass index increased significantly by 0.66 ± 1.3 kg/m2 (p = 0.040). There were correlations between weight gain and changes in brain metabolism in premotor areas, including the left and right superior gyri (Brodmann area, BA 6), left superior gyrus (BA 8), the dorsolateral prefrontal cortex (right middle gyrus, BAs 9 and 46), and the left and right somatosensory association cortices (BA 7). However, we found no correlation between weight gain and metabolic changes in limbic and associative areas. Additionally, there was a trend toward a correlation between reduced dyskinesia and weight gain (r = 0.428, p = 0.067). These findings suggest that, unlike STN-DBS, motor improvement is the major contributing factor for weight gain following GPi-DBS PD, confirming the motor selectivity of this target. PMID:27070317

  13. Weight Gain following Pallidal Deep Brain Stimulation: A PET Study

    PubMed Central

    Sauleau, Paul; Drapier, Sophie; Duprez, Joan; Houvenaghel, Jean-François; Dondaine, Thibaut; Haegelen, Claire; Drapier, Dominique; Jannin, Pierre; Robert, Gabriel; Le Jeune, Florence; Vérin, Marc

    2016-01-01

    The mechanisms behind weight gain following deep brain stimulation (DBS) surgery seem to be multifactorial and suspected depending on the target, either the subthalamic nucleus (STN) or the globus pallidus internus (GPi). Decreased energy expenditure following motor improvement and behavioral and/or metabolic changes are possible explanations. Focusing on GPi target, our objective was to analyze correlations between changes in brain metabolism (measured with PET) and weight gain following GPi-DBS in patients with Parkinson’s disease (PD). Body mass index was calculated and brain activity prospectively measured using 2-deoxy-2[18F]fluoro-D-glucose PET four months before and four months after the start of GPi-DBS in 19 PD patients. Dopaminergic medication was included in the analysis to control for its possible influence on brain metabolism. Body mass index increased significantly by 0.66 ± 1.3 kg/m2 (p = 0.040). There were correlations between weight gain and changes in brain metabolism in premotor areas, including the left and right superior gyri (Brodmann area, BA 6), left superior gyrus (BA 8), the dorsolateral prefrontal cortex (right middle gyrus, BAs 9 and 46), and the left and right somatosensory association cortices (BA 7). However, we found no correlation between weight gain and metabolic changes in limbic and associative areas. Additionally, there was a trend toward a correlation between reduced dyskinesia and weight gain (r = 0.428, p = 0.067). These findings suggest that, unlike STN-DBS, motor improvement is the major contributing factor for weight gain following GPi-DBS PD, confirming the motor selectivity of this target. PMID:27070317

  14. Low Birth Weight and Risk of Progression to End Stage Renal Disease in IgA Nephropathy—A Retrospective Registry-Based Cohort Study

    PubMed Central

    Svarstad, Einar; Leh, Sabine; Marti, Hans-Peter; Reisæther, Anna Varberg

    2016-01-01

    Background Low Birth Weight (LBW) is a surrogate for fetal undernutrition and is associated with impaired nephron development in utero. In this study, we investigate whether having been born LBW and/or small for gestational age (SGA) predict progression to ESRD in IgA nephropathy (IgAN) patients. Study Design Retrospective registry-based cohort study. Settings & Participants The Medical Birth Registry has recorded all births since 1967 and the Norwegian Renal Registry has recorded all patients with ESRD since 1980. Based on data from the Norwegian Kidney Biopsy Registry we included all patients diagnosed with IgAN in Norway from 1988–2013. These registries were linked and we analysed risk of progression to ESRD associated with LBW (defined as birth weight less than the 10th percentile) and/or SGA (defined as birth weight less than the 10th percentile for gestational week) by Cox regression statistics. Results We included 471 patients, of whom 74 developed ESRD. As compared to patients without LBW, patients with LBW had a hazard ratio (HR) of 2.0 (95% confidence interval 1.1–3.7) for the total cohort, 2.2 (1.1–4.4) for males and 1.3 (0.30–5.8) for females. Corresponding HRs for SGA were 2.2 (1.1–4.2), 2.7 (1.4–5.5) and 0.8 (0.10–5.9). Further analyses showed that as compared to patients with neither LBW nor SGA, patients with either SGA or LBW did not have significantly increased risks (HRs of 1.3–1.4) but patients who were both LBW and SGA had an increased risk (HR 3.2 (1.5–6.8). Limitation Mean duration of follow-up only 10 years and maximum age only 46 years. Conclusion Among IgAN patients, LBW and/or SGA was associated with increased risk for progression to ESRD, the association was stronger in males. PMID:27092556

  15. Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus

    PubMed Central

    Gulberti, A.; Moll, C.K.E.; Hamel, W.; Buhmann, C.; Koeppen, J.A.; Boelmans, K.; Zittel, S.; Gerloff, C.; Westphal, M.; Schneider, T.R.; Engel, A.K.

    2015-01-01

    Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing. PMID:26594626

  16. Subthalamic Nucleus Deep Brain Stimulation Impacts Language in Early Parkinson's Disease

    PubMed Central

    Phillips, Lara; Litcofsky, Kaitlyn A.; Pelster, Michael; Gelfand, Matthew

    2012-01-01

    Although deep brain stimulation (DBS) of the basal ganglia improves motor outcomes in Parkinson's disease (PD), its effects on cognition, including language, remain unclear. This study examined the impact of subthalamic nucleus (STN) DBS on two fundamental capacities of language, grammatical and lexical functions. These functions were tested with the production of regular and irregular past-tenses, which contrast aspects of grammatical (regulars) and lexical (irregulars) processing while controlling for multiple potentially confounding factors. Aspects of the motor system were tested by contrasting the naming of manipulated (motor) and non-manipulated (non-motor) objects. Performance was compared between healthy controls and early-stage PD patients treated with either DBS/medications or medications alone. Patients were assessed on and off treatment, with controls following a parallel testing schedule. STN-DBS improved naming of manipulated (motor) but not non-manipulated (non-motor) objects, as compared to both controls and patients with just medications, who did not differ from each other across assessment sessions. In contrast, STN-DBS led to worse performance at regulars (grammar) but not irregulars (lexicon), as compared to the other two subject groups, who again did not differ. The results suggest that STN-DBS negatively impacts language in early PD, but may be specific in depressing aspects of grammatical and not lexical processing. The finding that STN-DBS affects both motor and grammar (but not lexical) functions strengthens the view that both depend on basal ganglia circuitry, although the mechanisms for its differential impact on the two (improved motor, impaired grammar) remain to be elucidated. PMID:22880117

  17. Final report of work carried out under contract with Los Alamos National Laboratory, June 1, 1989--May 31, 1990

    SciTech Connect

    Not Available

    1990-12-31

    This report contains information about a research program where the effects of streptozyatocin has on diabetes. The researchers look at biochemical, physiological, and metabolic processes. Other things of interest to the researchers include; filtration by kidneys, number of nephrons per kidney, and microperfusion studies performed to learn more about the effects of unmodified and glucosylated albumin.

  18. High Light-Dependent Phosphorylation of Photosystem II Inner Antenna CP29 in Monocots Is STN7 Independent and Enhances Nonphotochemical Quenching1

    PubMed Central

    Betterle, Nico; Ballottari, Matteo; Baginsky, Sacha; Bassi, Roberto

    2015-01-01

    Phosphorylation of the photosystem II antenna protein CP29 has been reported to be induced by excess light and further enhanced by low temperature, increasing resistance to these stressing factors. Moreover, high light-induced CP29 phosphorylation was specifically found in monocots, both C3 and C4, which include the large majority of food crops. Recently, knockout collections have become available in rice (Oryza sativa), a model organism for monocots. In this work, we have used reverse genetics coupled to biochemical and physiological analysis to elucidate the molecular basis of high light-induced phosphorylation of CP29 and the mechanisms by which it exerts a photoprotective effect. We found that kinases and phosphatases involved in CP29 phosphorylation are distinct from those reported to act in State 1-State 2 transitions. In addition, we elucidated the photoprotective role of CP29 phosphorylation in reducing singlet oxygen production and enhancing excess energy dissipation. We thus established, in monocots, a mechanistic connection between phosphorylation of CP29 and nonphotochemical quenching, two processes so far considered independent from one another. PMID:25501945

  19. Radio-frequency ablation helps preserve nephrons in salvage of failed microwave ablation for a renal cancer in a solitary kidney.

    PubMed

    Castle, Scott M; Salas, Nelson; Leveillee, Raymond J

    2013-01-01

    Recurrent tumors after renal ablative therapy present a challenge for clinicians. New ablative modalities, including microwave ablation (MWA), have very limited experience in methods of retreating ablation failures. Additionally, in MWA, no long-term outcomes have been reported. In patients having local tumor recurrence, options for surveillance or surgical salvage must be assessed. We present a case to help assess radio-frequency ablation (RFA) for salvage of failed MWA. We report a 63-year-old male with a 4.33-cm renal mass in a solitary kidney undergoing laparoscopic MWA with simultaneous peripheral fiber-optic thermometry (Lumasense, Santa Clara, CA, USA) as primary treatment. Follow-up contrast-enhanced computed tomography (CT) scan was performed at 1 and 4.3 months post-op with failure occurring at 4.3 months as evidenced by persistent enhancement. Subsequently, a laparoscopic RFA (LRFA) with simultaneous peripheral fiber-optic thermometry was performed as salvage therapy. Clinical and radiological follow-up with a contrast-enhanced CT scan at 1 and 11 months post-RFA showed no evidence of disease or enhancement. Creatinine values pre-MWA, post-MWA, and post-RFA were 1.01, 1.14, and 1.17 mg/ml, respectively. This represents a 15% decrease in estimated glomerular filtration rate (eGFR) (79 to 67 ml/min) post-MWA and no change in eGFR post-RFA. Local kidney tumor recurrence often requires additional therapy and a careful decisionmaking process. It is desirable not only to preserve kidney function in patients with a solitary kidney or chronic renal insufficiency, but also to achieve cancer control. We show the feasibility of RFA for salvage treatment of local recurrence of a T1b tumor in a solitary kidney post-MWA. PMID:23662010

  20. Activation of caspase-3 and its correlation with shear force in bovine skeletal muscles during postmortem conditioning.

    PubMed

    Cao, J-X; Ou, C-R; Zou, Y-F; Ye, K-P; Zhang, Q-Q; Khan, M A; Pan, D-D; Zhou, G

    2013-09-01

    The study was aimed at exploring the mechanism of tenderization by establishing a correlation between caspase-3 activity and shear force, verifying the activation occurring by analyzing active caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) fragments, and understanding the pathways involved in activation of caspase-3 by evaluating its correlation with caspase-8 and -9 activities in LM, semitendinosus (STN), and psoas minor (PM) muscles. The results indicated that shear force decreased at 48 h in PM (P < 0.01), LM (P < 0.01), and STN (P < 0.05). We detected p22, p23, p20, and p18 caspase fragments as well as distinctive PARP fragments of 24 kDa by caspase-3 and 36 kDa by µ-calpain. Caspase-3 activity correlated with shear force negatively at 24 and 48 h in STN (P < 0.01 at 24 h; P < 0.01 at 48 h), PM (P < 0.001 at 24 h; P < 0.01 at 48 h), and LM muscles (P < 0.05 at 24 h; P < 0.01 at 48 h). The greatest activities of caspase-8 (P < 0.001 in PM and STN; P < 0.01 in LM) and caspase-9 (P < 0.001 in muscles) appeared at 4 h whereas that of caspase-3 was at 24 h (P < 0.001 in muscles). Caspase-9 activity correlated positively with caspase-3 at 4, 24, and 48 h in STN (P < 0.01 at 4 h; P < 0.05 at 24 h; P < 0.001 at 48 h) and at 4 and 96 h in PM (P < 0.001 at 4 h; P < 0.05 at 96 h) and LM muscles (P < 0.001 at 4 h; P < 0.001 at 96 h). The caspase-8 activity correlated with caspase-3 at 4, 48, and 96 h in STN (P < 0.05 at 4 h; P < 0.001 at 48 h; P < 0.05 at 96 h), at 4 and 24 h in PM (P < 0.001 at 4 h; P < 0.05 at 24 h), and at 4 and 96 h in LM (P < 0.001 at 4 h; P < 0.01 at 96 h). We concluded that caspase-3 was associated with the decline of shear force; the activation of caspase-3 was mediated by caspases -8 and -9 in muscles. However, more detailed studies are needed to define the precise mechanism for the cleavage of pro-caspases -8 and -9 during conditioning. PMID:23893998

  1. Subthalamic Nucleus Deep Brain Stimulation May Reduce Medication Costs in Early Stage Parkinson’s Disease

    PubMed Central

    Hacker, Mallory L.; Currie, Amanda D.; Molinari, Anna L.; Turchan, Maxim; Millan, Sarah M.; Heusinkveld, Lauren E.; Roach, Jonathon; Konrad, Peter E.; Davis, Thomas L.; Neimat, Joseph S.; Phibbs, Fenna T.; Hedera, Peter; Byrne, Daniel W.; Charles, David

    2016-01-01

    Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson’s disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT). Objective: The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs. Methods: Medication data collected at each visit were used to calculate medication costs. Medications were converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS. Results: Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of $7,150 over the study period. Projected medication cost savings over 10 years reach $64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months (p <  0.05; OR = 0.2; 95% CI: 0.04–0.97). Conclusions: STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD. PMID:26967937

  2. Spatiotemporal visualization of deep brain stimulation-induced effects in the subthalamic nucleus.

    PubMed

    Yousif, Nada; Borisyuk, Roman; Pavese, Nicola; Nandi, Dipankar; Bain, Peter

    2012-07-01

    Deep brain stimulation (DBS) is a successful surgical therapy used to treat the disabling symptoms of movement disorders such as Parkinson's disease. It involves the chronic stimulation of disorder-specific nuclei. However, the mechanisms that lead to clinical improvements remain unclear. Consequently, this slows the optimization of present-day DBS therapy and hinders its future development and application. We used a computational model to calculate the distribution of electric potential induced by DBS and study the effect of stimulation on the spiking activity of a subthalamic nucleus (STN) projection neuron. We previously showed that such a model can reveal detailed spatial effects of stimulation in the vicinity of the electrode. However, this multi-compartmental STN neuron model can fire in either a burst or tonic mode and, in this study, we hypothesized that the firing mode of the cell will have a major impact on the DBS-induced effects. Our simulations showed that the bursting model exhibits behaviour observed in studies of high-frequency stimulation of STN neurons, such as the presence of a silent period at stimulation offset and frequency-dependent stimulation effects. We validated the model by simulating the clinical parameter settings used for a Parkinsonian patient and showed, in a patient-specific anatomical model, that the region of affected tissue is consistent with clinical observations of the optimal DBS site. Our results demonstrated a method of quantitatively assessing neuronal changes induced by DBS, to maximize therapeutic benefit and minimize unwanted side effects. PMID:22805069

  3. Deep brain stimulation of the subthalamic nucleus facilitates coordination of hand preshaping in Parkinson's disease.

    PubMed

    Schettino, L F; Van Erp, E; Hening, W; Lessig, S; Song, D; Barba, D; Poizner, H

    2009-01-01

    Several studies have found that Parkinson's disease (PD) disrupts the organization of complex motor sequences regardless of the influence of parkinsonian medications. A clear candidate for the neural bases of such deficits, which we term "coordinative," is the failure to integrate propioceptive and visual information by cortico-striatal circuits in a timed fashion. Recent reports, however, have indicated that deep-brain stimulation of the subthalamic nucleus (STN DBS) may result in an improvement in coordinative deficits beyond the amelioration of "intensive deficits" such as bradykinesia and scaling errors. The present study examined the spatio-temporal organization underlying the shaping of the hand during reaching to grasp objects differing in shape. Six PD patients ON and OFF their STN DBS when OFF their concomitant medications and six age-matched controls participated in this study. STN DBS improved the coordination involved in preshaping the hand while grasping. We discuss these results in light of our earlier work with PD patients on and off dopamine replacement therapy. PMID:19922392

  4. Effects of Subthalamic Nucleus Stimulation on Emotional Prosody Comprehension in Parkinson's Disease

    PubMed Central

    Kreifelts, Benjamin; Krüger, Rejko; Wächter, Tobias

    2011-01-01

    Background Although impaired decoding of emotional prosody has frequently been associated with Parkinson's disease (PD), to date only few reports have sought to explore the effect of Parkinson's treatment on disturbances of prosody decoding. In particular, little is known about how surgical treatment approaches such as high frequency deep brain stimulation (DBS) affect emotional speech perception in patients with PD. Accordingly, the objective of this study was to evaluate the effect of subthalamic nucleus (STN) stimulation on prosody processing. Methodology/Principal Findings To this end the performance of 13 PD patients on three tasks requiring the decoding of emotional speech was assessed and subsequently compared to the performance of healthy control individuals. To delineate the effect of STN-DBS, all patients were tested with stimulators turned on as well as with stimulators turned off. Results revealed that irrespective of whether assessments were made “on” or “off” stimulation, patients' performance was less accurate as compared to healthy control participants on all tasks employed in this study. However, while accuracy appeared to be unaffected by stimulator status, a facilitation of reactions specific to highly conflicting emotional stimulus material (i.e. stimulus material presenting contradicting emotional messages on a verbal and non-verbal prosodic level) was observed during “on” stimulation assessments. Conclusion In sum, presented results suggest that the processing of emotional speech is indeed modulated by STN-DBS. Observed alterations might, on the one hand, reflect a more efficient processing of highly conflicting stimulus material following DBS. However, on the other hand, given the lack of an improvement in accuracy, increased impulsivity associated with STN stimulation needs to be taken into consideration. PMID:21552518

  5. Chemical mass balance source apportionment for combined PM 2.5 measurements from U.S. non-urban and urban long-term networks

    NASA Astrophysics Data System (ADS)

    Antony Chen, L.-W.; Watson, John G.; Chow, Judith C.; DuBois, David W.; Herschberger, Lisa

    2010-12-01

    The Minnesota Particulate Matter 2.5 (PM 2.5) Source Apportionment Study was undertaken to explore the utility of PM 2.5 mass, element, ion, and carbon measurements from long-term speciation networks for pollution source attribution. Ambient monitoring data at eight sites across the state were retrieved from the archives of the Interagency Monitoring of Protected Visual Environments (IMPROVE) and the Speciation Trends Network (STN; part of the Chemical Speciation Network [CSN]) and analyzed by an Effective Variance - Chemical Mass Balance (EV-CMB) receptor model with region-specific geological source profiles developed in this study. PM 2.5 was apportioned into contributions of fugitive soil dust, calcium-rich dust, taconite (low grade iron ore) dust, road salt, motor vehicle exhaust, biomass burning, coal-fired utility, and secondary aerosol. Secondary sulfate and nitrate contributed strongly (49-71% of PM 2.5) across all sites and was dominant (≥60%) at IMPROVE sites. Vehicle exhausts accounted for 20-70% of the primary PM 2.5 contribution, largely exceeding the proportion in the primary PM 2.5 emission inventory. The diesel exhaust contribution was separable from the gasoline engine exhaust contribution at the STN sites. Higher detection limits for several marker elements in the STN resulted in non-detectable coal-fired boiler contributions which were detected in the IMPROVE data. Despite the different measured variables, analytical methods, and detection limits, EV-CMB results from a nearby IMPROVE-STN non-urban/urban sites showed similar contributions from regional sources - including fugitive dust and secondary aerosol. Seasonal variations of source contributions were examined and extreme PM 2.5 episodes were explained by both local and regional pollution events.

  6. Effects of subthalamic nucleus stimulation on motor cortex plasticity in Parkinson disease

    PubMed Central

    Kim, Sang Jin; Udupa, Kaviraja; Ni, Zhen; Moro, Elena; Gunraj, Carolyn; Mazzella, Filomena; Lozano, Andres M.; Hodaie, Mojgan; Lang, Anthony E.

    2015-01-01

    Objective: We hypothesized that subthalamic nucleus (STN) deep brain stimulation (DBS) will improve long-term potentiation (LTP)-like plasticity in motor cortex in Parkinson disease (PD). Methods: We studied 8 patients with PD treated with STN-DBS and 9 age-matched healthy controls. Patients with PD were studied in 4 sessions in medication (Med) OFF/stimulator (Stim) OFF, Med-OFF/Stim-ON, Med-ON/Stim-OFF, and Med-ON/Stim-ON states in random order. Motor evoked potential amplitude and cortical silent period duration were measured at baseline before paired associated stimulation (PAS) and at 3 different time intervals (T0, T30, T60) up to 60 minutes after PAS in the abductor pollicis brevis and abductor digiti minimi muscles. Results: Motor evoked potential size significantly increased after PAS in controls (+67.7% of baseline at T30) and in patients in the Med-ON/Stim-ON condition (+55.8% of baseline at T30), but not in patients in the Med-OFF/Stim-OFF (−0.4% of baseline at T30), Med-OFF/Stim-ON (+10.3% of baseline at T30), and Med-ON/Stim-OFF conditions (+17.3% of baseline at T30). Cortical silent period duration increased after PAS in controls but not in patients in all test conditions. Conclusions: Our findings suggest that STN-DBS together with dopaminergic medications restore LTP-like plasticity in motor cortex in PD. Restoration of cortical plasticity may be one of the mechanisms of how STN-DBS produces clinical benefit. PMID:26156511

  7. Estimation of organic carbon blank values and error structures of the speciation trends network data for source apportionment

    SciTech Connect

    Eugene Kim; Philip K. Hopke; Youjun Qin

    2005-08-01

    Because the particulate organic carbon (OC) concentrations reported in U.S. Environment Protection Agency Speciation Trends Network (STN) data were not blank corrected, the OC blank concentrations were estimated using the intercept in particulate matter {lt} 2.5 {mu}m in aerodynamic diameter (PM2.5) regression against OC concentrations. The estimated OC blank concentrations ranged from 1 to 2.4 {mu}g/m{sup 3} showing higher values in urban areas for the 13 monitoring sites in the northeastern United States. In the STN data, several different samplers and analyzers are used, and various instruments show different method detection limit (MDL) values, as well as errors. A comprehensive set of error structures that would be used for numerous source apportionment studies of STN data was estimated by comparing a limited set of measured concentrations and their associated uncertainties. To examine the estimated error structures and investigate the appropriate MDL values, PM2.5 samples collected at a STN site in Burlington, VT, were analyzed through the application of the positive matrix factorization. A total of 323 samples that were collected between December 2000 and December 2003 and 49 species based on several variable selection criteria were used, and eight sources were successfully identified in this study with the estimated error structures and min values among different MDL values from the five instruments: secondary sulfate aerosol (41%) identified as the result of emissions from coal-fired power plants, secondary nitrate aerosol (20%), airborne soil (15%), gasoline vehicle emissions (7%), diesel emissions (7%), aged sea salt (4%), copper smelting (3%), and ferrous smelting (2%). Time series plots of contributions from airborne soil indicate that the highly elevated impacts from this source were likely caused primarily by dust storms.

  8. Intensive Voice Treatment (LSVT®LOUD) for Parkinson’s disease following Deep Brain Stimulation of the Subthalamic Nucleus

    PubMed Central

    Spielman, Jennifer; Mahler, Leslie; Halpern, Angela; Gilley, Phllip; Klepitskaya, Olga; Ramig, Lorraine

    2011-01-01

    Purpose Intensive voice therapy (LSVT®LOUD) can effectively manage voice and speech symptoms associated with idiopathic Parkinson disease (PD). This small-group study evaluated voice and speech in individuals with and without deep brain stimulation of the subthalamic nucleus (STN-DBS) before and after LSVT LOUD, to determine whether outcomes for surgical subjects were comparable to non-surgical cohorts. Methods Eight subjects with PD (four with STN-DBS and four without) received LSVT LOUD four times a week for four weeks. Four additional subjects with PD remained untreated. Voice intensity (SPL), Vowel Articulation Index (VAI), the Voice Handicap Index (VHI), and a structured interview were evaluated before and after treatment and again six months later. Results Both treated groups showed significant increases in SPL from pre to post and six-month follow up. VAI was significantly higher for the treated groups compared to the untreated subjects at follow up. Several treated individuals had significant clinical improvement in VHI scores, particularly within the LSVT-DBS group. Treated individuals reported improvements in voice and speech in structured interviews; however, answers suggest more variable long-term maintenance within the LSVT-DBS group. The untreated group exhibited no significant changes in any measure throughout the study. Conclusions Results support LSVT LOUD for treating voice and speech in individuals with PD following STN-DBS surgery. However, modifications may be required to maintain functional improvements. PMID:21724193

  9. Seasonal variation in the biochemical composition of red seaweed ( Catenella repens) from Gangetic delta, northeast coast of India

    NASA Astrophysics Data System (ADS)

    Banerjee, Kakoli; Ghosh, Rajrupa; Homechaudhuri, Sumit; Mitra, Abhijit

    2009-10-01

    The biochemical composition of red seaweeds, Catenella repens was investigated in this present study along with subsequent analysis of relevant physico-chemical variables. In this study, the relationship between the nutritive components of this species and the ambient environmental parameters was established. Protein content varied from 2.78 ± 0.30% of dry weight (stn.3) to 16.03 ± 0.96% of dry weight (stn.1) with highest values during monsoon. The protein levels were positively correlated with dissolved nitrate content and negatively correlated with water temperature (except stn.3) and salinity. Carbohydrate content of this species varied significantly ( p < 0.05) during pre-monsoon between stations and the values showed positive relationship with salinity and surface water temperature. In contrast to carbohydrate, lipid concentration was lowest in values and varied very slightly between seasons and stations. Astaxanthin content of the seaweed species was greater in pre-monsoon than monsoon and post-monsoon in all the selected stations. Compared with the three seasons, samples of red seaweed collected in pre-monsoon has high carbohydrate-astaxanthin in contrast to protein-lipid which showed high values during monsoon. Statistical analysis computed among the environmental and biochemical parameters suggests the potential role played by the abiotic parameters on biosynthetic pathways of seaweed. This paper also highlights the influence of the nutritional quality of water that can be used for mass cultivation of Catenella repens.

  10. Altitudinal gradients of soil and vegetation carbon and nitrogen in a high altitude nature reserve of Karakoram ranges.

    PubMed

    Shedayi, Arshad Ali; Xu, Ming; Naseer, Iqnaa; Khan, Babar

    2016-01-01

    This study aimed to investigate the correlation of carbon and nitrogen in soil and leaves with the altitude, vegetation type, herbaceous biomass (HB), litter mass (LM) and with each other. Soil and leaf samples collected from different forest types along altitudinal gradients in the Karakoram Mountains. Dry and gas law methods were used for the chemical analysis. Regression models used for correlation analysis and T test for comparison. The correlation of soil total carbon (STC) and soil total nitrogen (STN) along altitudinal gradients and correlation between soil organic carbon (SOC) and STN was significantly positive with the values R(2) = 0.1684, p = 0.01, R(2) = 0.1537, p = 0.009 and R(2) = 0.856, p = 7.31E-10 respectively, while it was non-significant between soil inorganic carbon (SIC) and altitude and also between SIC and STN. The concentration of SOC and STN was highest in the broad leaved Betula utilis forest (22.31, 1.6 %) and least in the mixed (Pinus, Juniper, Betula) forest soil (0.85, 0.09 %) respectively. In the tree species leaf total carbon (LTC) and leaf total nitrogen (LTN) were highest in the Pinus wallichiana (PW) (632.54, 19.77), and least in the Populus alba (87.59, 4.06). In the shrub species LTC and LTN nitrogen were highest in the Rosa webiana (235.64, 7.45) and least in the Astragalus gilgitensis (43.45, 1.60) respectively. Total carbon and total nitrogen showed a slightly decreasing and increasing trend with altitude in the leaf and soil samples, respectively. The mean nitrogen and carbon was higher in the leaves of trees (3, 97.95) than in the shrubs (2.725, 74.24) and conifers (2.26, 76.46) than in the leaves of the deciduous (2, 46.36) trees. The correlation between LTC and STN was non-significant. Strong significant (R(2) = 0.608, p = 0.003) and weak non-significant (R(2) = 0.04, p = 0.32) relationships were found in STN and STC with LM and HB respectively. SOC (75.15 %) was found to be the main contributor to

  11. Understanding the impact of deep brain stimulation on ambulatory activity in advanced Parkinson's disease.

    PubMed

    Rochester, Lynn; Chastin, Sebastien Francois Martin; Lord, Sue; Baker, Katherine; Burn, David John

    2012-06-01

    Whilst deep brain stimulation of the subthalamic nucleus (DBS-STN) improves the motor symptoms of Parkinson's disease (PD), its effect on daily activity is unknown. We aimed to quantify changes in ambulatory activity following DBS-STN in advanced PD using novel accelerometry based measures that describe changes to the volume and pattern of walking. Seventeen participants with advanced PD were measured over a 7-day period using an activPAL (™) activity monitor. Data were collected 6 weeks before and 6 months after surgery and included measures that describe the volume and pattern of ambulatory activity (number of steps per day, accumulation, diversity and variability of walking time), alongside standard measures for disease severity, freezing of gait, gait speed, and extended activities of daily living. Activity outcomes were compared pre- and 6 months post-surgery using linear mixed models and correlated with standard outcomes. The results of this study are despite significant improvements in motor symptoms after surgery, the volume of ambulatory activity (total number of steps per day) did not change (P = 0.468). However, significant increases in length and variability of walking bouts emerged, suggesting improvements in diversity and flexibility of walking patterns. Motor severity and extended activities of daily living scores were significantly correlated with walking bout variability but not with volume of walking. Thus, the conclusions are reduction in motor symptom severity after DBS-STN translated into selective improvements in daily activity. Novel measures derived from accelerometry provide a discrete measure of performance and allow closer interpretation of the impact of DBS-STN on real-world activity. PMID:22086738

  12. A spiking Basal Ganglia model of synchrony, exploration and decision making

    PubMed Central

    Mandali, Alekhya; Rengaswamy, Maithreye; Chakravarthy, V. Srinivasa; Moustafa, Ahmed A.

    2015-01-01

    To make an optimal decision we need to weigh all the available options, compare them with the current goal, and choose the most rewarding one. Depending on the situation an optimal decision could be to either “explore” or “exploit” or “not to take any action” for which the Basal Ganglia (BG) is considered to be a key neural substrate. In an attempt to expand this classical picture of BG function, we had earlier hypothesized that the Indirect Pathway (IP) of the BG could be the subcortical substrate for exploration. In this study we build a spiking network model to relate exploration to synchrony levels in the BG (which are a neural marker for tremor in Parkinson's disease). Key BG nuclei such as the Sub Thalamic Nucleus (STN), Globus Pallidus externus (GPe) and Globus Pallidus internus (GPi) were modeled as Izhikevich spiking neurons whereas the Striatal output was modeled as Poisson spikes. The model is cast in reinforcement learning framework with the dopamine signal representing reward prediction error. We apply the model to two decision making tasks: a binary action selection task (similar to one used by Humphries et al., 2006) and an n-armed bandit task (Bourdaud et al., 2008). The model shows that exploration levels could be controlled by STN's lateral connection strength which also influenced the synchrony levels in the STN-GPe circuit. An increase in STN's lateral strength led to a decrease in exploration which can be thought as the possible explanation for reduced exploratory levels in Parkinson's patients. Our simulations also show that on complete removal of IP, the model exhibits only Go and No-Go behaviors, thereby demonstrating the crucial role of IP in exploration. Our model provides a unified account for synchronization, action section, and explorative behavior. PMID:26074761

  13. Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models.

    PubMed

    Lee, B; Lee, H; Nam, Y R; Oh, J H; Cho, Y H; Chang, J W

    2005-08-01

    In this study, we report the amelioration of parkinsonian symptoms in rat Parkinson's disease (PD) models, as a result of the expression of glutamate decarboxylase (GAD) 65 with a modified cytomegalovirus (CMV) promoter. The transfer of the gene for gamma-amino butryic acid (GAD), the rate-limiting enzyme in gama-amino butrylic acid (GABA) production, has been investigated as a means to increase inhibitory synaptic activity. Electrophysiological evidence suggests that the transfer of the GAD65 gene to the subthalamic nucleus (STN) can change the excitatory output of this nucleus to inhibitory output. Our in vitro results also demonstrated higher GAD65 expression in cells transfected with the JDK promoter, as compared to cells transfected with the CMV promoter. Also, a rat PD model in which recombinant adeno-associated virus-2 (rAAV2)-JDK-GAD65 was delivered into the STN exhibited significant behavioral improvements, as compared to the saline-injected group. Interestingly, we observed that these behavioral improvements were more obvious in rat PD models in which rAAV2-JDK-GAD65 was injected into the STN than in rat PD models in which rAAV2-CMV-GAD65 was injected into the STN. Moreover, according to electrophysiological data, the rAAV2-JDK-GAD65-injected group exhibited more constant improvements in firing rates than did the rAAV2-CMV-GAD65-injected group. These data indicate that the JDK promoter, when coupled with GAD65 expression, is more effective with regard to parkinsonian symptoms than is the CMV promoter. PMID:15829994

  14. Deep Brain Stimulation in Early Stage Parkinson’s Disease: Operative Experience from a Prospective, Randomized Clinical Trial

    PubMed Central

    Kahn, Elyne; D'Haese, Pierre-Francois; Dawant, Benoit; Allen, Laura; Kao, Chris; Charles, P. David; Konrad, Peter

    2013-01-01

    Background Recent evidence suggests that STN-DBS may have a disease-modifying effect in early PD. A randomized, prospective study is underway to determine whether STN-DBS in early PD is safe and tolerable. Objectives / Methods Fifteen of thirty early PD patients were randomized to receive STN-DBS implants in an IRB-approved protocol. Operative technique, location of DBS leads, and perioperative adverse events are reported. Active contact used for stimulation in these patients were compared with 47 advanced PD patients undergoing an identical procedure by the same surgeon. Results Fourteen of the 15 patients did not sustain any long-term (> 3 months) complications from the surgery. One subject suffered a stroke resulting in mild cognitive changes and slight right arm and face weakness. The average optimal contact used in symptomatic treatment of early PD patients was: anterior −1.1±1.7mm, lateral 10.7±1.7mm, superior −3.3±2.5mm (AC-PC coordinates). This location is statistically no different (0.77mm, p> 0.05) than the optimal contact used in treatment of 47 advanced PD patients. Conclusions The perioperative adverse events in this trial of subjects with early stage PD are comparable to that reported for STN-DBS in advanced PD. The active contact position used in early PD is not significantly different from that used in late stage disease. This is the first report of the operative experience from a randomized, surgical-versus-best-medical-therapy trial for the early treatment of Parkinson’s disease. PMID:21890575

  15. Subthalamic Nucleus Discharge Patterns during Movement in the Normal Monkey and Parkinsonian Patient

    PubMed Central

    Gale, John T.; Shields, Donald C.; Jain, Felipe A.; Amirnovin, Ramin; Eskandar, Emad N.

    2009-01-01

    The pathophysiology of Parkinson disease (PD) is characterized by derangements in the discharge rates, bursting patterns, and oscillatory activity of basal ganglia (BG) neurons. In this study, subthalamic nucleus (STN) neuronal activity patterns in humans with PD was compared with that in the normal monkey during performance of similar volitional movements. Single-unit STN recordings were collected while PD patients and animals moved a joystick in the direction of targets presented on a monitor. When discharge rates in all PD human and normal monkey neurons were compared, no significant differences were observed. However, when neurons were classified by peri-movement response type (i.e., excited, inhibited, or unresponsive to movement) statistical differences were demonstrated – most significantly among PD excited neurons. Analysis of burst activity demonstrated inter- and intra-burst activities were greater in the PD human compared to the monkey irrespective of neuronal response type. Moreover, simultaneously recorded neurons in the human demonstrated consistent oscillatory synchronization at restricted frequency bands, whereas synchronized oscillatory neurons in the monkey were not restricted to distinct frequencies. During movement, discharge and burst rates were positively correlated, independent of subject or neuronal response type; however, rates and oscillatory activity were more strongly correlated in the PD human than the normal monkey. Interestingly, across all domains of analysis, STN neurons in PD demonstrated reduced response variability when compared to STN neurons in the normal monkey brain. Thus, the net effect of PD may be a reduction in the physiological degrees of freedom of BG neurons with diminished information carrying capacity. PMID:19167367

  16. The network of causal interactions for beta oscillations in the pedunculopontine nucleus, primary motor cortex, and subthalamic nucleus of walking parkinsonian rats.

    PubMed

    Li, Min; Zhou, Ming; Wen, Peng; Wang, Qiang; Yang, Yong; Xiao, Hu; Xie, Zhengyuan; Li, Xing; Wang, Ning; Wang, Jinyan; Luo, Fei; Chang, Jingyu; Zhang, Wangming

    2016-08-01

    Oscillatory activity has been well-studied in many structures within cortico-basal ganglia circuits, but it is not well understood within the pedunculopontine nucleus (PPN), which was recently introduced as a potential target for the treatment of gait and postural impairments in advanced stages of Parkinson's disease (PD). To investigate oscillatory activity in the PPN and its relationship with oscillatory activity in cortico-basal ganglia circuits, we simultaneously recorded local field potentials in the PPN, primary motor cortex (M1), and subthalamic nucleus (STN) of 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats during resting and walking. After analysis of power spectral density, coherence, and partial Granger causality, three major findings emerged: 1) after 6-OHDA lesions, beta band oscillations were enhanced in all three regions during walking; 2) the direction of information flow for beta oscillations among the three structures was STN→M1, STN→PPN, and PPN→M1; 3) after the treatment of levodopa, beta activity in the three regions was reduced significantly and the flow of beta band was also abrogated. Our results suggest that beta activity in the PPN is transmitted from the basal ganglia and probably comes from the STN, and the STN plays a dominant role in the network of causal interactions for beta activity. Thus, the STN may be a potential source of aberrant beta band oscillations in PD. Levodopa can inhibit beta activity in the PPN of parkinsonian rats but cannot relieve parkinsonian patients' axial symptoms clinically. Therefore, beta oscillations may not be the major cause of axial symptoms. PMID:27163550

  17. Task specific inter-hemispheric coupling in human subthalamic nuclei

    PubMed Central

    Darvas, Felix; Hebb, Adam O.

    2014-01-01

    Cortical networks and quantitative measures of connectivity are integral to the study of brain function. Despite lack of direct connections between left and right subthalamic nuclei (STN), there are apparent physiological connections. During clinical examination of patients with Parkinson’s disease (PD), this connectivity is exploited to enhance signs of PD, yet our understanding of this connectivity is limited. We hypothesized that movement leads to synchronization of neural oscillations in bilateral STN, and we implemented phase coherence, a measure of phase-locking between cortical sites in a narrow frequency band, to demonstrate this synchronization. We analyzed task specific phase synchronization and causality between left and right STN local field potentials (LFPs) recorded from both hemispheres simultaneously during a cued movement task in four subjects with PD who underwent Deep Brain Stimulation (DBS) surgery. We used a data driven approach to determine inter-hemispheric channel pairs and frequencies with a task specific increase in phase locking.We found significant phase locking between hemispheres in alpha frequency (8–12 Hz) in all subjects concurrent with movement of either hand. In all subjects, phase synchronization increased over baseline upon or prior to hand movement onset and lasted until the motion ceased. Left and right hand movement showed similar patterns. Granger causality (GC) at the phase-locking frequencies between synchronized electrodes revealed a unidirectional causality from right to left STN regardless of which side was moved.Phase synchronization across hemispheres between basal ganglia supports existence of a bilateral network having lateralized regions of specialization for motor processing. Our results suggest this bilateral network is activated by a unilateral motor program. Understanding phase synchronization in natural brain functions is critical to development of future DBS systems that augment goal directed behavioral

  18. Long-term impact on quality of life of subthalamic nucleus stimulation in Parkinson's disease.

    PubMed

    Lezcano, Elena; Gómez-Esteban, Juan Carlos; Tijero, Beatriz; Bilbao, Gaizka; Lambarri, Imanol; Rodriguez, Olivia; Villoria, Rafael; Dolado, Ainara; Berganzo, Koldo; Molano, Ana; de Gopegui, Edurne Ruiz; Pomposo, Iñigo; Gabilondo, Iñigo; Zarranz, Juan José

    2016-05-01

    Long-term impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on health-related quality of life (HRQOL) and associated factors in patients with Parkinson's disease (PD) are not clear. In this prospective study, we included 69 PD patients (64 % men, mean age 61.3 ± 7.4 and disease duration 13.2 ± 5.7 years) undergoing STN-DBS. They were evaluated preoperatively (baseline), 1 and 5 years postoperatively assessing 39-item Parkinson's Disease Questionnaire (PDQ-39), Schwab and England Activities of Daily Living Scale (SEADL), Unified Parkinson's Disease Rating Scale (UPDRS) off- and on-medication, patient diaries, dopaminergic treatment, mortality and surgical complications. Five years postoperatively, off-medication, there were improvements from baseline in UPDRS-II and III total (27.2 and 26.7 %, respectively) and SEADL (18.6 % more completely independent patients) (p < 0.05) scores, while on-medication, there was a deterioration in UPDRS-III (37.8 %, mainly axial signs) (p < 0.05) and minor improvements in SEADL (3.7 %). While at 1 year PDQ-39, the summary index improved substantially (36.5 %) (p < 0.05), at 5 years patients regressed (only 8.8 %) (p < 0.05), though changes in PDQ-39 subscores remained significant, with improvements in ADL (18.8 %), emotional well-being (19.0 %), stigma (36.4 %) and discomfort (20.6 %), despite worsening in communication (47.8 %) (p < 0.05). Lower preoperative PDQ-39 summary index and greater 1-year UPDRS-III-off total score gain predicted better long-term HRQOL. STN-DBS produces long-term improvements in HRQOL in PD. Preoperative HRQOL and short-term postoperative changes in off-medication motor status may predict long-term HRQOL in PD following STN-DBS. PMID:26964542

  19. Dissecting Human Skeletal Muscle Troponin Proteoforms by Top-down Mass Spectrometry

    PubMed Central

    Chen, Yi-Chen; Sumandea, Marius P.; Larsson, Lars; Moss, Richard L.; Ge, Ying

    2015-01-01

    Skeletal muscles are the most abundant tissues in the human body. They are composed of a heterogeneous collection of muscle fibers that perform various functions. Skeletal muscle troponin (sTn) regulates skeletal muscle contraction and relaxation. sTn consists of 3 subunits, troponin I (TnI), troponin T (TnT), and troponin C (TnC). TnI inhibits the actomyosin Mg2+-ATPase, TnC binds Ca2+, and TnT is the tropomyosin (Tm)-binding subunit. The cardiac and skeletal isoforms of Tn share many similarities but the roles of modifications of Tn in the two muscles may differ. The modifications of cardiac Tn are known to alter muscle contractility and have been well-characterized. However, the modification status of sTn remains unclear. Here, we have employed top-down mass spectrometry (MS) to decipher the modifications of human sTnT and sTnI. We have extensively characterized sTnT and sTnI proteoforms, including alternatively spliced isoforms and post-translationally modified forms, found in human skeletal muscle with high mass accuracy and comprehensive sequence coverage. Moreover, we have localized the phosphorylation site of slow sTnT isoform III to Ser1 by tandem MS with electron capture dissociation. This is the first study to comprehensively characterize human sTn and also the first to identify the basal phosphorylation site for human sTnT by top-down MS. PMID:25613324

  20. Simple solution for preventing cerebrospinal fluid loss and brain shift during multitrack deep brain stimulation surgery in the semisupine position: polyethylene glycol hydrogel dural sealant capping: rapid communication.

    PubMed

    Takumi, Ichiro; Mishina, Masahiro; Hironaka, Kohei; Oyama, Kenichi; Yamada, Akira; Adachi, Koji; Hamamoto, Makoto; Kitamura, Shin; Yoshida, Daizo; Teramoto, Akira

    2013-01-01

    This study evaluated preliminary findings on the efficacy of polyethylene glycol (PEG) hydrogel dural sealant capping for the prevention of cerebrospinal fluid (CSF) leakage and pneumocephalus during deep brain stimulation (DBS) surgery in the semisupine position. Group A consisted of 5 patients who underwent bilateral subthalamic nucleus (STN)-DBS surgery without PEG hydrogel dural sealant capping. Group B consisted of 5 patients who underwent bilateral STN-DBS surgery with PEG hydrogel dural sealant capping. The immediate postoperative intracranial air volume was measured in all patients and compared between the 2 groups using the Welch test. Adverse effects were also examined in both groups. The intracranial air volume in Group A was 32.3 ± 12.3 ml (range 19.1-42.5 ml), whereas that in Group B was 1.3 ± 1.5 ml (range 0.0-3.5 ml), showing a significant difference (p < 0.005). No hemorrhage or venous air embolisms were observed in either group. The effect of brain shift was discriminated by STN recordings in Group B. These preliminary findings indicate that PEG hydrogel dural sealant capping may reduce adverse effects related to CSF leakage and brain shift during DBS surgery. PMID:23358161

  1. Transplantation of mouse embryonic stem cell-derived neurons into the striatum, subthalamic nucleus and substantia nigra, and behavioral recovery in hemiparkinsonian rats.

    PubMed

    Inden, Masatoshi; Kim, Do-hoon; Qi, Meirigeng; Kitamura, Yoshihisa; Yanagisawa, Daijiro; Nishimura, Kaneyasu; Tsuchiya, Daiju; Takata, Kazuyuki; Hayashi, Kousuke; Taniguchi, Takashi; Yoshimoto, Kanji; Shimohama, Shun; Sumi, Shoichiro; Inoue, Kazutomo

    2005-10-28

    Usefulness of the in vitro and in vivo generation of neural precursors from embryonic stem (ES) cells has been widely discussed, but functional recovery in animal models of Parkinson's disease (PD) is not fully understood. The aim of this study was to investigate a transplantation strategy for PD by assessing whether double-transplants in the striatum (ST) and substantia nigra (SN), or ST and subthalamic nucleus (STN) induce functional recovery in 6-hydroxydopamine-lesioned rats. Methamphetamine-induced rotation was significantly reduced by transplantation of mouse ES cell-derived neurons into the ST, but not the STN or SN alone. Double-transplantation was also effective at recovering rotational behavior. Although immunoreactivity for tyrosine hydroxylase (TH) was almost completely lost in the ipsilateral striatum in hemiparkinsonian rats, TH immunoreactivity was detected in transplanted cells and sprouting fibers in the ST, STN and SN. These results suggest that both the involvement of ST as a place of transplantation and the number of ES cell-derived neurons are essential factors for efficacy on hemiparkinsonian behaviors. PMID:16023291

  2. Virulence genes detection of Salmonella serovars isolated from pork and slaughterhouse environment in Ahmedabad, Gujarat

    PubMed Central

    Chaudhary, J. H.; Nayak, J. B.; Brahmbhatt, M. N.; Makwana, P. P.

    2015-01-01

    Aim: The aim was to detect virulence gene associated with the Salmonella serovars isolated from pork and Slaughterhouse environment. Materials and Methods: Salmonella isolates (n=37) used in this study were isolated from 270 pork and slaughter house environmental samples collected from the Ahmedabad Municipal Corporation Slaughter House, Ahmedabad, Gujarat, India. Salmonella serovars were isolated and identified as per BAM USFDA method and serotyped at National Salmonella and Escherichia Centre, Central Research Institute, Kasauli (Himachal Pradesh, India). Polymerase chain reaction technique was used for detection of five genes, namely invA, spvR, spvC, fimA and stn among different serovars of Salmonella. Results: Out of a total of 270 samples, 37 (13.70%) Salmonella were isolated with two serovars, namely Enteritidis and Typhimurium. All Salmonella serovars produced 284 bp invA gene, 84 bp fimA and 260 bp amplicon for enterotoxin (stn) gene whereas 30 isolates possessed 310 bp spvR gene, but no isolate possessed spvC gene. Conclusion: Presence of invA, fimA and stn gene in all isolates shows that they are the specific targets for Salmonella identification and are capable of producing gastroenteric illness to humans, whereas 20 Typhimurium serovars and 10 Enteritidis serovars can able to produce systemic infection. PMID:27047008

  3. The serendipity case of the pedunculopontine nucleus low-frequency brain stimulation: chasing a gait response, finding sleep, and cognition improvement.

    PubMed

    Stefani, Alessandro; Peppe, Antonella; Galati, Salvatore; Bassi, Mario Stampanoni; D'Angelo, Vincenza; Pierantozzi, Mariangela

    2013-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious therapy for Parkinson's disease (PD) but its effects on non-motor facets may be detrimental. The low-frequency stimulation (LFS) of the pedunculopontine nucleus (PPN or the nucleus tegmenti pedunculopontini - PPTg-) opened new perspectives. In our hands, PPTg-LFS revealed a modest influence on gait but increased sleep quality and degree of attentiveness. At odds with potential adverse events following STN-DBS, executive functions, under PPTg-ON, ameliorated. A recent study comparing both targets found that only PPTg-LFS improved night-time sleep and daytime sleepiness. Chances are that different neurosurgical groups influence either the PPN sub-portion identified as pars dissipata (more interconnected with GPi/STN) or the caudal PPN region known as pars compacta, preferentially targeting intralaminar and associative nucleus of the thalamus. Yet, the wide electrical field delivered affects a plethora of en passant circuits, and a fine distinction on the specific pathways involved is elusive. This review explores our angle of vision, by which PPTg-LFS activates cholinergic and glutamatergic ascending fibers, influencing non-motor behaviors. PMID:23761781

  4. Morphological changes of glutamatergic synapses in animal models of Parkinson’s disease

    PubMed Central

    Villalba, Rosa M.; Mathai, Abraham; Smith, Yoland

    2015-01-01

    The striatum and the subthalamic nucleus (STN) are the main entry doors for extrinsic inputs to reach the basal ganglia (BG) circuitry. The cerebral cortex, thalamus and brainstem are the key sources of glutamatergic inputs to these nuclei. There is anatomical, functional and neurochemical evidence that glutamatergic neurotransmission is altered in the striatum and STN of animal models of Parkinson’s disease (PD) and that these changes may contribute to aberrant network neuronal activity in the BG-thalamocortical circuitry. Postmortem studies of animal models and PD patients have revealed significant pathology of glutamatergic synapses, dendritic spines and microcircuits in the striatum of parkinsonians. More recent findings have also demonstrated a significant breakdown of the glutamatergic corticosubthalamic system in parkinsonian monkeys. In this review, we will discuss evidence for synaptic glutamatergic dysfunction and pathology of cortical and thalamic inputs to the striatum and STN in models of PD. The potential functional implication of these alterations on synaptic integration, processing and transmission of extrinsic information through the BG circuits will be considered. Finally, the significance of these pathological changes in the pathophysiology of motor and non-motor symptoms in PD will be examined. PMID:26441550

  5. Manganese-Induced Atypical Parkinsonism Is Associated with Altered Basal Ganglia Activity and Changes in Tissue Levels of Monoamines in the Rat

    PubMed Central

    Bouabid, Safa; Delaville, Claire; De Deurwaerdère, Philippe; Lakhdar-Ghazal, Nouria; Benazzouz, Abdelhamid

    2014-01-01

    Manganese neurotoxicity is associated with motor and cognitive disturbances known as Manganism. However, the mechanisms underlying these deficits remain unknown. Here we investigated the effects of manganese intoxication on motor and non-motor parkinsonian-like deficits such as locomotor activity, motor coordination, anxiety and “depressive-like” behaviors. Then, we studied the impact of this intoxication on the neuronal activity, the globus pallidus (GP) and subthalamic nucleus (STN). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, norepinephrine and serotonin) has been determined. The experiments were carried out in adult Sprague-Dawley rats, daily treated with MnCl2 (10 mg/kg/, i.p.) for 5 weeks. We show that manganese progressively reduced locomotor activity as well as motor coordination in parallel with the manifestation of anxiety and “depressive-like” behaviors. Electrophysiological results show that, while majority of GP and STN neurons discharged regularly in controls, manganese increased the number of GP and STN neurons discharging irregularly and/or with bursts. Biochemical results show that manganese significantly decreased tissue levels of norepinephrine and serotonin with increased metabolism of dopamine in the striatum. Our data provide evidence that manganese intoxication is associated with impaired neurotransmission of monoaminergic systems, which is at the origin of changes in basal ganglia neuronal activity and the manifestation of motor and non-motor deficits similar to those observed in atypical Parkinsonism. PMID:24896650

  6. Manganese-induced atypical parkinsonism is associated with altered Basal Ganglia activity and changes in tissue levels of monoamines in the rat.

    PubMed

    Bouabid, Safa; Delaville, Claire; De Deurwaerdère, Philippe; Lakhdar-Ghazal, Nouria; Benazzouz, Abdelhamid

    2014-01-01

    Manganese neurotoxicity is associated with motor and cognitive disturbances known as Manganism. However, the mechanisms underlying these deficits remain unknown. Here we investigated the effects of manganese intoxication on motor and non-motor parkinsonian-like deficits such as locomotor activity, motor coordination, anxiety and "depressive-like" behaviors. Then, we studied the impact of this intoxication on the neuronal activity, the globus pallidus (GP) and subthalamic nucleus (STN). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, norepinephrine and serotonin) has been determined. The experiments were carried out in adult Sprague-Dawley rats, daily treated with MnCl2 (10 mg/kg/, i.p.) for 5 weeks. We show that manganese progressively reduced locomotor activity as well as motor coordination in parallel with the manifestation of anxiety and "depressive-like" behaviors. Electrophysiological results show that, while majority of GP and STN neurons discharged regularly in controls, manganese increased the number of GP and STN neurons discharging irregularly and/or with bursts. Biochemical results show that manganese significantly decreased tissue levels of norepinephrine and serotonin with increased metabolism of dopamine in the striatum. Our data provide evidence that manganese intoxication is associated with impaired neurotransmission of monoaminergic systems, which is at the origin of changes in basal ganglia neuronal activity and the manifestation of motor and non-motor deficits similar to those observed in atypical Parkinsonism. PMID:24896650

  7. Critical reappraisal of DBS targeting for movement disorders.

    PubMed

    Guzzi, Giusy; Della Torre, Attilio; Chirchiglia, Domenico; Volpentesta, Giorgio; Lavano, Angelo

    2016-06-01

    Deep brain stimulation (DBS) is used as a surgical treatment of movement disorders such as Parkinson's disease, dystonia and essential tremor. Fundamental understanding of DBS effects on the pathological neural circuitry remains insufficient. In 2002 DBS of the subthalamic nucleus (STN) and the globus pallidus internus (GPi) was approved for use in patients with PD. Next year, DBS of Gpi and STN for dystonia received a Humanitarian Device exemption from the FDA. The commonly targets for DBS are subthalamic nucleus (STN) or globus pallidus internus (GPi) for Parkinson's disease, Gpi for dystonia and ventro-intermediate (VIM) nucleus of the thalamus for essential tremor. However, VIM DBS cannot sufficiently improve akinesia and rigidity. Pedunculopontine nucleus (PPN) is currently investigated as potential target to improve gait and posture. It is determined that DBS sometimes influences not only motor functions but also the cognitive and affective functions of patients. In this article we review the present state of DBS for movement disorders, appropriate indications, practical effects and stimulation-induced adverse events established in previous studies. We discuss target selection and the effect of DBS on motor and non-motor symptoms of Parkinson's disease, dystonia and essential tremor. PMID:27015393

  8. Fine particulate matter source apportionment for the chemical speciation trends network site at Birmingham, Alabama, using positive matrix factorization

    SciTech Connect

    Baumann, K.; Jayanty, R.K.; Flanagan, J.B.

    2008-01-15

    The Positive Matrix Factorization (PMF) receptor model version 1.1 was used with data from the fine particulate matter (PM2.5) Chemical Speciation Trends Network (STN) to estimate source contributions to ambient PM2.5 in a highly industrialized urban setting in the southeastern United States. Model results consistently resolved 10 factors that are interpreted as two secondary, five industrial, one motor vehicle, one road dust, and one biomass burning sources. It was found that most PMF factors did not cleanly represent single source types and instead are 'contaminated' by other sources. Secondary particulate matter formed by atmospheric processes, such as sulfate and secondary OC, contribute the majority of ambient PM2.5 and exhibit strong seasonality 37 {+-} 10% winter vs. 55 {+-} 16% summer average. Motor vehicle emissions constitute the biggest primary PM2.5 mass contribution. In summary, this study demonstrates the utility of the EC tracer method to effectively blank-correct the OC concentrations in the STN dataset. In addition, examination of the effect of input uncertainty estimates on model results indicates that the estimated uncertainties currently being provided with the STN data may be somewhat lower than the levels needed for optimum modeling results. An appendix , available to members on the website www.awma lists stationary sources of PM2.5 within 10 km of the NHBM site and PM2.5 emissions greater than 1 ton per year. 71 refs., 7 figs., 9 tabs.

  9. A new biomarker for subthalamic deep brain stimulation for patients with advanced Parkinson’s disease—a pilot study

    NASA Astrophysics Data System (ADS)

    Gmel, Gerrit E.; Hamilton, Tara J.; Obradovic, Milan; Gorman, Robert B.; Single, Peter S.; Chenery, Helen J.; Coyne, Terry; Silburn, Peter A.; Parker, John L.

    2015-12-01

    Objective. Deep brain stimulation (DBS) has become the standard treatment for advanced stages of Parkinson’s disease (PD) and other motor disorders. Although the surgical procedure has improved in accuracy over the years thanks to imaging and microelectrode recordings, the underlying principles that render DBS effective are still debated today. The aim of this paper is to present initial findings around a new biomarker that is capable of assessing the efficacy of DBS treatment for PD which could be used both as a research tool, as well as in the context of a closed-loop stimulator. Approach. We have used a novel multi-channel stimulator and recording device capable of measuring the response of nervous tissue to stimulation very close to the stimulus site with minimal latency, rejecting most of the stimulus artefact usually found with commercial devices. We have recorded and analyzed the responses obtained intraoperatively in two patients undergoing DBS surgery in the subthalamic nucleus (STN) for advanced PD. Main results. We have identified a biomarker in the responses of the STN to DBS. The responses can be analyzed in two parts, an initial evoked compound action potential arising directly after the stimulus onset, and late responses (LRs), taking the form of positive peaks, that follow the initial response. We have observed a morphological change in the LRs coinciding with a decrease in the rigidity of the patients. Significance. These initial results could lead to a better characterization of the DBS therapy, and the design of adaptive DBS algorithms that could significantly improve existing therapies and help us gain insights into the functioning of the basal ganglia and DBS.

  10. Distal Convoluted Tubule

    PubMed Central

    Ellison, David H.

    2014-01-01

    The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice. PMID:24855283

  11. Toward quantitative proteomics of organ substructures: implications for renal physiology.

    PubMed

    Velic, Ana; Macek, Boris; Wagner, Carsten A

    2010-09-01

    Organs are complex structures that consist of multiple tissues with different levels of gene expression. To achieve comprehensive coverage and accurate quantitation data, organs ideally should be separated into morphologic and/or functional substructures before gene or protein expression analysis. However, because of complex morphology and elaborate isolation protocols, to date this often has been difficult to achieve. Kidneys are organs in which functional and morphologic subdivision is especially important. Each subunit of the kidney, the nephron, consists of more than 10 subsegments with distinct morphologic and functional characteristics. For a full understanding of kidney physiology, global gene and protein expression analyses have to be performed at the level of the nephron subsegments; however, such studies have been extremely rare to date. Here we describe the latest approaches in quantitative high-accuracy mass spectrometry-based proteomics and their application to quantitative proteomics studies of the whole kidney and nephron subsegments, both in human beings and in animal models. We compare these studies with similar studies performed on other organ substructures. We argue that the newest technologies used for preparation, processing, and measurement of small amounts of starting material are finally enabling global and subsegment-specific quantitative measurement of protein levels in the kidney and other organs. These new technologies and approaches are making a decisive impact on our understanding of the (patho)physiological processes at the molecular level. PMID:21044760

  12. A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures

    PubMed Central

    Webb, Carol F.; Wirsig-Wiechmann, Celeste R.; Lakiza, Olga; Obara, Tomoko

    2015-01-01

    Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a−/− kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. PMID:26111446

  13. Renal effects of continuous negative pressure breathing

    NASA Technical Reports Server (NTRS)

    Kinney, M. J.; Discala, V. A.

    1975-01-01

    Continuous negative pressure breathing (CNPB) was utilized to simulate the thoracic vascular distension of zero g or space, in 11 anesthetized rats. The animals underwent renal clearance and micropuncture renal nephron studies before, during, and after CNPB. Rats were pretreated with a high salt diet and I-M desoxycorticosterone (DOCA) in excess. None of these rats diuresed with CNPB. In contrast 5 of the 7 remaining rats increased the fraction of the filtered sodium excreted (C sub Na/GFR, p .05) and their urinary flow rate (V, p .05). Potassium excretion increased (U sub k V, p .05). End proximal tubular fluid specimen's TF/P inulin ratios were unchanged. Whole kidney and single nephron glomerular filtration rates fell 10%. CNPB, a mechanism for atrial distension, appears to cause, in rats, a decrease in distal tubular sodium, water and potassium reabsorption. Exogenous mineral-corticoid prevents the diuresis, saluresis, and kaluresis.

  14. Nodular renal blastoma in kidney with multicystic dysplasia. Report of a case.

    PubMed

    Corsi, A; Boldrini, R; Caione, P; Bosman, C

    1995-04-01

    The clinico-pathologic association of nodular renal blastema, multicystic kidney and obstructive uropathy has been recently identified. We report on a female patient diagnosed as having unilater multicystic dysplasia by prenatal ultrasonography. The patient was nephrectomized at the age of 6 1/2 months. Examination of the resected kidney revealed multiple unilocular cysts in the cortex and hypoplasia of the homolateral ureter; histological study confirmed the presence of multiple cysts limited to the renal cortex, and revealed, among them, multiple cortical metanephric blastema cells islands. Our case supports a relationship between nodular renal blastema, cortical cysts and obstructive uropathy; ureter hypoplasia could cause intraluminal back pressure, with consequent abnormal development of the ampullae, normally endowed in nephronic anlagens induction, cystic tubular ectasia and persistence of nodular renal blastema. The peripheral location of renal nodular blastema and cysts supports a late error in nephrogenesis, at the time of formation of the last generation of nephrons. PMID:8532415

  15. Role of hypoxia during nephrogenesis.

    PubMed

    Hemker, Shelby L; Sims-Lucas, Sunder; Ho, Jacqueline

    2016-10-01

    Mammals develop in a physiologically hypoxic state, and the oxygen tension of different tissues in the embryo is precisely controlled. Deviation from normal oxygenation, such as what occurs in placental insufficiency, can disrupt fetal development. Several studies demonstrate that intrauterine hypoxia has a negative effect on kidney development. As nascent nephrons are forming from nephron progenitors in the nephrogenic zone, they are exposed to varying oxygen tension by virtue of the development of the renal vasculature. Thus, nephrogenesis may be linked to oxygen tension. However, the mechanism(s) by which this occurs remains unclear. This review focuses on what is known about molecular mechanisms active in physiological and pathological hypoxia and their effects on kidney development. PMID:26872484

  16. Irreversible Electroporation (IRE) in Renal Tumors.

    PubMed

    Narayanan, Govindarajan; Doshi, Mehul H

    2016-02-01

    Small renal masses (SRMs) have been traditionally managed with surgical resection. Minimally invasive nephron-sparing treatment methods are preferred to avoid harmful consequences of renal insufficiency, with partial nephrectomy (PN) considered the gold standard. With increase in the incidence of the SRMs and evolution of ablative technologies, percutaneous ablation is now considered a viable treatment alternative to surgical resection with comparable oncologic outcomes and better nephron-sparing property. Traditional thermal ablative techniques suffer from unique set of challenges in treating tumors near vessels or critical structures. Irreversible electroporation (IRE), with its non-thermal nature and connective tissue-sparing properties, has shown utility where traditional ablative techniques face challenges. This review presents the role of IRE in renal tumors based on the most relevant published literature on the IRE technology, animal studies, and human experience. PMID:26769468

  17. Functional Genetic Targeting of Embryonic Kidney Progenitor Cells Ex Vivo

    PubMed Central

    Junttila, Sanna; Saarela, Ulla; Halt, Kimmo; Manninen, Aki; Pärssinen, Heikki; Lecca, M. Rita; Brändli, André W.; Sims-Lucas, Sunder; Skovorodkin, Ilya

    2015-01-01

    The embryonic mammalian metanephric mesenchyme (MM) is a unique tissue because it is competent to generate the nephrons in response to Wnt signaling. An ex vivo culture in which the MM is separated from the ureteric bud (UB), the natural inducer, can be used as a classic tubule induction model for studying nephrogenesis. However, technological restrictions currently prevent using this model to study the molecular genetic details before or during tubule induction. Using nephron segment-specific markers, we now show that tubule induction in the MM ex vivo also leads to the assembly of highly segmented nephrons. This induction capacity was reconstituted when MM tissue was dissociated into a cell suspension and then reaggregated (drMM) in the presence of human recombinant bone morphogenetic protein 7/human recombinant fibroblast growth factor 2 for 24 hours before induction. Growth factor–treated drMM also recovered the capacity for organogenesis when recombined with the UB. Cell tracking and time-lapse imaging of chimeric drMM cultures indicated that the nephron is not derived from a single progenitor cell. Furthermore, viral vector-mediated transduction of green fluorescent protein was much more efficient in dissociated MM cells than in intact mesenchyme, and the nephrogenic competence of transduced drMM progenitor cells was preserved. Moreover, drMM cells transduced with viral vectors mediating Lhx1 knockdown were excluded from the nephric tubules, whereas cells transduced with control vectors were incorporated. In summary, these techniques allow reproducible cellular and molecular examinations of the mechanisms behind nephrogenesis and kidney organogenesis in an ex vivo organ culture/organoid setting. PMID:25201883

  18. Deep brain stimulation of pallidal versus subthalamic for patients with Parkinson’s disease: a meta-analysis of controlled clinical trials

    PubMed Central

    Xu, Fan; Ma, Wenbin; Huang, Yongmin; Qiu, Zhihai; Sun, Lei

    2016-01-01

    Background Parkinson’s disease (PD) is a common neurodegenerative disorder that affects many people every year. Deep brain stimulation (DBS) is an effective nonpharmacological method to treat PD motor symptoms. This meta-analysis was conducted to evaluate the efficacy of subthalamic nucleus (STN)-DBS versus globus pallidus internus (GPi)-DBS in treating advanced PD. Methods Controlled clinical trials that compared STN-DBS to GPi-DBS for short-term treatment of PD in adults were researched up to November 2015. The primary outcomes were the Unified Parkinson’s Disease Rating Scale Section (UPDRS) III score and the levodopa-equivalent dosage (LED) after DBS. The secondary outcomes were the UPDRS II score and the Beck Depression Inventory (BDI) score. Results Totally, 13 studies containing 1,148 PD patients were included in this meta-analysis to compare STN-DBS versus GPi-DBS. During the off-medication state, the pooled weighted mean difference (WMD) of UPDRS III and II scores were −2.18 (95% CI =−5.11 to 0.74) and −1.96 (95% CI =−3.84 to −0.08), respectively. During the on-medication state, the pooled WMD of UPDRS III and II scores were 0.15 (95% CI =−1.14 to 1.44) and 1.01 (95% CI =0.12 to 1.89), respectively. After DBS, the pooled WMD of LED and BDI were −254.48 (95% CI =−341.66) and 2.29 (95% CI =0.83 to 3.75), respectively. Conclusion These results indicate that during the off-medication state, the STN-DBS might be superior to GPi-DBS in improving the motor function and activities of daily living for PD patients; but during the on-medication state, the opposite result is observed. Meanwhile, the STN-DBS is superior at reducing the LED, whereas the GPi-DBS shows a significantly greater reduction in BDI score after DBS. PMID:27382286

  19. Chronic L-DOPA administration increases the firing rate but does not reverse enhanced slow frequency oscillatory activity and synchronization in substantia nigra pars reticulata neurons from 6-hydroxydopamine-lesioned rats.

    PubMed

    Aristieta, A; Ruiz-Ortega, J A; Miguelez, C; Morera-Herreras, T; Ugedo, L

    2016-05-01

    The pathophysiology of Parkinson's disease (PD) and of L-DOPA-induced dyskinesia (LID) is associated with dysfunctional neuronal activity in several nuclei of the basal ganglia. Moreover, high levels of oscillatory activity and synchronization have also been described in both intra- and inter-basal ganglia nuclei and the cerebral cortex. However, the relevance of these alterations in the motor symptomatology related to Parkinsonism and LID is not fully understood. Recently, we have shown that subthalamic neuronal activity correlates with axial abnormal movements and that a subthalamic nucleus (STN) lesion partially reduces LID severity as well as the expression of some striatal molecular modifications. The aim of the present study was to assess, through single-unit extracellular recording techniques under urethane anaesthesia, neuronal activity of the substantia nigra pars reticulata (SNr) and its relationship with LID and STN hyperactivity together with oscillatory and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned and dyskinetic rats. Twenty-four hours after the last injection of L-DOPA the firing rate and the inhibitory response to an acute challenge of L-DOPA of SNr neurons from dyskinetic animals were increased with respect to those found in intact and 6-OHDA-lesioned rats. Moreover, there was a significant correlation between the mean firing rate of SNr neurons and the severity of the abnormal movements (limb and orolingual subtypes). There was also a significant correlation between the firing activity of SNr and STN neurons recorded from dyskinetic rats. In addition, low frequency band oscillatory activity and synchronization both within the SNr or STN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals and not or slightly affected by chronic treatment with L-DOPA. Altogether, these results indicate that neuronal SNr firing activity is relevant in dyskinesia and may be driven by STN hyperactivity. Conversely

  20. Uteroplacental insufficiency alters nephrogenesis and downregulates cyclooxygenase-2 expression in a model of IUGR with adult-onset hypertension.

    PubMed

    Baserga, Mariana; Hale, Merica A; Wang, Zheng Ming; Yu, Xing; Callaway, Christopher W; McKnight, Robert A; Lane, Robert H

    2007-05-01

    Clinical and animal studies indicate that intrauterine growth restriction (IUGR) following uteroplacental insufficiency (UPI) reduces nephron number and predisposes toward renal insufficiency early in life and increased risk of adult-onset hypertension. In this study, we hypothesized that the inducible enzyme cyclooxygenase-2 (COX-2), a pivotal protein in nephrogenesis, constitutes a mechanism through which UPI and subsequent glucocorticoid overexposure can decrease nephron number. We further hypothesized that UPI downregulates the key enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts corticosterone to inert 11-dehydrocorticosterone, thereby protecting both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) from the actions of corticosterone. Following bilateral uterine ligation on the pregnant rat, UPI significantly decreased renal COX-2, 11beta-HSD2, and GR mRNA and protein levels, but upregulated expression of MR at birth. At day 21 of life, 11beta-HSD2, GR, and also MR mRNA and protein levels were downregulated. UPI did not affect blood pressures (BP) at day 21 of life but significantly increased systolic BP in both genders at day 140. We conclude that in our animal model, UPI decreases fetal COX-2 expression during a period of active nephrogenesis in the IUGR rat, which is also characterized by decreased nephron number and adult-onset hypertension. PMID:17272666

  1. Converting enzyme inhibition and the glomerular hemodynamic response to glycine in diabetic rats.

    PubMed

    Slomowitz, L A; Peterson, O W; Thomson, S C

    1999-07-01

    GFR normally increases during glycine infusion. This response is absent in humans and rats with established diabetes mellitus. In diabetic patients, angiotensin-converting enzyme inhibition (ACEI) restores the effect of glycine on GFR. To ascertain the glomerular hemodynamic basis for this effect of ACEI, micropuncture studies were performed in male Wistar-Froemter rats after 5 to 6 wk of insulin-treated streptozotocin diabetes. The determinants of single-nephron GFR (SNGFR) were assessed in each rat before and during glycine infusion. Studies were performed in diabetics, diabetics after 5 d of ACEI (enalapril in the drinking water), and weight-matched controls. Diabetic rats manifest renal hypertrophy and glomerular hyperfiltration but not glomerular capillary hypertension. ACEI reduced glomerular capillary pressure, increased glomerular ultrafiltration coefficient, and did not mitigate hyperfiltration. In controls, glycine increased SNGFR by 30% due to increased nephron plasma flow. In diabetics, glycine had no effect on any determinant of SNGFR. In ACEI-treated diabetics, the SNGFR response to glycine was indistinguishable from nondiabetics, but the effect of glycine was mediated by greater ultrafiltration pressure rather than by greater plasma flow. These findings demonstrate that: (1) The absent response to glycine in established diabetes does not indicate that renal functional reserve is exhausted by hyperfiltration; and (2) ACEI restores the GFR response to glycine in established diabetes, but this response is mediated by increased ultrafiltration pressure rather than by increased nephron plasma flow. PMID:10405200

  2. Atlas of Cellular Dynamics during Zebrafish Adult Kidney Regeneration

    PubMed Central

    McCampbell, Kristen K.; Springer, Kristin N.; Wingert, Rebecca A.

    2015-01-01

    The zebrafish is a useful animal model to study the signaling pathways that orchestrate kidney regeneration, as its renal nephrons are simple, yet they maintain the biological complexity inherent to that of higher vertebrate organisms including mammals. Recent studies have suggested that administration of the aminoglycoside antibiotic gentamicin in zebrafish mimics human acute kidney injury (AKI) through the induction of nephron damage, but the timing and details of critical phenotypic events associated with the regeneration process, particularly in existing nephrons, have not been characterized. Here, we mapped the temporal progression of cellular and molecular changes that occur during renal epithelial regeneration of the proximal tubule in the adult zebrafish using a platform of histological and expression analysis techniques. This work establishes the timing of renal cell death after gentamicin injury, identifies proliferative compartments within the kidney, and documents gene expression changes associated with the regenerative response of proliferating cells. These data provide an important descriptive atlas that documents the series of events that ensue after damage in the zebrafish kidney, thus availing a valuable resource for the scientific community that can facilitate the implementation of zebrafish research to delineate the mechanisms that control renal regeneration. PMID:26089919

  3. A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures

    SciTech Connect

    Webb, Carol F.; Ratliff, Michelle L.; Powell, Rebecca; Wirsig-Wiechmann, Celeste R.; Lakiza, Olga; Obara, Tomoko

    2015-08-07

    Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a−/− kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. - Highlights: • An ARID3a-deficient mouse kidney cell line expresses multiple progenitor markers. • This cell line spontaneously forms multiple nephron-like structures in vitro. • This cell line formed mouse kidney structures in immunocompromised medaka fish kidneys. • Our data identify a novel model system for studying kidney development.

  4. Zeb1 Is a Potential Regulator of Six2 in the Proliferation, Apoptosis and Migration of Metanephric Mesenchyme Cells.

    PubMed

    Gu, Yuping; Zhao, Ya; Zhou, Yuru; Xie, Yajun; Ju, Pan; Long, Yaoshui; Liu, Jianing; Ni, Dongsheng; Cao, Fen; Lyu, Zhongshi; Mao, Zhaomin; Hao, Jin; Li, Yiman; Wan, Qianya; Kanyomse, Quist; Liu, Yamin; Ren, Die; Ning, Yating; Li, Xiaofeng; Zhou, Qin; Li, Bing

    2016-01-01

    Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2. PMID:27509493

  5. Prokineticin receptor 1 is required for mesenchymal-epithelial transition in kidney development.

    PubMed

    Arora, Himanshu; Boulberdaa, Mounia; Qureshi, Rehana; Bitirim, Verda; Messadeq, Nadia; Dolle, Pascal; Nebigil, Canan G

    2016-08-01

    Identification of factors regulating renal development is important to understand the pathogenesis of congenital kidney diseases. Little is known about the molecular mechanism of renal development and functions triggered by the angiogenic hormone prokineticin-2 and its receptor, PKR1. Utilizing the Gata5 (G5)-Cre and Wilms tumor 1 (Wt1)(GFP)cre transgenic lines, we generated mutant mice with targeted PKR1 gene disruptions in nephron progenitors. These mutant mice exhibited partial embryonic and postnatal lethality. Kidney developmental defects in PKR(G5-/-) mice are manifested in the adult stage as renal atrophy with glomerular defects, nephropathy, and uremia. PKR1(Wt1-/-) embryos exhibit hypoplastic kidneys with premature glomeruli and necrotic nephrons as a result of impaired proliferation and increased apoptosis in Wt1(+) renal mesenchymal cells. PKR1 regulates renal mesenchymal-epithelial transition (MET) that is involved in formation of renal progenitors, regulating glomerulogenesis toward forming nephrons during kidney development. In the isolated embryonic Wt1(+) renal cells, overexpression or activation of PKR1 promotes MET defined by the transition from elongated cell to octagonal cell morphology, and alteration of the expression of MET markers via activating NFATc3 signaling. Together, these results establish PKR1 via NFATc3 as a crucial modifier of MET processing to the development of nephron. Our study should facilitate new therapeutic opportunities in human renal disorders.-Arora, H., Boulberdaa, M., Qureshi, R., Bitirim, V., Messadeq, N., Dolle, P., Nebigil, C. G. Prokineticin receptor 1 is required for mesenchymal-epithelial transition in kidney development. PMID:27084889

  6. Zeb1 Is a Potential Regulator of Six2 in the Proliferation, Apoptosis and Migration of Metanephric Mesenchyme Cells

    PubMed Central

    Gu, Yuping; Zhao, Ya; Zhou, Yuru; Xie, Yajun; Ju, Pan; Long, Yaoshui; Liu, Jianing; Ni, Dongsheng; Cao, Fen; Lyu, Zhongshi; Mao, Zhaomin; Hao, Jin; Li, Yiman; Wan, Qianya; Kanyomse, Quist; Liu, Yamin; Ren, Die; Ning, Yating; Li, Xiaofeng; Zhou, Qin; Li, Bing

    2016-01-01

    Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2. PMID:27509493

  7. Biofeasibility Study.

    ERIC Educational Resources Information Center

    Chaparian, Michael

    1995-01-01

    Discusses the use of bioremediation as a method for disposing of contaminants by exploiting natural biodegradation processes. The process of conducting a biofeasibility study and a case study are reviewed. (LZ)

  8. Intelligence Studies

    ERIC Educational Resources Information Center

    Monaghan, Peter

    2009-01-01

    To make an academic study of matters inherently secret and potentially explosive seems a tall task. But a growing number of scholars are drawn to understanding spycraft. The interdisciplinary field of intelligence studies is mushrooming, as scholars trained in history, international studies, and political science examine such subjects as the…

  9. Social Studies.

    ERIC Educational Resources Information Center

    Bieber, Edward

    The product of a Special Studies Institute, this teacher developed resource guide for the emotionally handicapped (K-6) presents social study concepts and activities relative to education in the urban out-of-doors. Focus is on the study of man (past, present, and future) interacting with his environment. Listed below are activity examples: (1)…

  10. College Studying.

    ERIC Educational Resources Information Center

    Nist, Sherrie L.; Simpson, Michele

    2002-01-01

    Notes that many students enter postsecondary institutions unprepared to meet the studying demands placed on them. Examines models and taxonomies that have guided researchers as they have investigated studying. Reviews research factors related to studying at the college level: course characteristics, learner characteristics, and learning…

  11. Toxicity Studies.

    PubMed

    2016-01-01

    Toxicity studies in the animal models are done to determine the dose level recommended for the treatment of disease as drug. This guideline enables the characterization of adverse effects following repeated daily inhalation exposure to a test. This chapter includes oral and dermal toxicity studies which are discussed as per OECD guidelines. Both acute and subacute toxicity studies are given special emphasis. PMID:26939270

  12. Calcium signaling triggered by ouabain protects the embryonic kidney from adverse developmental programming.

    PubMed

    Khodus, Georgiy R; Kruusmägi, Markus; Li, Juan; Liu, Xiao-Li; Aperia, Anita

    2011-09-01

    The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards formation of the kidney's functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that the sodium-potassium-adenosine triphosphatase (Na, K-ATPase) ligand ouabain triggers, via the Na, K-ATPase/ inositol 1,4,5-trisphosphate receptor signalosome, a calcium-nuclear factor-kappa B (NF-κB) signal that protects kidney development from adverse effects of malnutrition. Serum deprivation resulted in severe retardation of nephron formation and robust increase in apoptotic rate, but in ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Depletion of intracellular calcium stores and inhibition of NF-κB activity abolished the rescuing effect of ouabain. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given low-protein diets and treated with ouabain or vehicle throughout pregnancy. PMID:21424905

  13. Comparison of the gene expression profiles from normal and Fgfrl1 deficient mouse kidneys reveals downstream targets of Fgfrl1 signaling.

    PubMed

    Gerber, Simon D; Amann, Ruth; Wyder, Stefan; Trueb, Beat

    2012-01-01

    Fgfrl1 (fibroblast growth factor receptor-like 1) is a transmembrane receptor that is essential for the development of the metanephric kidney. It is expressed in all nascent nephrogenic structures and in the ureteric bud. Fgfrl1 null mice fail to develop the metanephric kidneys. Mutant kidney rudiments show a dramatic reduction of ureteric branching and a lack of mesenchymal-to-epithelial transition. Here, we compared the expression profiles of wildtype and Fgfrl1 mutant kidneys to identify genes that act downstream of Fgfrl1 signaling during the early steps of nephron formation. We detected 56 differentially expressed transcripts with 2-fold or greater reduction, among them many genes involved in Fgf, Wnt, Bmp, Notch, and Six/Eya/Dach signaling. We validated the microarray data by qPCR and whole-mount in situ hybridization and showed the expression pattern of candidate genes in normal kidneys. Some of these genes might play an important role during early nephron formation. Our study should help to define the minimal set of genes that is required to form a functional nephron. PMID:22432025

  14. A qualitative analysis of the kidney structure of Meliphagid honeyeaters from wet and arid environments.

    PubMed

    Casotti, G; Richardson, K C

    1993-04-01

    The qualitative ultrastructural renal anatomy was examined in 4 species of honeyeater (parvorder Corvi) inhabiting 2 distinctly different environments. The kidneys of the wet zone New Holland honeyeater Phylidonyris novaehollandiae and little wattlebird Anthochaera lunulata were compared with those of the arid zone white-fronted honeyeater Phylidonyris albifrons and spiny-cheeked honeyeater Acanthogenys rufogularis. The size and structure of glomeruli were similar between species. In all species, except in P. novaehollandiae, the proximal tubule cells contained wide intercellular spaces filled with basolateral cell membrane interdigitations. Medullary nephron tubules were arranged in a sequential manner in all species. Thick and thin limbs of Henle were separated by the collecting ducts and extended the entire length of the medulla, a situation not found in muscicapid passerines. This tubular arrangement is not entirely consistent with the proposed single-effect countercurrent multiplier theory. The thin limb of Henle consisted of only one epithelium type, which had wide intercellular spaces. The thick limb of Henle consisted of 2 types of epithelial cells, each having narrow intercellular spaces, but with varying degrees of cell membrane infoldings. The ultrastructural morphology of the limbs of Henle in honeyeaters differed from those of muscicapid passerines. The ultrastructure of the distal nephron was similar in each species studied. All of the above nephron characteristics are considered to enable honeyeaters to absorb a large proportion of solutes and water from the glomerular filtrate. PMID:8376198

  15. A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5' end of Pkd1.

    PubMed

    Starremans, P G; Li, X; Finnerty, P E; Guo, L; Takakura, A; Neilson, E G; Zhou, J

    2008-06-01

    Autosomal dominant polycystic kidney disease, a leading cause of end-stage renal disease in adults, is characterized by progressive focal cyst formation in the kidney. Embryonic lethality of Pkd1-targeted mice limits the use of these mice. Here we developed a floxed allele of Pkd1 exons 2-6. Global deletion mutants developed polyhydramnios, hydrops fetalis, polycystic kidney and pancreatic disease. Somatic Pkd1 inactivation in the kidney was achieved by crossing Pkd1(flox) mice with transgenic mice expressing Cre controlled by a gamma-glutamyltranspeptidase promoter. These mutants developed cysts in both proximal and distal nephron segments and survived for about 4 weeks. Somatic loss of heterozygosity was shown in a reporter mouse strain to cause cystogenesis. Some cysts in young mice are positive for multiple tubular markers and a mesenchymal marker, suggesting a delay in tubular epithelial differentiation. A higher cell proliferation rate was observed in distal nephron segments probably accounting for the faster growth rate of distal cysts. Although we observed an overall increase in apoptosis in cystic kidneys, there was no difference between proximal or distal nephron segments. We also found increased cyclic AMP, aquaporin 2 and vasopressin type 2 receptor mRNA levels, and apical membrane translocation of aquaporin 2 in cystic kidneys, all of which may contribute to the differential cyst growth rate observed. The accelerated polycystic kidney phenotype of these mice provides an excellent model for studying molecular pathways of cystogenesis and to test therapeutic strategies. PMID:18385665

  16. Comparison of the Gene Expression Profiles from Normal and Fgfrl1 Deficient Mouse Kidneys Reveals Downstream Targets of Fgfrl1 Signaling

    PubMed Central

    Gerber, Simon D.; Amann, Ruth; Wyder, Stefan; Trueb, Beat

    2012-01-01

    Fgfrl1 (fibroblast growth factor receptor-like 1) is a transmembrane receptor that is essential for the development of the metanephric kidney. It is expressed in all nascent nephrogenic structures and in the ureteric bud. Fgfrl1 null mice fail to develop the metanephric kidneys. Mutant kidney rudiments show a dramatic reduction of ureteric branching and a lack of mesenchymal-to-epithelial transition. Here, we compared the expression profiles of wildtype and Fgfrl1 mutant kidneys to identify genes that act downstream of Fgfrl1 signaling during the early steps of nephron formation. We detected 56 differentially expressed transcripts with 2-fold or greater reduction, among them many genes involved in Fgf, Wnt, Bmp, Notch, and Six/Eya/Dach signaling. We validated the microarray data by qPCR and whole-mount in situ hybridization and showed the expression pattern of candidate genes in normal kidneys. Some of these genes might play an important role during early nephron formation. Our study should help to define the minimal set of genes that is required to form a functional nephron. PMID:22432025

  17. Compensatory renal hypertrophy and the handling of an acute nephrotoxicant in a model of aging.

    PubMed

    Oliveira, Cláudia S; Joshee, Lucy; Zalups, Rudolfs K; Bridges, Christy C

    2016-03-01

    Aging often results in progressive losses of functioning nephrons, which can lead to a significant reduction in overall renal function. Because of age-related pathological changes, the remaining functional nephrons within aged kidneys may be unable to fully counteract physiological and/or toxicological challenges. We hypothesized that when the total functional renal mass of aged rats is reduced by 50%, the nephrons within the remnant kidney do not fully undergo the functional and physiological changes that are necessary to maintain normal fluid and solute homeostasis. We also tested the hypothesis that the disposition and handling of a nephrotoxicant are altered significantly in aged kidneys following an acute, 50% reduction in functional renal mass. To test these hypotheses, we examined molecular indices of renal cellular hypertrophy and the disposition of inorganic mercury (Hg(2+)), a model nephrotoxicant, in young control, young uninephrectomized (NPX), aged control and aged NPX Wistar rats. We found that the process of aging reduces the ability of the remnant kidney to undergo compensatory renal growth. In addition, we found that an additional reduction in renal mass in aged animals alters the disposition of Hg(2+) and potentially alters the risk of renal intoxication by this nephrotoxicant. To our knowledge, this study represents the first report of the handling of a nephrotoxicant in an aged animal following a 50% reduction in functional renal mass. PMID:26768998

  18. Laparoscopic and Percutaneous Ablative Techniques in the Treatment of Renal Cell Carcinoma

    PubMed Central

    Perry, Kent; Zisman, Amnon; Pantuck, Allan J; Janzen, Nicolette; Schulam, Peter; Belldegrun, Arie S

    2002-01-01

    Widespread use of computed tomography, ultrasound, and magnetic resonance imaging has led to an increase in detection of relatively small renal masses, and approaches to managing them have evolved in the last two decades. Indications for nephron-sparing surgery have expanded, and minimally invasive procedures, which can confer advantages over open surgery, are now available. Ablative techniques offer a combination of nephron-sparing and minimally invasive approaches. Ablative techniques include cryoablation, radiofrequency ablation (RFA), and high-intensity focused ultrasound (HIFU). Cryoablation and RFA have been relatively safe. HIFU has been associated with serious side effects in animal models, and is not yet acceptable for use in humans. Ablative techniques require long-term studies to confirm lasting efficacy. The best modality for tumor targeting, monitoring of therapy, and follow-up is still under investigation. Debate exists regarding the best method for ensuring adequate intraoperative tumor cryoablation. For minimally invasive ablative measures to gain a place as nephron-sparing approaches, they should show both equivalent efficacy and reduced morbidity relative to those of open partial nephrectomy. These techniques should currently be reserved for selected patients and should be compared to the evolving modality of laparoscopic partial nephrectomy. PMID:16985666

  19. Aerosal studies

    NASA Technical Reports Server (NTRS)

    Harris, F. S., Jr.

    1976-01-01

    Various methods of measuring aerosols were studied in terms of the best methods to use, the instruments or techniques actually employed, and those techniques applied in field measurements on air quality as influenced by rocket launch effluents, and in an urban environment. Further studies were initiated on the remote sensing of aerosols by satellites and the influence of aerosols on visibility. The characterization of aerosols by measurement of scattered light was studied on Mie theory calculations.

  20. Stream Studies.

    ERIC Educational Resources Information Center

    Hamilton City Board of Education (Ontario).

    This manual provides teachers with some knowledge of ecological study methods and techniques used in collecting data when plants and animals are studied in the field. Most activities deal with the interrelatedness of plant and animal life to the structure and characteristics of a stream and pond. Also included in this unit plan designed for the…

  1. Women's Studies.

    ERIC Educational Resources Information Center

    Davis, James E., Ed.; Davis, Hazel K., Ed.

    1981-01-01

    The 16 articles in this journal issue deal with women's studies within the English curriculum. Topics discussed in the articles include (1) the feminist challenge to the male-centered curriculum in higher education; (2) the women's movement and women's studies; (3) connotations of the word "girl"; (4) women in English education; (5) the new…

  2. Study Skills.

    ERIC Educational Resources Information Center

    Thomas, Anne

    1993-01-01

    Three developments lend support to the idea that schools must help teach study skills: (1) advances in cognitive psychology that suggest children are active learners; (2) society's concern for at-risk students; and (3) growing demands for improved student performance. There is evidence that systematic study skills instruction does improve academic…

  3. Studying Zooarchaeology

    ERIC Educational Resources Information Center

    Moore, Molly; Wolf, Deborah; Butler, Virginia L.

    2012-01-01

    Children often associate the study of bones with dinosaurs or crime scenes. This unit introduces students to "zooarchaeology," the study of animal remains from archaeological sites. Students in grades 3-5 engage in hands-on activities examining bones, shells, and other "hard parts" of animals. They use their observations as a starting point for…

  4. SISTER STUDY

    EPA Science Inventory

    The Sister Study will investigate the role of genetic, environmental, and lifestyle factors on the risk of breast cancer and other diseases in sisters of women with breast cancer. This research study will enroll 50,000 women who live in the United States and who are the cancer-fr...

  5. Social Studies.

    ERIC Educational Resources Information Center

    White, Cam, Ed.

    This document contains the following papers on social studies instruction and technology: (1) "Waking the Sleeping Giant: Social Studies Teacher Educators Collaborate To Integrate Technology into Methods' Courses" (Cheryl Mason, Marsha Alibrandi, Michael Berson, Kara Dawson, Rich Diem, Tony Dralle, David Hicks, Tim Keiper, and John Lee); (2)…

  6. HETEROSYNAPTIC REGULATION OF EXTERNAL GLOBUS PALLIDUS INPUTS TO THE SUBTHALAMIC NUCLEUS BY MOTOR CORTEX

    PubMed Central

    Chu, Hong-Yuan; Atherton, Jeremy F.; Wokosin, David; Surmeier, D. James; Bevan, Mark D.

    2014-01-01

    SUMMARY The two principal movement-suppressing pathways of the basal ganglia, the so-called hyperdirect and indirect pathways interact within the subthalamic nucleus (STN). An appropriate level and pattern of hyperdirect pathway cortical excitation and indirect pathway external globus pallidus (GPe) inhibition of the STN are critical for normal movement and greatly perturbed in Parkinson’s disease. Here, we demonstrate that motor cortical inputs to the STN heterosynaptically regulate through activation of postsynaptic NMDA receptors the number of functional GABAA receptor-mediated GPe-STN inputs. Thus, a homeostatic mechanism, intrinsic to the STN, balances cortical excitation by adjusting the strength of GPe inhibition. However, following loss of dopamine, excessive cortical activation of STN NMDA receptors triggers GPe-STN inputs to strengthen abnormally, contributing to the emergence of pathological, correlated activity. PMID:25578364

  7. Culture Studies: Hawaiian Studies Project.

    ERIC Educational Resources Information Center

    Hazama, Dorothy, Ed.

    Reports and materials from the Hawaiian Studies Project are presented. The document, designed for elementary school teachers contains two major sections. The first section describes the planning phase of the project, the Summer Institute for Hawaiian Culture Studies (1976) and the follow-up workshops and consultant help (1976-77). The appendix to…

  8. NEUROTOXICITY STUDIES

    EPA Science Inventory

    The neurotoxicity of DBPs in general has not been well characterized. The literature provides reports of neurotoxicity of DCA following exposures to relatively high doses. Studies completed at EPA, however, have shown that relatively low doses of DCA (as low as 16 mg/kg/day; simi...

  9. Readability Study.

    ERIC Educational Resources Information Center

    White, Robert; Jordan, William

    A readability study for the Albuquerque Technical-Vocational Institute (T-VI) was undertaken to provide information regarding the reading ability required to complete training and to function in entry-level jobs. Readability formulas were applied to materials used in training and on the job. In addition, students were tested for level of reading,…

  10. Case Studies

    ERIC Educational Resources Information Center

    Ritter, Lois A., Ed.; Sue, Valerie M., Ed.

    2007-01-01

    This article presents two case studies using online surveys for evaluation. The authors begin with an example of a needs assessment survey designed to measure the amount of help new students at a university require in their first year. They then discuss the follow-up survey conducted by the same university to measure the effectiveness of the…

  11. MEDIEVAL STUDIES.

    ERIC Educational Resources Information Center

    MARTONFFY, ANDREA PONTECORVO; AND OTHERS

    A CURRICULUM GUIDE ON MEDIEVAL STUDIES IS PRESENTED, INCLUDING TEACHER MATERIALS AND STUDENT PROBLEM SETS. THE TEACHER MATERIALS DESCRIBE AND EXPLAIN THE ECONOMIC, SOCIAL, AND POLITICAL ASPECTS OF MANORIAL LIFE--THE PREDOMINANT FORM OF AGRICULTURAL LIFE IN NORTHERN FRANCE, ENGLAND, AND GERMANY DURING THE PERIOD FROM APPROXIMATELY 800 TO 1300 A.D.…

  12. IMMUNOTOXICITY STUDIES

    EPA Science Inventory

    Few D/DBPs have been evaluated for effects on the immune system, but certain studies suggest that immunosuppression may follow exposure to D/DBPs. Suppressed immune function is associated with increased susceptibility to infectious disease and certain types of cancer in humans a...

  13. Discipline Study.

    ERIC Educational Resources Information Center

    Queer, Glenn E.

    This report discusses a study designed to elicit opinions from Pittsburgh School District principals, parents, and teachers concerning corporal punishment and other disciplinary action. Questionnaires were aimed at (1) determining reactions to current regulations governing the use of corporal punishment, (2) eliciting instances of experience or…

  14. Research Study

    ERIC Educational Resources Information Center

    Glick, Ashley

    2010-01-01

    Background: Action Research about my 2nd grade classroom in the Buffalo School District. I examined three areas of interest and tried to find some conclusions related to behavior management. Purpose: The purpose of this study is how will implementing procedures, rules, and consequences help improve student behavior. Research Design: Descriptive;…

  15. Dynamics of Urinary Calprotectin after Renal Ischaemia

    PubMed Central

    Ebbing, Jan; Seibert, Felix S.; Pagonas, Nikolaos; Bauer, Frederic; Miller, Kurt; Kempkensteffen, Carsten; Günzel, Karsten; Bachmann, Alexander; Seifert, Hans H.; Rentsch, Cyrill A.; Ardelt, Peter; Wetterauer, Christian; Amico, Patrizia; Babel, Nina; Westhoff, Timm H.

    2016-01-01

    Background: Urinary calprotectin has been identified as a promising biomarker for acute kidney injury. To date, however, the time-dependent changes of this parameter during acute kidney injury remain elusive. The aim of the present work was to define the time-course of urinary calprotectin secretion after ischaemia/reperfusion-induced kidney injury in comparison to neutrophil gelatinase—associated lipocalin, thereby monitoring the extent of tubular damage in nephron sparing surgery for kidney tumours. Methods: The study population consisted of 42 patients. Thirty-two patients underwent either open or endoscopic nephron sparing surgery for kidney tumours. During the surgery, the renal arterial pedicle was clamped with a median ischaemic time of 13 minutes (interquartile range, 4.5–20.3 minutes) in 26 patients. Ten retro-peritoneoscopic living donor nephrectomy patients and 6 nephron sparing surgery patients in whom the renal artery was not clamped served as controls. Urinary calprotectin and neutrophil gelatinase—associated lipocalin concentrations were repeatedly measured by enzyme-linked immunosorbent assay and assessed according to renal function parameters. Results: Urinary concentrations of calprotectin and neutrophil gelatinase—associated lipocalin increased significantly after ischaemia/reperfusion injury, whereas concentrations remained unchanged after nephron sparing surgery without ischaemia/reperfusion injury and after kidney donation. Calprotectin and neutrophil gelatinase—associated lipocalin levels were significantly increased 2 and 8 hours, respectively, post-ischaemia. Both proteins reached maximal concentrations after 48 hours, followed by a subsequent persistent decrease. Maximal neutrophil gelatinase—associated lipocalin and calprotectin concentrations were 9-fold and 69-fold higher than their respective baseline values. The glomerular filtration rate was only transiently impaired at the first post-operative day after ischaemia

  16. Study Design for Sequencing Studies.

    PubMed

    Honaas, Loren A; Altman, Naomi S; Krzywinski, Martin

    2016-01-01

    Once a biochemical method has been devised to sample RNA or DNA of interest, sequencing can be used to identify the sampled molecules with high fidelity and low bias. High-throughput sequencing has therefore become the primary data acquisition method for many genomics studies and is being used more and more to address molecular biology questions. By applying principles of statistical experimental design, sequencing experiments can be made more sensitive to the effects under study as well as more biologically sound, hence more replicable. PMID:27008009

  17. Retrospective studies.

    PubMed

    Silveira, Patrícia Pelufo; Manfro, Gisele Gus

    2015-01-01

    Large retrospective, epidemiological studies accumulated in the late 1980s, providing increasing evidence to the deeply rooted thought that perinatal events could persistently affect the individual's functioning and health/disease patterns throughout the lifetime. Evidences of such associations can be found in the literature since the beginning of the twentieth century, but studies from Barker, Hales, and colleagues serve as an important hallmark. They proposed the "thrifty phenotype" hypothesis, stating that poor nutrition in fetal and early infant life is detrimental to the development and function of the individuals' organism, predisposing them to the later development of adult chronic diseases. At first used to explain the increased risk for type 2 diabetes in low birth weight individuals, the hypothesis was soon adapted to other systems, becoming one of the core assumptions of the Developmental Origins of Adult Health and Disease (DOHaD) model. The central nervous system is also vulnerable to the effects of environmental variation during fetal or neonatal life. Many researchers have explored the effects of perinatal programming on the human neurodevelopment, and some aspects of the brain structure and/or functioning (such as cognitive function, physiological reactivity to stress, and the risk for behavioral disorders or psychopathology) were shown to be modifiable by the exposure to certain adverse events early in life such as neonatal infections, exposure to gestational psychosocial stress, nutrition during gestation, exposure to drugs, or tobacco smoking during pregnancy. Until recently, most studies focused on birth weight as a strong surrogate of the intrauterine environment, investigating the effects of low birth weight (as a marker of suboptimal fetal environment) on a variety of neurodevelopmental outcomes. Despite the fact that literature reviews on this topic are as old as 1940, the more recent retrospective studies are summarized in this chapter

  18. Cholera studies*

    PubMed Central

    Pollitzer, R.

    1956-01-01

    The first portion of this study describes in detail the different aspects of stool examinations, including the collection, preservation, and pooling of specimens, macroscopic and bacterioscopic examination, enrichment methods, and cultivation on a variety of solid media. The author also deals with the examination of vomits and of water. The performance and value of different identification tests (agglutination, haemolysis, and bacteriophage) and confirmatory tests are then considered. An annex is included on bacteriological procedures in the laboratory diagnosis of cholera. PMID:13356145

  19. Cholera studies*

    PubMed Central

    Pollitzer, R.

    1957-01-01

    Discussing the symptomatology of cholera, the author deals first with the incubation period, the clinical types, choleraic diarrhoea, and cholerine; he then considers in detail the various stages of cholera gravis and the relapses and complications that may be met. This is followed by sections on diagnosis and differential diagnosis, and on prognosis and the various factors influencing it. The author's highly detailed review of the treatment of cholera which concludes this study is divided into three parts, dealing with attempts at specific therapy, with infusion treatment, and with adjuvant treatment. PMID:13426761

  20. Anticorrosion studies

    NASA Technical Reports Server (NTRS)

    Boerio, J.

    1986-01-01

    The aging behavior of chemically bonded interfaces between metals and pottants, such as ethylene vinyl acetate (EVA) was studied using the Dow Corning primer systems. It was observed that the primers seem to function as anticorrosive agents on metal surfaces. It was demonstrated that EVA, and the A-11861 EVA/glass primer stops corrosion of the aluminum used on the back surfaces of crystalline silicon solar cells. However, this same treatment does not work for the aluminum on the back surfaces of amorphous silicon solar cells.

  1. Ethnobotanical Study.

    PubMed

    2016-01-01

    Ethnobotany is the study of interrelationships between human cultures and plants, animals, and other organisms in their environment. It also creates an awareness of the link between biodiversity and cultural diversity. From the beginning of civilization, people have been using plants for various purposes like food, shelter, medicines, etc. Ethnobotanists play a key role in exploring these kinds of information from indigenous people which creates a gateway for formulating a novel drug. The content in this chapter deals with these aspects in an approachable manner. PMID:26939258

  2. Anticorrosion studies

    NASA Astrophysics Data System (ADS)

    Boerio, J.

    The aging behavior of chemically bonded interfaces between metals and pottants, such as ethylene vinyl acetate (EVA) was studied using the Dow Corning primer systems. It was observed that the primers seem to function as anticorrosive agents on metal surfaces. It was demonstrated that EVA, and the A-11861 EVA/glass primer stops corrosion of the aluminum used on the back surfaces of crystalline silicon solar cells. However, this same treatment does not work for the aluminum on the back surfaces of amorphous silicon solar cells.

  3. Cholera studies*

    PubMed Central

    Swaroop, S.; Pollitzer, R.

    1955-01-01

    In this study, figures relating to cholera deaths occurring in individual countries, from 1900 to 1952, are recorded as well as the incidence of the disease from 1923 up to the present time. The mode of spread of cholera from its endemic home in India to outside countries is described in relation to favourable seasons, main routes followed by the infection, and the role played by large religious gatherings. The incidence of the disease in the various seaports infected within recent years is discussed. PMID:14364186

  4. Plague studies*

    PubMed Central

    Pollitzer, R.

    1953-01-01

    In examining the control and prevention of plague, the author pays particular attention to the control of commensal rodents and their fleas. The various rat poisons in current use, their efficacy and practical application, and the dangers involved in their manipulation are described in great detail. The author also discusses other anti-rodent measures such as fumigation, rat-proofing, sanitation, protection of food, etc. The second part of the study deals with: vector control—the outstanding value of DDT application in rodent-flea control is emphasized—, the direct control of bubonic and pneumonic plague, and the control of the spread of plague at a distance. PMID:20603968

  5. Complementary Study

    SciTech Connect

    Yamada, H.

    2009-02-19

    In this lecture, it is emphasized that sufficient resolution of scientific issues for a fusion energy reactor can be given by complementary studies. Key scientific issues for a fusion energy reactor and ITER addressed by a complementary study in the Large Helical Device (LHD) are discussed. It should be noted that ITER is definitely a necessary condition but not a sufficient condition. Helical systems including stellarators and heliotrons are defined as alternative concepts. These approaches also aim at a fusion energy reactor based on their own concept and simultaneously benefit progress in tokamaks, more specifically ITER itself. The exact science to manage a 3-D geometry has been being developed in helical systems. A physical model with much accuracy and breadth will demonstrate its applicability to ITER. Topics to validate ''complementary'' approaches such as 3-D equilibrium, interchange MHD mode, control of radial electric field and structure formation, dynamics of a magnetic island, density limit and edge plasmas are discussed. Complementary is not Supplementary. ITER is complementary to development of a helical fusion energy reactor as well. Complementary approaches transcend existing disciplinary horizons and enable big challenges.

  6. Nutritional studies

    NASA Technical Reports Server (NTRS)

    Rambaut, P. C.; Smith, M. C., Jr.; Wheeler, H. O.

    1975-01-01

    Detailed metabolic studies were conducted of the Apollo 16 and Apollo 17 flight crews, and the results are presented in tabular form. Intake and absorption data are also included. Apollo nutrient intakes were found to be characteristically hypocaloric. Estimates of body composition changes from metabolic balance data, from preflight and postflight weights and volumes, and from total body water and potassium provide no evidence for diminished caloric requirements during a flight. As observed during the Gemini Program and during periods of bed rest, measurements of bone density and metabolic balance confirm a tendency toward loss of skeletal tissue in weightlessness. No evidence exists that any inflight metabolic anomaly, including hypokalemia, was induced by marginal or deficient nutrient intakes. In general, the Apollo crewmen were well nourished and exhibited normal gastroenterological functions, although appetite was somewhat diminished and the organoleptic response to food was somewhat modified during flight.

  7. Plague studies*

    PubMed Central

    Pollitzer, R.

    1953-01-01

    Epidemiological aspects of (a) bubonic plague and (b) primary pneumonic plague are discussed separately in this study. The cause, spread, and persistence of bubonic outbreaks are dealt with. In the case of primary pneumonic plague, the author systematically reviews the factors influencing the spread of the disease: climatic and social conditions, infectivity of the patients, immunity, and control measures. In discussing the cause of pneumonic plague outbreaks, the author deals with the possible influence of a special virulence of pneumonic strains, the role of the rodent and flea species involved, and the possibility of a pneumotropismus acquired by Pasteurella pestis. The periodicity (cyclical and secular) of bubonic plague epidemics is discussed with a view to the possible forecasting of future epidemics. The author indicates the influence of race, age, sex, and occupation on the incidence of both forms of the disease. PMID:13082391

  8. Cholera studies*

    PubMed Central

    Pollitzer, R.

    1957-01-01

    In discussing prevention, the author deals first with the provision of permanently safe water, supplied from waterworks or wells, and with other improvements in environmental sanitation. Control of food and drinks, public health propaganda and education, and vaccination are also considered under this heading. The greater part of this study is devoted to suppressive measures, affecting the individual, the environment, and persons in the mass. Discussion of the isolation, detection and management of cholera patients, the management of contacts, and the management and treatment of carriers is followed by sections on, inter alia, disinfection, temporary improvements in water supplies, fly control, and personal prophylaxis. In dealing with mass prophylaxis, the author pays particular attention to vaccination. In the concluding sections he goes into the control of pilgrimages and local and international quarantine measures. PMID:13479774

  9. Cholera studies*

    PubMed Central

    Pollitzer, R.

    1957-01-01

    The first section of this study deals with areas where cholera is endemic and with the conditions normally favouring endemicity. Turning next to epidemics, the author discusses their origin and types, climatic influences on them, their periodicity and the possibility of forecasting them, the role played in them by different serological races of V. cholerae, and the causes of their decline. In a section on the factors governing the local spread of cholera, he considers contact and water-borne infection; the role of contaminated food and drink, of fomites, of flies, and of carriers; and the incidence according to sex, age, race, and occupation. The last part deals with factors governing the spread of cholera over longer distances, and includes discussion of the effect of movements of individuals and groups and of assemblies of the population on pilgrimages or at religious festivals. PMID:13472431

  10. Plague studies*

    PubMed Central

    Pollitzer, R.

    1953-01-01

    The author examines in detail the symptomatology, diagnosis, and treatment of plague, and outlines the problem of the length of the incubation period. The clinical features commonly met with in all severely-affected plague patients, regardless of the primary localization of the infection, are described. The author then deals with the symptomatology and manifestations of bubonic plague as compared to those of primary pneumonic plague. The importance of a clinical diagnosis, from the point of view of prevention, is stressed, and the differential diagnosis of various forms of the disease is described. The study contains a detailed discussion of the respective merits of antibiotic treatment, serotherapy, and sulfonamide treatment. The author points out that the outstanding success of streptomycin and some other antibiotics will probably relegate the sulfonamides to the second rank in the treatment of bubonic plague. PMID:13082390

  11. Systems Studies

    SciTech Connect

    Graham, R.L.

    1998-03-17

    The Systems Studies Activity had two objectives: (1) to investigate nontechnical barriers to the deployment of biomass production and supply systems and (2) to enhance and extend existing systems models of bioenergy supply and use. For the first objective, the Activity focused on existing bioenergy markets. Four projects were undertaken: a comparative analysis of bioenergy in Sweden and Austria; a one-day workshop on nontechnical barriers jointly supported by the Production Systems Activity; the development and testing of a framework for analyzing barriers and drivers to bioenergy markets; and surveys of wood pellet users in Sweden, Austria and the US. For the second objective, two projects were undertaken. First, the Activity worked with the Integrated BioEnergy Systems (TBS) Activity of TEA Bioenergy Task XIII to enhance the BioEnergy Assessment Model (BEAM). This model is documented in the final report of the IBS Activity. The Systems Studies Activity contributed to enhancing the feedstock portion of the model by developing a coherent set of willow, poplar, and switchgrass production modules relevant to both the US and the UK. The Activity also developed a pretreatment module for switchgrass. Second, the Activity sponsored a three-day workshop on modeling bioenergy systems with the objectives of providing an overview of the types of models used to evaluate bioenergy and promoting communication among bioenergy modelers. There were nine guest speakers addressing different types of models used to evaluate different aspects of bioenergy, ranging from technoeconomic models based on the ASPEN software to linear programming models to develop feedstock supply curves for the US. The papers from this workshop have been submitted to Biomass and Bioenergy and are under editorial review.

  12. Toxin-induced pore formation is hindered by intermolecular hydrogen bonding in sphingomyelin bilayers.

    PubMed

    García-Linares, Sara; Palacios-Ortega, Juan; Yasuda, Tomokazu; Åstrand, Mia; Gavilanes, José G; Martínez-del-Pozo, Álvaro; Slotte, J Peter

    2016-06-01

    Sticholysin I and II (StnI and StnII) are pore-forming toxins that use sphingomyelin (SM) for membrane binding. We examined how hydrogen bonding among membrane SMs affected the StnI- and StnII-induced pore formation process, resulting in bilayer permeabilization. We compared toxin-induced permeabilization in bilayers containing either SM or dihydro-SM (lacking the trans Δ(4) double bond of the long-chain base), since their hydrogen-bonding properties are known to differ greatly. We observed that whereas both StnI and StnII formed pores in unilamellar vesicles containing palmitoyl-SM or oleoyl-SM, the toxins failed to similarly form pores in vesicles prepared from dihydro-PSM or dihydro-OSM. In supported bilayers containing OSM, StnII bound efficiently, as determined by surface plasmon resonance. However, StnII binding to supported bilayers prepared from dihydro-OSM was very low under similar experimental conditions. The association of the positively charged StnII (at pH7.0) with unilamellar vesicles prepared from OSM led to a concentration-dependent increase in vesicle charge, as determined from zeta-potential measurements. With dihydro-OSM vesicles, a similar response was not observed. Benzyl alcohol, which is a small hydrogen-bonding compound with affinity to lipid bilayer interfaces, strongly facilitated StnII-induced pore formation in dihydro-OSM bilayers, suggesting that hydrogen bonding in the interfacial region originally prevented StnII from membrane binding and pore formation. We conclude that interfacial hydrogen bonding was able to affect the membrane association of StnI- and StnII, and hence their pore forming capacity. Our results suggest that other types of protein interactions in bilayers may also be affected by hydrogen-bonding origination from SMs. PMID:26975250

  13. Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator

    NASA Astrophysics Data System (ADS)

    Connolly, Allison T.; Muralidharan, Abirami; Hendrix, Claudia; Johnson, Luke; Gupta, Rahul; Stanslaski, Scott; Denison, Tim; Baker, Kenneth B.; Vitek, Jerrold L.; Johnson, Matthew D.

    2015-12-01

    Objective. Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach. Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results. LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects’ limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. Significance. This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject’s symptomatology.

  14. Improved Sequence Learning with Subthalamic Nucleus Deep Brain Stimulation: Evidence for Treatment-Specific Network Modulation

    PubMed Central

    Mure, Hideo; Tang, Chris C.; Argyelan, Miklos; Ghilardi, Maria-Felice; Kaplitt, Michael G.; Dhawan, Vijay; Eidelberg, David

    2015-01-01

    We used a network approach to study the effects of anti-parkinsonian treatment on motor sequence learning in humans. Eight Parkinson’s disease (PD) patients with bilateral subthalamic nucleus (STN) deep brain stimulation underwent H2 15Opositron emission tomography (PET) imaging to measure regional cerebral blood flow (rCBF) while they performed kinematically matched sequence learning and movement tasks at baseline and during stimulation. Network analysis revealed a significant learning-related spatial covariance pattern characterized by consistent increases in subject expression during stimulation (p = 0.008, permutation test). The network was associated with increased activity in the lateral cerebellum, dorsal premotor cortex, and parahippocampal gyrus, with covarying reductions in the supplementary motor area (SMA) and orbitofrontal cortex. Stimulation-mediated increases in network activity correlated with concurrent improvement in learning performance (p < 0.02). To determine whether similar changes occurred during dopaminergic pharmacotherapy, we studied the subjects during an intravenous levodopa infusion titrated to achieve a motor response equivalent to stimulation. Despite consistent improvement in motor ratings during infusion, levodopa did not alter learning performance or network activity. Analysis of learning-related rCBF in network regions revealed improvement in baseline abnormalities with STN stimulation but not levodopa. These effects were most pronounced in the SMA. In this region, a consistent rCBF response to stimulation was observed across subjects and trials (p = 0.01), although the levodopa response was not significant. These findings link the cognitive treatment response in PD to changes in the activity of a specific cerebello-premotor cortical network. Selective modulation of overactive SMA–STN projection pathways may underlie the improvement in learning found with stimulation. PMID:22357863

  15. Target Selection Recommendations Based on Impact of Deep Brain Stimulation Surgeries on Nonmotor Symptoms of Parkinson's Disease

    PubMed Central

    Wang, Xiao-Hong; Zhang, Lin; Sperry, Laura; Olichney, John; Farias, Sarah Tomaszewski; Shahlaie, Kiarash; Chang, Norika Malhado; Liu, Ying; Wang, Su-Ping; Wang, Cui

    2015-01-01

    Objective: This review examines the evidence that deep brain stimulation (DBS) has extensive impact on nonmotor symptoms (NMSs) of patients with Parkinson's disease (PD). Data Sources: We retrieved information from the PubMed database up to September, 2015, using various search terms and their combinations including PD, NMSs, DBS, globus pallidus internus (GPi), subthalamic nucleus (STN), and ventral intermediate thalamic nucleus. Study Selection: We included data from peer-reviewed journals on impacts of DBS on neuropsychological profiles, sensory function, autonomic symptoms, weight changes, and sleep disturbances. For psychological symptoms and cognitive impairment, we tried to use more reliable proofs: Random, control, multicenter, large sample sizes, and long period follow-up clinical studies. We categorized the NMSs into four groups: those that would improve definitively following DBS; those that are not significantly affected by DBS; those that remain controversial on their surgical benefit; and those that can be worsened by DBS. Results: In general, it seems to be an overall beneficial effect of DBS on NMSs, such as sensory, sleep, gastrointestinal, sweating, cardiovascular, odor, urological symptoms, and sexual dysfunction, GPi-DBS may produce similar results; Both STN and Gpi-DBS are safe with regard to cognition and psychology over long-term follow-up, though verbal fluency decline is related to DBS; The impact of DBS on behavioral addictions and dysphagia is still uncertain. Conclusions: As the motor effects of STN-DBS and GPi-DBS are similar, NMSs may determine the target choice in surgery of future patients. PMID:26668154

  16. Deep Brain Stimulation for Parkinson’s Disease: Recent Trends and Future Direction

    PubMed Central

    FUKAYA, Chikashi; YAMAMOTO, Takamitsu

    2015-01-01

    To date, deep brain stimulation (DBS) has already been performed on more than 120,000 patients worldwide and in more than 7,000 patients in Japan. However, fundamental understanding of DBS effects on the pathological neural circuitry remains insufficient. Recent studies have specifically shown the importance of cortico-striato-thalamo-cortical (CSTC) loops, which were identified as functionally and anatomically discrete units. Three main circuits exist in the CSTC loops, namely, the motor, associative, and limbic circuits. From these theoretical backgrounds, it is determined that DBS sometimes influences not only motor functions but also the cognitive and affective functions of Parkinson’s disease (PD) patients. The main targets of DBS for PD are subthalamic nucleus (STN) and globus pallidus interna (GPi). Ventralis intermedius (Vim)-DBS was found to be effective in improving tremor. However, Vim-DBS cannot sufficiently improve akinesia and rigidity. Therefore, Vim-DBS is seldom carried out for the treatment of PD. In this article, we review the present state of DBS, mainly STN-DBS and GPi-DBS, for PD. In the first part of the article, appropriate indications and practical effects established in previous studies are discussed. The findings of previous investigations on the complications caused by the surgical procedure and on the adverse events induced by DBS itself are reviewed. In the second part, we discuss target selection (GPi vs. STN) and the effect of DBS on nonmotor symptoms. In the final part, as issues that should be resolved, the suitable timing of surgery, symptoms unresponsive to DBS such as on-period axial symptoms, and the related postoperative programing of stimulation parameters, are discussed. PMID:25925761

  17. Deep Brain Stimulation Reduces Neuronal Entropy in the MPTP-Primate Model of Parkinson's Disease

    PubMed Central

    Dorval, Alan D.; Russo, Gary S.; Hashimoto, Takao; Xu, Weidong; Grill, Warren M.; Vitek, Jerrold L.

    2008-01-01

    High-frequency stimulation (HFS) of the subthalamic nucleus (STN) or internal segment of the globus pallidus is a clinically successful treatment for the motor symptoms of Parkinson's disease. However, the mechanisms by which HFS alleviates these symptoms are not understood. Whereas initial studies focused on HFS-induced changes in neuronal firing rates, recent studies suggest that changes in patterns of neuronal activity may correlate with symptom alleviation. We hypothesized that effective STN HFS reduces the disorder of neuronal firing patterns in the basal ganglia thalamic circuit, minimizing the pathological activity associated with parkinsonism. Stimulating leads were implanted in the STN of two rhesus monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Action potentials were recorded from neurons of the internal and external globus pallidus and the motor thalamus (ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis) during HFS that reduced motor symptoms and during clinically ineffective low-frequency stimulation (LFS). Firing pattern entropy was calculated from the recorded spike times to quantify the disorder of the neuronal activity. The firing pattern entropy of neurons within each region of the pallidum and motor thalamus decreased in response to HFS (n ≥ 18 and P ≤ 0.02 in each region), whereas firing rate changes were specific to pallidal neurons only. In response to LFS, firing rates were unchanged, but firing pattern entropy increased throughout the circuit (n ≥ 24 and P ≤ 10−4 in each region). These data suggest that the clinical effectiveness of HFS is correlated with, and potentially mediated by, a regularization of the pattern of neuronal activity throughout the basal ganglia thalamic circuit. PMID:18784271

  18. Probing the O-Glycoproteome of Gastric Cancer Cell Lines for Biomarker Discovery*

    PubMed Central

    Campos, Diana; Freitas, Daniela; Gomes, Joana; Magalhães, Ana; Steentoft, Catharina; Gomes, Catarina; Vester-Christensen, Malene B.; Ferreira, José Alexandre; Afonso, Luis P.; Santos, Lúcio L.; Pinto de Sousa, João; Mandel, Ulla; Clausen, Henrik; Vakhrushev, Sergey Y.; Reis, Celso A.

    2015-01-01

    Circulating O-glycoproteins shed from cancer cells represent important serum biomarkers for diagnostic and prognostic purposes. We have recently shown that selective detection of cancer-associated aberrant glycoforms of circulating O-glycoprotein biomarkers can increase specificity of cancer biomarker assays. However, the current knowledge of secreted and circulating O-glycoproteins is limited. Here, we used the COSMC KO “SimpleCell” (SC) strategy to characterize the O-glycoproteome of two gastric cancer SimpleCell lines (AGS, MKN45) as well as a gastric cell line (KATO III) which naturally expresses at least partially truncated O-glycans. Overall, we identified 499 O-glycoproteins and 1236 O-glycosites in gastric cancer SimpleCells, and a total 47 O-glycoproteins and 73 O-glycosites in the KATO III cell line. We next modified the glycoproteomic strategy to apply it to pools of sera from gastric cancer and healthy individuals to identify circulating O-glycoproteins with the STn glycoform. We identified 37 O-glycoproteins in the pool of cancer sera, and only nine of these were also found in sera from healthy individuals. Two identified candidate O-glycoprotein biomarkers (CD44 and GalNAc-T5) circulating with the STn glycoform were further validated as being expressed in gastric cancer tissue. A proximity ligation assay was used to show that CD44 was expressed with the STn glycoform in gastric cancer tissues. The study provides a discovery strategy for aberrantly glycosylated O-glycoproteins and a set of O-glycoprotein candidates with biomarker potential in gastric cancer. PMID:25813380

  19. Resiliency in adolescents at high-risk for substance abuse: flexible adaptation via subthalamic nucleus and linkage to drinking and drug use in early adulthood

    PubMed Central

    Weiland, Barbara J.; Nigg, Joel T.; Welsh, Robert C.; Yau, Wai-Ying Wendy; Zubieta, Jon-Kar; Zucker, Robert A.; Heitzeg, Mary M.

    2012-01-01

    Introduction The personality trait resiliency is the ability to flexibly adapt impulse control relative to contextual demand. Low resiliency has been linked to later alcohol/drug problems. The underlying psychological and neural mechanisms are unknown but neurocomputational models suggested relations between resiliency and working memory. Cortical-striatal connectivity has been proposed to underlie adaptive switches between cautious and risky behaviors. Methods Working memory was probed in sixty-seven 18–22 year olds from a larger community study of alcoholism, using the n-back task during functional magnetic resonance imaging. Functional connectivity between task-related regions was investigated with psychophysiological interaction analysis. Resiliency was measured in early teen years and related to early adulthood measures of drinking/drug use, task activation and connectivity. Relationships with risk factors, including family history, age of drinking onset and number of alcohol problems were also investigated. Results Higher resiliency was related to lower levels of substance use, fewer alcohol problems and better working memory performance. Whole brain regression revealed resiliency negatively correlated with activation of subthalamic nucleus (STN) and pallidum during the n-back. High and Low resiliency quartile groups (n=17 each) differed in coupling strength between STN and median cingulate cortex, a region of reduced activation during working memory. The High resiliency group had later onset of drinking, fewer alcohol problems, had used fewer illicit drugs and were less likely to smoke cigarettes than their Low resiliency counterparts, Conclusions These findings suggest that resiliency in early adolescence may protect against alcohol problems and drug use, though the direction of this effect is currently unknown. This protective factor may relate to executive functioning as supported by the finding of a neural link shared between resiliency and working

  20. Bilateral subthalamic stimulation impairs cognitive–motor performance in Parkinson's disease patients

    PubMed Central

    Voelcker-Rehage, Claudia; Hallahan, Katie; Vitek, Megan; Bamzai, Rashi; Vitek, Jerrold L.

    2008-01-01

    Deep brain stimulation (DBS) is a surgical procedure that has been shown effective in improving the cardinal motor signs of advanced Parkinson's disease, however, declines in cognitive function have been associated with bilateral subthalamic nucleus (STN) DBS. Despite the fact that most activities of daily living clearly have motor and cognitive components performed simultaneously, postoperative assessments of cognitive and motor function occur, in general, in isolation of one another. The primary aim of this study was to determine the effects of unilateral and bilateral STN DBS on upper extremity motor function and cognitive performance under single- and dual-task conditions in advanced Parkinson's disease patients. Data were collected from eight advanced Parkinson's disease patients between the ages of 48 and 70 years (mean 56.5) who had bilaterally placed STN stimulators. Stimulation parameters for DBS devices were optimized clinically and were stable for at least 6 months prior to study participation. Data were collected while patients were Off anti-parkinsonian medications under three stimulation conditions: Off stimulation, unilateral DBS and bilateral DBS. In each stimulation condition patients performed a cognitive (n-back task) and motor (force tracking) task under single- and dual-task conditions. During dual-task conditions, patients performed the n-back and force-maintenance task simultaneously. Under relatively simple dual-task conditions there were no differences in cognitive or motor performance under unilateral and bilateral stimulation. As dual-task complexity increased, cognitive and motor performance was significantly worse with bilateral compared with unilateral stimulation. In the most complex dual-task condition (i.e. 2-back + force tracking), bilateral stimulation resulted in a level of motor performance that was similar to the Off stimulation condition. Significant declines in cognitive and motor function under modest dual-task conditions

  1. Swallowing and deep brain stimulation in Parkinson's disease: a systematic review.

    PubMed

    Troche, Michelle S; Brandimore, Alexandra E; Foote, Kelly D; Okun, Michael S

    2013-09-01

    The purpose of this review is to assess the current state of the literature on the topic of deep brain stimulation (DBS) and its effects on swallowing function in Parkinson's disease (PD). Pubmed, Cochrane review, and web of science searches were completed on all articles addressing DBS that contained a swallowing outcome measure. Outcome measures included the penetration/aspiration scale, pharyngeal transit time, oropharyngeal residue, drooling, aspiration pneumonia, death, hyolaryngeal excursion, epiglottic inversion, UPDRS scores, and presence of coughing/throat clearing during meals. The search identified 13 studies specifically addressing the effects of DBS on swallowing. Critical assessment of the 13 identified peer-reviewed publications revealed nine studies employing an experimental design, (e.g. "on" vs. "off", pre- vs. post-DBS) and four case reports. None of the nine experimental studies were found to identify clinically significant improvement or decline in swallowing function with DBS. Despite these findings, several common threads were identified across experimental studies and will be examined in this review. Additionally, available data demonstrate that, although subthalamic nucleus (STN) stimulation has been considered to cause more impairment to swallowing function than globus pallidus internus (GPi) stimulation, there are no experimental studies directly comparing swallowing function in STN vs. GPi. Moreover, there has been no comparison of unilateral vs. bilateral DBS surgery and the coincident effects on swallowing function. This review includes a critical analysis of all experimental studies and discusses methodological issues that should be addressed in future studies. PMID:23726461

  2. Intraoperative MRI for optimizing electrode placement for deep brain stimulation of the subthalamic nucleus in Parkinson disease.

    PubMed

    Cui, Zhiqiang; Pan, Longsheng; Song, Huifang; Xu, Xin; Xu, Bainan; Yu, Xinguang; Ling, Zhipei

    2016-01-01

    OBJECT The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement. This study reports on the evaluation of intraoperative MRI (iMRI) for adjusting deviated electrodes to the accurate anatomical position during DBS surgery and acute intracranial changes. METHODS Two hundred and six DBS electrodes were implanted in the subthalamic nucleus (STN) in 110 patients with Parkinson disease. All patients underwent iMRI after implantation to define the accuracy of lead placement. Fifty-six DBS electrode positions in 35 patients deviated from the center of the STN, according to the result of the initial postplacement iMRI scans. Thus, we adjusted the electrode positions for placement in the center of the STN and verified this by means of second or third iMRI scans. Recording was performed in adjusted parameters in the x-, y-, and z-axes. RESULTS Fifty-six (27%) of 206 DBS electrodes were adjusted as guided by iMRI. Electrode position was adjusted on the basis of iMRI 62 times. The sum of target coordinate adjustment was -0.5 mm in the x-axis, -4 mm in the y-axis, and 15.5 mm in the z-axis; the total of distance adjustment was 74.5 mm in the x-axis, 88 mm in the y-axis, and 42.5 mm in the z-axis. After adjustment with the help of iMRI, all electrodes were located in the center of the STN. Intraoperative MRI revealed 2 intraparenchymal hemorrhages in 2 patients, brain shift in all patients, and leads penetrating the lateral ventricle in 3 patients. CONCLUSIONS The iMRI technique can guide surgeons as they adjust deviated electrodes to improve the accuracy of implanting the electrodes into the correct anatomical position. The iMRI technique can also immediately demonstrate acute changes such as hemorrhage and brain shift during DBS surgery. PMID:26274983

  3. Neurophysiological modulation of the subthalamic nucleus by pallidal stimulation in Parkinson's disease

    PubMed Central

    Sterio, D; Rezai, A; Mogilner, A; Zonenshayn, M; Gracies, J; Kathirithamby, K; Beric, A

    2002-01-01

    Objectives: Current models of basal ganglia dysfunction in Parkinson's disease suggest a pivotal role of subthalamic nucleus (STN) hyperactivity. There is a direct excitatory output to the globus pallidus internus (GPi), which in turn hyperinhibits the motor thalamus and leads to a lack of cortical facilitation. The model, however, does not address the reciprocal influence of GPi on STN activity. Methods: Measurement of immediate changes in STN single cell activity after GPi deep brain stimulation (DBS). Results: An opposite effect of GPi DBS in the dorsal versus ventral STN was found. There was an almost exclusive reduction of firing rate in the dorsal region of the STN, whereas the cells in the ventral region exhibited facilitation similar to the recordings from the substantia nigra pars reticulata. Conclusion: Although these findings require confirmation, they suggest that the current theories of GPi DBS action, which do not include a GPi-STN modulation, are most likely incomplete. PMID:11861688

  4. Subthalamic nucleus deep brain stimulation induces impulsive action when patients with Parkinson's disease act under speed pressure.

    PubMed

    Pote, Inês; Torkamani, Mariam; Kefalopoulou, Zinovia-Maria; Zrinzo, Ludvic; Limousin-Dowsey, Patricia; Foltynie, Thomas; Speekenbrink, Maarten; Jahanshahi, Marjan

    2016-07-01

    The subthalamic nucleus (STN) is proposed to modulate response thresholds and speed-accuracy trade-offs. In situations of conflict, the STN is considered to raise response thresholds, allowing time for the accumulation of information to occur before a response is selected. Conversely, speed pressure is thought to reduce the activity of the STN and lower response thresholds, resulting in fast, errorful responses. In Parkinson's disease (PD), subthalamic nucleus deep brain stimulation (STN-DBS) reduces the activity of the nucleus and improves motor symptoms. We predicted that the combined effects of STN stimulation and speed pressure would lower STN activity and lead to fast, errorful responses, hence resulting in impulsive action. We used the motion discrimination 'moving-dots' task to assess speed-accuracy trade-offs, under both speed and accuracy instructions. We assessed 12 patients with PD and bilateral STN-DBS and 12 age-matched healthy controls. Participants completed the task twice, and the patients completed it once with STN-DBS on and once with STN-DBS off, with order counterbalanced. We found that STN stimulation was associated with significantly faster reaction times but more errors under speed instructions. Application of the drift diffusion model showed that stimulation resulted in lower response thresholds when acting under speed pressure. These findings support the involvement of the STN in the modulation of speed-accuracy trade-offs and establish for the first time that speed pressure alone, even in the absence of conflict, can result in STN stimulation inducing impulsive action in PD. PMID:26892884

  5. Expression profile of mucin-associated sialyl-Tn antigen in Chinese patients with different colorectal lesions (adenomas, carcinomas)

    PubMed Central

    Xu, Feng; Fan, Cuizhen; Fan, Shanshan; Liu, Fuquan; Wen, Tao; An, Guangyu; Feng, Guosheng

    2015-01-01

    Background: The sialyl-Tn (sTn) antigen is a mucin-associated carbohydrate antigen expressed by numerous human carcinomas, and is also claimed to be a prognostic factor in colorectal cancer. But the associations between sTn and colorectal cancer remain elusive and controversial. Here, we investigated the expression profile of sTn antigen in a series of human colorectal tissue samples including normal colon, colorectal adenomas, and colorectal carcinomas (CRCs), with an aim to analyzing whether sTn plays a role in the progression and development of Chinese patients with CRCs. Methods: Immunohistochemical staining of sTn antigen was performed in formalin-fixed, paraffin-embedded colonic sections from 4 healthy controls, 44 patients with colorectal adenomas, and 186 patients with primary CRCs. Results: No sTn antigen was detected in normal colonic tissues. There were 41 of 44 patients with colorectal adenomas (93.2%), and 141 of 186 patients with CRCs (75.8%) found to express sTn antigen. The patterns of sTn localization were different in adenomas and carcinomas of colonic tissues. Colorectal adenomas showed predominant supranuclear distribution of sTn antigen, while carcinomas revealed apical membrane, mucin droplet and diffuse cytoplasmic localization. Notably, sTn was significantly associated with the degree of differentiation (P = 0.006) and perineural invasion (P = 0.041) of the tumors, but was independent of age, gender, tumor location, depth of penetration, status of lymph nodes, lymphovascular invasion and TNM stage. Conclusions: These results indicate that sTn may play a role in initiating colorectal carcinogenesis and promoting tumor progression. Determination of sTn expression and localization may assist in evaluating malignant status of colorectal lesions. PMID:26617889

  6. Fostering Effective Studying and Study Planning with Study Questions

    ERIC Educational Resources Information Center

    Wilhelm, Pascal; Pieters, Jules M.

    2007-01-01

    In a course on biological psychology and neuropsychology, study questions were provided that also appeared as test questions in the course exam. This method was introduced to support students in active processing and reproduction of the study texts, and study planning. Data were gathered to test the hypothesis that study question use would be…

  7. Observations of minor planets.

    NASA Astrophysics Data System (ADS)

    Observations made at the following stations are published: Bucharest, Catania, Caussols, Cent. Astron. Yebes, Cerro Tololo Interam. Obs., Chirorin, Crimean Astrophys. Obs. (52nd Report), Eur. South. Obs., Falkensee, Geisei, Goethe Link Obs., Göttingen, Haute Provence, Hemingford Abbots, JCPM Oi Stn., Kambah (near Canberra), Kitt Peak, Klet', Le Creusot, Lick Obs., Lincoln Lab., Lowell Obs., Lowell Obs. Anderson Mesa Stn., Madonnna di Dossobuono, Mt. John Obs., Mt. Palomar, Oak Ridge Obs., Purple Mountain Obs., Quonochontaug Stn. (Rhode Island), Reintal, S. Vittore (Bologna), Seewalchen, Siding Spring, Skalnaté Pleso, Spec. Astrophys. Obs., Steward Obs., Sydney, Tautenburg, Telford, Tokyo Obs. Kiso Stn., Turku, Zimmerwald.

  8. Magnetic resonance imaging of the subthalamic nucleus for deep brain stimulation.

    PubMed

    Chandran, Arjun S; Bynevelt, Michael; Lind, Christopher R P

    2016-01-01

    The subthalamic nucleus (STN) is one of the most important stereotactic targets in neurosurgery, and its accurate imaging is crucial. With improving MRI sequences there is impetus for direct targeting of the STN. High-quality, distortion-free images are paramount. Image reconstruction techniques appear to show the greatest promise in balancing the issue of geometrical distortion and STN edge detection. Existing spin echo- and susceptibility-based MRI sequences are compared with new image reconstruction methods. Quantitative susceptibility mapping is the most promising technique for stereotactic imaging of the STN. PMID:26295914

  9. Case Study: Testing with Case Studies

    ERIC Educational Resources Information Center

    Herreid, Clyde Freeman

    2015-01-01

    This column provides original articles on innovations in case study teaching, assessment of the method, as well as case studies with teaching notes. This month's issue discusses using case studies to test for knowledge or lessons learned.

  10. Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis.

    PubMed

    Xu, Jingyue; Liu, Han; Chai, Ok Hee; Lan, Yu; Jiang, Rulang

    2016-01-01

    Renal hypoplasia is a common cause of pediatric renal failure and several adult-onset diseases. Recent studies have associated a variant of the OSR1 gene with reduction of newborn kidney size and function in heterozygotes and neonatal lethality with kidney defects in homozygotes. How OSR1 regulates kidney development and nephron endowment is not well understood, however. In this study, by using the recently developed CRISPR genome editing technology, we genetically labeled the endogenous Osr1 protein and show that Osr1 interacts with Wt1 in the developing kidney. Whereas mice heterozygous for either an Osr1 or Wt1 null allele have normal kidneys at birth, most mice heterozygous for both Osr1 and Wt1 exhibit defects in metanephric kidney development, including unilateral or bilateral kidney agenesis or hypoplasia. The developmental defects in the Osr1+/-Wt1+/- mouse embryos were detected as early as E10.5, during specification of the metanephric mesenchyme, with the Osr1+/-Wt1+/- mouse embryos exhibiting significantly reduced Pax2-positive and Six2-positive nephron progenitor cells. Moreover, expression of Gdnf, the major nephrogenic signal for inducing ureteric bud outgrowth, was significantly reduced in the metanephric mesenchyme in Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- littermates. By E11.5, as the ureteric buds invade the metanephric mesenchyme and initiate branching morphogenesis, kidney morphogenesis was significantly impaired in the Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- embryos. These results indicate that Osr1 and Wt1 act synergistically to regulate nephron endowment by controlling metanephric mesenchyme specification during early nephrogenesis. PMID:27442016

  11. Impact of renal medullary three-dimensional architecture on oxygen transport.

    PubMed

    Fry, Brendan C; Edwards, Aurélie; Sgouralis, Ioannis; Layton, Anita T

    2014-08-01

    We have developed a highly detailed mathematical model of solute transport in the renal medulla of the rat kidney to study the impact of the structured organization of nephrons and vessels revealed in anatomic studies. The model represents the arrangement of tubules around a vascular bundle in the outer medulla and around a collecting duct cluster in the upper inner medulla. Model simulations yield marked gradients in intrabundle and interbundle interstitial fluid oxygen tension (PO2), NaCl concentration, and osmolality in the outer medulla, owing to the vigorous active reabsorption of NaCl by the thick ascending limbs. In the inner medulla, where the thin ascending limbs do not mediate significant active NaCl transport, interstitial fluid composition becomes much more homogeneous with respect to NaCl, urea, and osmolality. Nonetheless, a substantial PO2 gradient remains, owing to the relatively high oxygen demand of the inner medullary collecting ducts. Perhaps more importantly, the model predicts that in the absence of the three-dimensional medullary architecture, oxygen delivery to the inner medulla would drastically decrease, with the terminal inner medulla nearly completely deprived of oxygen. Thus model results suggest that the functional role of the three-dimensional medullary architecture may be to preserve oxygen delivery to the papilla. Additionally, a simulation that represents low medullary blood flow suggests that the separation of thick limbs from the vascular bundles substantially increases the risk of the segments to hypoxic injury. When nephrons and vessels are more homogeneously distributed, luminal PO2 in the thick ascending limb of superficial nephrons increases by 66% in the inner stripe. Furthermore, simulations predict that owing to the Bohr effect, the presumed greater acidity of blood in the interbundle regions, where thick ascending limbs are located, relative to that in the vascular bundles, facilitates the delivery of O2 to support the

  12. Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis

    PubMed Central

    Xu, Jingyue; Liu, Han; Chai, Ok Hee; Jiang, Rulang

    2016-01-01

    Renal hypoplasia is a common cause of pediatric renal failure and several adult-onset diseases. Recent studies have associated a variant of the OSR1 gene with reduction of newborn kidney size and function in heterozygotes and neonatal lethality with kidney defects in homozygotes. How OSR1 regulates kidney development and nephron endowment is not well understood, however. In this study, by using the recently developed CRISPR genome editing technology, we genetically labeled the endogenous Osr1 protein and show that Osr1 interacts with Wt1 in the developing kidney. Whereas mice heterozygous for either an Osr1 or Wt1 null allele have normal kidneys at birth, most mice heterozygous for both Osr1 and Wt1 exhibit defects in metanephric kidney development, including unilateral or bilateral kidney agenesis or hypoplasia. The developmental defects in the Osr1+/-Wt1+/- mouse embryos were detected as early as E10.5, during specification of the metanephric mesenchyme, with the Osr1+/-Wt1+/- mouse embryos exhibiting significantly reduced Pax2-positive and Six2-positive nephron progenitor cells. Moreover, expression of Gdnf, the major nephrogenic signal for inducing ureteric bud outgrowth, was significantly reduced in the metanephric mesenchyme in Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- littermates. By E11.5, as the ureteric buds invade the metanephric mesenchyme and initiate branching morphogenesis, kidney morphogenesis was significantly impaired in the Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- embryos. These results indicate that Osr1 and Wt1 act synergistically to regulate nephron endowment by controlling metanephric mesenchyme specification during early nephrogenesis. PMID:27442016

  13. ACTS Satellite Telemammography Network Experiments

    NASA Technical Reports Server (NTRS)

    Kachmar, Brian A.; Kerczewski, Robert J.

    2000-01-01

    The Satellite Networks and Architectures Branch of NASA's Glenn Research Center has developed and demonstrated several advanced satellite communications technologies through the Advanced Communications Technology Satellite (ACTS) program. One of these technologies is the implementation of a Satellite Telemammography Network (STN) encompassing NASA Glenn, the Cleveland Clinic Foundation. the University of Virginia, and the Ashtabula County Medical Center. This paper will present a look at the STN from its beginnings to the impact it may have on future telemedicine applications. Results obtained using the experimental ACTS satellite demonstrate the feasibility of Satellite Telemammography. These results have improved teleradiology processes and mammography image manipulation, and enabled advances in remote screening methodologies. Future implementation of satellite telemammography using next generation commercial satellite networks will be explored. In addition, the technical aspects of the project will be discussed, in particular how the project has evolved from using NASA developed hardware and software to commercial off the shelf (COTS) products. Development of asymmetrical link technologies was an outcome of this work. Improvements in the display of digital mammographic images, better understanding of end-to-end system requirements, and advances in radiological image compression were achieved as a result of the research. Finally, rigorous clinical medical studies are required for new technologies such as digital satellite telemammography to gain acceptance in the medical establishment. These experiments produced data that were useful in two key medical studies that addressed the diagnostic accuracy of compressed satellite transmitted digital mammography images. The results of these studies will also be discussed.

  14. Cortical Potentials Evoked by Deep Brain Stimulation in the Subthalamic Area

    PubMed Central

    Devergnas, Annaelle; Wichmann, Thomas

    2011-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been used since the mid-1990s as a treatment for patients with Parkinson's disease, and more recently also in other conditions, such as dystonia or obsessive compulsive disorder. Non-invasive studies of cortical evoked potentials (EPs) that follow individual STN–DBS stimuli has provided us with insights about the conduction of the DBS pulses to the cortex. Such EPs have multiple components of different latencies, making it possible to distinguish short-latency and long-latency responses (3–8 ms and 18–25 ms latency, respectively). The available evidence indicates that these short- and long-latency EPs correspond to conduction from the STN stimulation site to the cortical recording location via anti- and orthodromic pathways, respectively. In this review we survey the literature from recording studies in human patients treated with STN–DBS for Parkinson's disease and other conditions, as well as recent animal studies (including our own) that have begun to elucidate details of the pathways, frequency dependencies, and other features of EPs. In addition, we comment on the possible clinical utility of this knowledge. PMID:21625611

  15. Guanidino compounds generate reactive oxygen species.

    PubMed

    Mori, A; Kohno, M; Masumizu, T; Noda, Y; Packer, L

    1996-09-01

    Methylguanidine, guanidinoacetic acid and guanidinosuccinic acid are endogenous substances in body tissues. Extremely high levels of these substances are known to be related to the pathogenesis of epilepsy and renal failure such as uremia. In this study it was demonstrated that methylguanidine, guanidinoacetic acid and guanidinosuccinic acid, and arginine generate hydroxyl radicals in aqueous solution. These findings suggest that a high level of guanidino compounds accumulating near or within cells such as neurons (in an epileptogenic focus) or nephrons (in uremic patients) may cause free radical damage leading to these clinical disorders. Arginine may have a similar role in the pathogenesis of hyperarginemia. PMID:8886279

  16. Instantaneous and continuous measurement of /sup 14/C-labeled substrate oxidation to /sup 14/CO2 by minute tissue specimens: an ionization chamber method

    SciTech Connect

    Davidson, W.D.; Klein, K.L.; Kurokawa, K.; Soll, A.H.

    1981-06-01

    The vibrating reed electrometer and ionization chamber have been adapted for the instantaneous and continuous measurement of /sup 14/C-labeled substrate oxidation to /sup 14/CO2 by minute quantities of isolated tissues. This modified technique, utilizing a ''closed'' circulation incubation system, is 10-50 times as sensitive as the previously described ''open'' circulation techniques. Substrate oxidation curves are described for human erythrocytes and polymorphonuclear leucocytes, canine parietal cells and isolated segments of the rat nephron. This apparatus should prove to be a useful tool for metabolic studies of small quantities of isolated tissue.

  17. The polyuria of paroxysmal atrial tachycardia

    NASA Technical Reports Server (NTRS)

    Kinney, M. J.; Stein, R. M.; Discala, V. A.

    1974-01-01

    Two patients with paroxysmal atrial fibrillation and an associated polyuria were studied to delineate the mechanism of the increase in urine flow. A striking saluresis was noted in both patients. The increased sodium excretion was probably due to decreased sodium reabsorption, perhaps at proximal tubular nephron sites. This inhibition of sodium reabsorption could explain both the saluresis and some part or all of the polyuria. Re-evaluation of earlier case reports reveals patterns of concomitant salt and water excretion consistent with this mechanism. The saluresis cannot be explained by the previously favored hypothesis of antidiuretic hormone inhibition.

  18. AGRICULTURAL HEALTH STUDY/PESTICIDE EXPOSURE STUDY

    EPA Science Inventory

    The Agricultural Health Study (AHS) is a prospective epidemiologic study of a large cohort of pesticide applicators and their spouses in Iowa and North Carolina. The Pesticide Exposure Study is a sub-study to evaluate exposure factors and to provide data to assess exposure cla...

  19. A combined approach of VNTR and MLST analysis: improving molecular typing of Argentinean isolates of Leptospira interrogans.

    PubMed

    Caimi, Karina; Varni, Vanina; Melendez, Yamil; Koval, Ariel; Brihuega, Bibiana; Ruybal, Paula

    2012-08-01

    Leptospirosis is an emerging infectious disease that has been identified as both a human and animal health problem worldwide. Regular outbreaks associated with specific risk factors have been reported in Argentina. However, there are no available data concerning the genetic population level for this pathogen. Therefore, the aim of this work was to describe the genetic diversity of Leptospira interrogans through the application of two molecular typing strategies: variable number of tandem repeats (VNTR) and multilocus sequence typing (MLST). For this purpose, seven reference strains and 18 non-epidemiologically related isolates from diverse hosts and Argentinean regions were analysed. Among them, nine genotypes and seven sequence types (STs), including three unreported STs, were described using VNTR and MLST, respectively. eBURST analysis demonstrated that ST37 was the most frequent and founder genotype of a clonal complex (CCs) containing STN1 and STN3, suggesting the importance of studying the serovars belonging to this CC in Argentina. The data from maximum parsimony analysis, which combined both techniques, achieved intra-serovar discrimination, surmounted microscopic agglutination test discrepancies and increased the discriminatory power of each technique applied separately. This study is the first to combine both strategies for L. interrogans typing to generate a more comprehensive molecular genotyping of isolates from Argentina in a global context. PMID:22850955

  20. Neuronal Complexity in Subthalamic Nucleus is Reduced in Parkinson's Disease.

    PubMed

    Vyas, Saurabh; Huang, He; Gale, John T; Sarma, Sridevi V; Montgomery, Erwin B

    2016-01-01

    Several theories posit increased Subthalamic Nucleus (STN) activity is causal to Parkinsonism, yet in our previous study we showed that activity from 113 STN neurons from two epilepsy patients and 103 neurons from nine Parkinson's disease (PD) patients demonstrated no significant differences in frequencies or in the coefficients of variation of mean discharge frequencies per 1-s epochs. We continued our analysis using point process modeling to capture higher order temporal dynamics; in particular, bursting, beta-band oscillations, excitatory and inhibitory ensemble interactions, and neuronal complexity. We used this analysis as input to a logistic regression classifier and were able to differentiate between PD and epilepsy neurons with an accuracy of 92%. We also found neuronal complexity, i.e., the number of states in a neuron's point process model, and inhibitory ensemble dynamics, which can be interpreted as a reduction in complexity, to be the most important features with respect to classification accuracy. Even in a dataset with no significant differences in firing rate, we observed differences between PD and epilepsy for other single-neuron measures. Our results suggest PD comes with a reduction in neuronal "complexity," which translates to a neuron's ability to encode information; the more complexity, the more information the neuron can encode. This is also consistent with studies correlating disease to loss of variability in neuronal activity, as the lower the complexity, the less variability. PMID:26168436

  1. Neural integrity is maintained by dystrophin in C. elegans

    PubMed Central

    Zhou, Shan

    2011-01-01

    The dystrophin protein complex (DPC), composed of dystrophin and associated proteins, is essential for maintaining muscle membrane integrity. The link between mutations in dystrophin and the devastating muscle failure of Duchenne’s muscular dystrophy (DMD) has been well established. Less well appreciated are the accompanying cognitive impairment and neuropsychiatric disorders also presented in many DMD patients, which suggest a wider role for dystrophin in membrane–cytoskeleton function. This study provides genetic evidence of a novel role for DYS-1/dystrophin in maintaining neural organization in Caenorhabditis elegans. This neuronal function is distinct from the established role of DYS-1/dystrophin in maintaining muscle integrity and regulating locomotion. SAX-7, an L1 cell adhesion molecule (CAM) homologue, and STN-2/γ-syntrophin also function to maintain neural integrity in C. elegans. This study provides biochemical data that show that SAX-7 associates with DYS-1 in an STN-2/γ-syntrophin–dependent manner. These results reveal a recruitment of L1CAMs to the DPC to ensure neural integrity is maintained. PMID:21242290

  2. Tractographical model of the cortico-basal ganglia and corticothalamic connections: Improving Our Understanding of Deep Brain Stimulation.

    PubMed

    Avecillas-Chasin, Josué M; Rascón-Ramírez, Fernando; Barcia, Juan A

    2016-05-01

    The cortico-basal ganglia and corticothalamic projections have been extensively studied in the context of neurological and psychiatric disorders. Deep brain stimulation (DBS) is known to modulate many of these pathways to produce the desired clinical effect. The aim of this work is to describe the anatomy of the main circuits of the basal ganglia using tractography in a surgical planning station. We used imaging studies of 20 patients who underwent DBS for movement and psychiatric disorders. We segmented the putamen, caudate nucleus (CN), thalamus, and subthalamic nucleus (STN), and we also segmented the cortical areas connected with these subcortical areas. We used tractography to define the subdivisions of the basal ganglia and thalamus through the generation of fibers from the cortical areas to the subcortical structures. We were able to generate the corticostriatal and corticothalamic connections involved in the motor, associative and limbic circuits. Furthermore, we were able to reconstruct the hyperdirect pathway through the corticosubthalamic connections and we found subregions in the STN. Finally, we reconstructed the cortico-subcortical connections of the ventral intermediate nucleus, the nucleus accumbens and the CN. We identified a feasible delineation of the basal ganglia and thalamus connections using tractography. These results could be potentially useful in DBS if the parcellations are used as targets during surgery. Clin. Anat. 29:481-492, 2016. © 2016 Wiley Periodicals, Inc. PMID:26779936

  3. Aging and the disposition and toxicity of mercury in rats.

    PubMed

    Bridges, Christy C; Joshee, Lucy; Zalups, Rudolfs K

    2014-05-01

    Progressive loss of functioning nephrons, secondary to age-related glomerular disease, can impair the ability of the kidneys to effectively clear metabolic wastes and toxicants from blood. Additionally, as renal mass is diminished, cellular hypertrophy occurs in functional nephrons that remain. We hypothesize that these nephrons are exposed to greater levels of nephrotoxicants, such as inorganic mercury (Hg(2+)), and thus are at an increased risk of becoming intoxicated by these compounds. The purpose of the present study was to characterize the effects of aging on the disposition and renal toxicity of Hg(2+) in young adult and aged Wistar rats. Paired groups of animals were injected (i.v.) with either a 0.5μmol·kg(-1) non-nephrotoxic or a 2.5μmol·kg(-1) nephrotoxic dose of mercuric chloride (HgCl2). Plasma creatinine and renal biomarkers of proximal tubular injury were greater in both groups of aged rats than in the corresponding groups of young adult rats. Histologically, evidence of glomerular sclerosis, tubular atrophy, interstitial inflammation and fibrosis were significant features of kidneys from aged animals. In addition, proximal tubular necrosis, especially along the straight segments in the inner cortex and outer stripe of the outer medulla was a prominent feature in the renal sections from both aged and young rats treated with the nephrotoxic dose of HgCl2. Our findings indicate 1) that overall renal function is significantly impaired in aged rats, resulting in chronic renal insufficiency and 2) the disposition of HgCl2 in aging rats is significantly altered compared to that of young rats. PMID:24548775

  4. Intracortical distribution of number and volume of glomeruli during postnatal maturation in the dog

    PubMed Central

    Horster, Michael; Kemler, Barry J.; Valtin, Heinz

    1971-01-01

    Morphometric analysis was carried out on kidneys of neonatal dogs in which function of the entire kidney and of single nephrons had been evaluated. Measurements were begun after neogenesis of nephrons had been completed, i.e., at the end of the 3rd postnatal wk. They were continued to 74 days by which time glomerular function, expressed per unit of renal weight, had reached the mature level. For statistical analysis, the cortical histogram at each age was divided into eight zones of equal depth between the capsule and corticomedullary junction. The mean total number of glomeruli in this beagle strain was 589 × 103 per kidney. The fraction of the total number of glomeruli was lowest in the subcapsular layer (3.9%) and highest (24.5%) in the zone immediately beneath from where it decreased almost linearly to a value of 4.5% in the juxtamedullary region. This numerical distribution did not change with age, which suggests that growth of nonglomerular structures proceeded at the same rate in all cortical layers. Volume of the glomerular tuft rose slightly between the subcapsular and next layer and remained constant down to the juxtamedullary region where it increased sharply. The juxtamedullary glomerulus was about 45% larger in volume than the other glomeruli. This intracortical distribution of glomerular volume did not vary between 23 and 74 days, although the volume of an individual glomerulus at each level increased slightly with age. Total glomerular volume increased by 33% during the postnatal period studied, whereas simultaneously nonglomerular cortical volume rose by 235%. On the assumption that nonglomerular tissue consists mainly of tubules, the data suggest that the rate of tubular growth far exceeded that of glomerular growth. Despite this difference in glomerular and tubular growth rates, analysis of single nephrons in these dogs demonstrates constant and mature proximal fractional reabsorption of sodium and water. Images PMID:5547276

  5. Mode of action of parathyroid hormone and cyclic adenosine 3′,5′-monophosphate on renal tubular phosphate reabsorption in the dog

    PubMed Central

    Agus, Zalman S.; Puschett, Jules B.; Senesky, Dorothy; Goldberg, Martin

    1971-01-01

    To evaluate the effects of parathyroid hormone and cyclic adenosine monophosphate on proximal tubular sodium and phosphate reabsorption, micropuncture studies were performed on dogs that received a highly purified preparation of parathyroid hormone (PTH), dibutyryl cyclic 3′,5′-adenosine monophosphate (cyclic AMP), 5′-AMP, and saline. PTH resulted in a 30-40% inhibition of sodium and phosphate reabsorption in the proximal tubule unassociated with a rise in either total kidney or single nephron glomerular filtration rate (GFR). The bulk of the phosphate rejected proximally was excreted in the final urine while sodium excretion rose minimally despite the marked proximal inhibition, consistent with the presence of reabsorptive sites in the distal nephron for sodium but not phosphate. The infusion of dibutyryl cyclic AMP either systemically or directly into the renal artery inhibited proximal sodium and phosphate reabsorption in the absence of changes in either total kidney or single nephron GFR, resembling the effects of PTH quantitatively and qualitatively. In contrast, another adenine nucleotide, 5′-AMP, did not inhibit the reabsorption of either sodium or phosphate. These observations support the thesis that renal effects of PTH are mediated via stimulation of renal cortical adenyl cyclase. The infusion of a moderate saline load, 25 ml/kg, also produced a similar inhibition of proximal tubular fractional sodium and phosphate reabsorption with a marked phosphaturia but only minimal natriuresis. Thus, changes in sodium and phosphate reabsorption occur in parallel in the proximal tubule when sodium reabsorption is inhibited either with volume expansion or with administration of “specific” phosphaturic agents such as PTH or cyclic AMP. These data are consistent with the thesis that phosphate reabsorption is dependent upon proximal tubular sodium reabsorption wherein the phosphaturic effect of PTH might be the result of a primary inhibition of proximal

  6. The Nature of Experimental Second-set Kidney Transport Rejection

    PubMed Central

    Dempster, W. J.

    1971-01-01

    The detailed characteristics of a nephrogram are more meaningful if studied in relation to the corresponding arteriogram. The appearance of a nephrogram in several forms of acute renal failure, including the second-set kidney transplant reaction, can be explained by a diversity of function among the nephrons. Those nephrons derived from outer cortical glomeruli are considered to be mainly geared to excretion and reabsorption whereas those nephrons derived from inner cortical glomeruli, are mainly geared to reabsorption and concentration. A nephrogram appearing in a severely oliguric or anuric kidney can be explained on the basis that outer cortical filtration has been seriously reduced or has ceased while inner cortical filtration continues but the filtrate is concentrated and reabsorbed. A kidney involved in this haemodynamic upset would more precisely be diagnosed as being in a state of acute excretory renal failure. The severe interference with excretory function is compatible with a total renal blood flow reduced by only 20-40 per cent. After several hours involvement in the severe haemodynamic upset evoked by a second-set kidney transplant reaction, inner cortical perfusion fails and at this stage no nephrogram is observed. A similar lack of a nephrogram associated with inadequate cortical perfusion was observed at 24 hr after subjecting a kidney to 2 hr total warm ischaemia which causes cortical necrosis. These principles permit a review of intravenous pyelographic techniques to be made with the recommendation of using small physiological doses of anti-diuretic substances, about half the currently recommended dose of contrast and free but not excessive access to water because the above injected doses of anti-diuretic hormone act maximally during an established water diuresis. ImagesFig. 3Fig. 2Fig. 5Fig. 6Fig. 1Fig. 8Fig. 4 PMID:4944362

  7. Glomerular hemodynamic alterations during acute hyperinsulinemia in normal and diabetic rats

    NASA Technical Reports Server (NTRS)

    Tucker, B. J.; Anderson, C. M.; Thies, R. S.; Collins, R. C.; Blantz, R. C.

    1992-01-01

    Treatment of insulin dependent diabetes invariably requires exogenous insulin to control blood glucose. Insulin treatment, independent of other factors associated with insulin dependent diabetes, may induce changes that affect glomerular function. Due to exogenous delivery of insulin in insulin dependent diabetes entering systemic circulation prior to the portal vein, plasma levels of insulin are often in excess of that observed in non-diabetics. The specific effects of hyperinsulinemia on glomerular hemodynamics have not been previously examined. Micropuncture studies were performed in control (non-diabetic), untreated diabetic and insulin-treated diabetic rats 7 to 10 days after administration of 65 mg/kg body weight streptozotocin. After the first period micropuncture measurements were obtained, 5 U of regular insulin (Humulin-R) was infused i.v., and glucose clamped at euglycemic values (80 to 120 mg/dl). Blood glucose concentration in non-diabetic controls was 99 +/- 6 mg/dl. In control rats, insulin infusion and glucose clamp increased nephron filtration rate due to decreases in both afferent and efferent arteriolar resistance (afferent greater than efferent) resulting in increased plasma flow and increased glomerular hydrostatic pressure gradient. However, insulin infusion and glucose clamp produced the opposite effect in both untreated and insulin-treated diabetic rats with afferent arteriolar vasoconstriction resulting in decreases in plasma flow, glomerular hydrostatic pressure gradient and nephron filtration rate. Thromboxane A2 (TX) synthetase inhibition partially decreased the vasoconstrictive response due to acute insulin infusion in diabetic rats preventing the decrease in nephron filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS).

  8. Sulfate transporters involved in sulfate secretion in the kidney are localized in the renal proximal tubule II of the elephant fish (Callorhinchus milii).

    PubMed

    Hasegawa, Kumi; Kato, Akira; Watanabe, Taro; Takagi, Wataru; Romero, Michael F; Bell, Justin D; Toop, Tes; Donald, John A; Hyodo, Susumu

    2016-07-01

    Most vertebrates, including cartilaginous fishes, maintain their plasma SO4 (2-) concentration ([SO4 (2-)]) within a narrow range of 0.2-1 mM. As seawater has a [SO4 (2-)] about 40 times higher than that of the plasma, SO4 (2-) excretion is the major role of kidneys in marine teleost fishes. It has been suggested that cartilaginous fishes also excrete excess SO4 (2-) via the kidney. However, little is known about the underlying mechanisms for SO4 (2-) transport in cartilaginous fish, largely due to the extraordinarily elaborate four-loop configuration of the nephron, which consists of at least 10 morphologically distinguishable segments. In the present study, we determined cDNA sequences from the kidney of holocephalan elephant fish (Callorhinchus milii) that encoded solute carrier family 26 member 1 (Slc26a1) and member 6 (Slc26a6), which are SO4 (2-) transporters that are expressed in mammalian and teleost kidneys. Elephant fish Slc26a1 (cmSlc26a1) and cmSlc26a6 mRNAs were coexpressed in the proximal II (PII) segment of the nephron, which comprises the second loop in the sinus zone. Functional analyses using Xenopus oocytes and the results of immunohistochemistry revealed that cmSlc26a1 is a basolaterally located electroneutral SO4 (2-) transporter, while cmSlc26a6 is an apically located, electrogenic Cl(-)/SO4 (2-) exchanger. In addition, we found that both cmSlc26a1 and cmSlc26a6 were abundantly expressed in the kidney of embryos; SO4 (2-) was concentrated in a bladder-like structure of elephant fish embryos. Our results demonstrated that the PII segment of the nephron contributes to the secretion of excess SO4 (2-) by the kidney of elephant fish. Possible mechanisms for SO4 (2-) secretion in the PII segment are discussed. PMID:27122370

  9. Case Study: Writing a Journal Case Study

    ERIC Educational Resources Information Center

    Prud'homme-Genereux, Annie

    2016-01-01

    This column provides original articles on innovations in case study teaching, assessment of the method, as well as case studies with teaching notes. This month's issue describes incorporating a journal article into the classroom by first converting it into a case study.

  10. Glutamate and GABA concentration changes in the globus pallidus internus of Parkinson's patients during performance of implicit and declarative memory tasks: a report of two subjects.

    PubMed

    Buchanan, Robert J; Gjini, Klevest; Darrow, David; Varga, Georgeta; Robinson, Jennifer L; Nadasdy, Zoltan

    2015-03-01

    The basal ganglia, typically associated with motor function, are involved in human cognitive processes, as demonstrated in behavioral, lesion, and noninvasive functional neuroimaging studies. Here we report task-contingent changes in concentrations of the neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) in the globus pallidus internus (GPi) of two patients with Parkinson's disease undergoing deep brain stimulation surgery by utilizing in-vivo microdialysis measurements during performance of implicit and declarative memory tasks. Performance of an implicit memory task (weather prediction task-WPT) was associated with increased levels of glutamate and GABA in the GPi compared to their concentrations at baseline. On the other hand, performance of a declarative memory task (verbal learning task-VLT) was associated with decreased levels of glutamate and GABA in GPi compared to baseline during the encoding and immediate recall phase with less conclusive results during the delayed recall phase. These results are in line with hypothesized changes in these neurotransmitter levels: an increase of excitatory (Glu) input from subthalamic nucleus (STN) to GPi during implicit memory task performance and a decrease of inhibitory inputs (GABA) from globus pallidus externus (GPe) and striatum to GPi during declarative memory performance. Consistent with our previous report on in-vivo neurotransmitter changes during tasks in STN, these data provide corroborative evidence for the direct involvement of basal ganglia in cognitive functions and complements our model of the functional circuitry of basal ganglia in the healthy and Parkinson's disease affected brain. PMID:25596441

  11. An update on the treatment of Parkinson's disease.

    PubMed

    Jankovic, Joseph

    2006-07-01

    Although levodopa remains the most effective symptomatic drug for Parkinson's disease (PD), its use is limited by the emergence of motor fluctuations and dyskinesias, particularly in young-onset patients. Dopamine agonists, catechol-O-methyltransferasee inhibitors and other anti-parkinsonian drugs have been found to diminish or prevent these complications and possibly to exert disease-modifying effects. The finding that the subthalamic nucleus (STN) and the globus pallidum internus (GPi) are abnormally active in PD has led to effective surgical treatments designed to improve patients' quality of life. The relative benefits of targeting STN or GPi with high-frequency stimulation are still being debated. Experimental therapeutics of PD include novel delivery systems, anti-apoptotic strategies and implantation of genetically engineered cells, and stem cells. Despite encouraging results from early pre-clinical and clinical studies, trials of human fetal grafts and intraventricular and intraparenchymal infusion of glial cell-line-derived neurotrophic factor have not shown clinically meaningful benefits. Future therapeutic strategies should focus not only on ameliorating the symptoms of PD, but also on neuroprotective or neurorescue therapies that can favorably modify the natural course of the disease and slow the progression of both motor and nonmotor manifestations of PD. PMID:16878274

  12. Role of the indirect pathway of the basal ganglia in perceptual decision making.

    PubMed

    Wei, Wei; Rubin, Jonathan E; Wang, Xiao-Jing

    2015-03-01

    The basal ganglia (BG) play an important role in motor control, reinforcement learning, and perceptual decision making. Modeling and experimental evidence suggest that, in a speed-accuracy tradeoff, the corticostriatal pathway can adaptively adjust a decision threshold (the amount of information needed to make a choice). In this study, we go beyond the focus of previous works on the direct and hyperdirect pathways to examine the contribution of the indirect pathway of the BG system to decision making in a biophysically based spiking network model. We find that the mechanism of adjusting the decision threshold by plasticity of the corticostriatal connections is effective, provided that the indirect pathway counterbalances the direct pathway in their projections to the output nucleus. Furthermore, in our model, changes within basal ganglia connections similar to those that arise in parkinsonism give rise to strong beta oscillations. Specifically, beta oscillations are produced by an abnormal enhancement of the interactions between the subthalamic nucleus (STN) and the external segment of globus pallidus (GPe) in the indirect pathway, with an oscillation frequency that depends on the excitatory cortical input to the STN and the inhibitory input to the GPe from the striatum. In a parkinsonian state characterized by pronounced beta oscillations, the mean reaction time and range of threshold variation (a measure of behavioral flexibility) are significantly reduced compared with the normal state. Our work thus reveals a specific circuit mechanism for impairments of perceptual decision making associated with Parkinson's disease. PMID:25740532

  13. Verbal Memory Decline following DBS for Parkinson’s Disease: Structural Volumetric MRI Relationships

    PubMed Central

    Geevarghese, Ruben; Lumsden, Daniel E.; Costello, Angela; Hulse, Natasha; Ayis, Salma; Samuel, Michael; Ashkan, Keyoumars

    2016-01-01

    Background Parkinson’s disease is a chronic degenerative movement disorder. The mainstay of treatment is medical. In certain patients Deep Brain Stimulation (DBS) may be offered. However, DBS has been associated with post-operative neuropsychology changes, especially in verbal memory. Objectives Firstly, to determine if pre-surgical thalamic and hippocampal volumes were related to verbal memory changes following DBS. Secondly, to determine if clinical factors such as age, duration of symptoms or motor severity (UPDRS Part III score) were related to verbal memory changes. Methods A consecutive group of 40 patients undergoing bilateral Subthalamic Nucleus (STN)-DBS for PD were selected. Brain MRI data was acquired, pre-processed and structural volumetric data was extracted using FSL. Verbal memory test scores for pre- and post-STN-DBS surgery were recorded. Linear regression was used to investigate the relationship between score change and structural volumetric data. Results A significant relationship was demonstrated between change in List Learning test score and thalamic (left, p = 0.02) and hippocampal (left, p = 0.02 and right p = 0.03) volumes. Duration of symptoms was also associated with List Learning score change (p = 0.02 to 0.03). Conclusion Verbal memory score changes appear to have a relationship to pre-surgical MRI structural volumetric data. The findings of this study provide a basis for further research into the use of pre-surgical MRI to counsel PD patients regarding post-surgical verbal memory changes. PMID:27557088

  14. Role of the Indirect Pathway of the Basal Ganglia in Perceptual Decision Making

    PubMed Central

    Wei, Wei; Rubin, Jonathan E.

    2015-01-01

    The basal ganglia (BG) play an important role in motor control, reinforcement learning, and perceptual decision making. Modeling and experimental evidence suggest that, in a speed–accuracy tradeoff, the corticostriatal pathway can adaptively adjust a decision threshold (the amount of information needed to make a choice). In this study, we go beyond the focus of previous works on the direct and hyperdirect pathways to examine the contribution of the indirect pathway of the BG system to decision making in a biophysically based spiking network model. We find that the mechanism of adjusting the decision threshold by plasticity of the corticostriatal connections is effective, provided that the indirect pathway counterbalances the direct pathway in their projections to the output nucleus. Furthermore, in our model, changes within basal ganglia connections similar to those that arise in parkinsonism give rise to strong beta oscillations. Specifically, beta oscillations are produced by an abnormal enhancement of the interactions between the subthalamic nucleus (STN) and the external segment of globus pallidus (GPe) in the indirect pathway, with an oscillation frequency that depends on the excitatory cortical input to the STN and the inhibitory input to the GPe from the striatum. In a parkinsonian state characterized by pronounced beta oscillations, the mean reaction time and range of threshold variation (a measure of behavioral flexibility) are significantly reduced compared with the normal state. Our work thus reveals a specific circuit mechanism for impairments of perceptual decision making associated with Parkinson's disease. PMID:25740532

  15. Impulsivities and Parkinson's disease: delay aversion is not worsened by Deep Brain Stimulation of the subthalamic nucleus.

    PubMed

    Torta, Diana M E; Vizzari, Vincenzo; Castelli, Lorys; Zibetti, Maurizio; Lanotte, Michele; Lopiano, Leonardo; Geminiani, Giuliano

    2012-01-01

    Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN) improves motor symptoms in Parkinson's disease (PD), but can exert detrimental effects on impulsivity. These effects are especially related to the inability to slow down when high-conflict choices have to be made. However, the influence that DBS has on delay aversion is still under-investigated. Here, we tested a group of 21 PD patients on and off stimulation (off medication) by using the Cambridge Gamble Task (CGT), a computerized task that allows the investigation of risk-related behaviours and delay aversion, and psychological questionnaires such as the Barratt Impulsiveness Scale (BIS), the Sensitivity to Punishment and to Reward Questionnaire (SPSRQ), and the Quick Delay Questionnaire (QDQ). We found that delay aversion scores on the CGT were no higher when patients were on stimulation as compared to when they were off stimulation. In contrast, PD patients reported feeling more impulsive in the off stimulation state, as revealed by significantly higher scores on the BIS. Higher scores on the sensitivity to punishment subscale of the SPSRQ highlighted that possible punishments influence patients' behaviours more than possible rewards. Significant correlations between delay aversion scores on the CGT and QDQ delay aversion subscale suggest that these two instruments can be used in synergy to reach a convergent validity. In conclusion, our results show that not all impulsivities are detrimentally affected by DBS of the STN and that the joint use of experimental paradigms and psychological questionnaires can provide useful insights in the study of impulsivity. PMID:22984415

  16. The effect of cholesterol on the long-range network of interactions established among sea anemone Sticholysin II residues at the water-membrane interface.

    PubMed

    García-Linares, Sara; Alm, Ida; Maula, Terhi; Gavilanes, José G; Slotte, Johan Peter; Martínez-Del-Pozo, Álvaro

    2015-04-01

    Actinoporins are α-pore forming proteins with therapeutic potential, produced by sea anemones. Sticholysin II (StnII) from Stichodactyla helianthus is one of its most extensively characterized members. These proteins remain stably folded in water, but upon interaction with lipid bilayers, they oligomerize to form a pore. This event is triggered by the presence of sphingomyelin (SM), but cholesterol (Chol) facilitates pore formation. Membrane attachment and pore formation require changes involving long-distance rearrangements of residues located at the protein-membrane interface. The influence of Chol on membrane recognition, oligomerization, and/or pore formation is now studied using StnII variants, which are characterized in terms of their ability to interact with model membranes in the presence or absence of Chol. The results obtained frame Chol not only as an important partner for SM for functional membrane recognition but also as a molecule which significantly reduces the structural requirements for the mentioned conformational rearrangements to occur. However, given that the DOPC:SM:Chol vesicles employed display phase coexistence and have domain boundaries, the observed effects could be also due to the presence of these different phases on the membrane. In addition, it is also shown that the Arg51 guanidinium group is strictly required for membrane recognition, independently of the presence of Chol. PMID:25815890

  17. Efficient ceramic anodes infiltrated with binary and ternary electrocatalysts for SOFCs operating at low temperatures

    NASA Astrophysics Data System (ADS)

    Hussain, A. Mohammed; Høgh, Jens V. T.; Zhang, Wei; Bonanos, Nikolaos

    2012-10-01

    Electrocatalyst precursor of various combinations: Pt, Ru, Pd, Ni and Gd-doped CeO2 (CGO) were infiltrated into a porous Sr0.94Ti0.9Nb0.1O3 (STN) backbone, to study the electrode performance of infiltrated ceramic anodes at low temperature ranges of 400-600 °C. The performance of the binary electrocatalyst infiltrated ceramic backbones are Pt-CGO>Ru-CGO>Pd-CGO>Ni-CGO. Ternary electrocatalyst of Ni-Pd-CGO and Ni-Pt-CGO showed the lowest polarization resistance of 0.31 and 0.11 Ωcm2, respectively at 600 °C in H2/3% H2O. The average particle size of the ternary electrocatalyst was larger than the binary Pd-CGO and Pt-CGO due to the particle coarsening of Ni nanoparticles. High resolution transmission electron microscopic analysis on the best performing Ni-Pt-CGO electrocatalyst infiltrated anode reveals the formation of Ni-Pt nanocrystalline alloy and a homogenous distribution of nanoparticles on STN backbone.

  18. Diffuse reflectance spectroscopy measurements for tissue-type discrimination during deep brain stimulation

    NASA Astrophysics Data System (ADS)

    Antonsson, Johan; Eriksson, Ola; Blomstedt, Patric; Bergenheim, A. Tommy; Hariz, Marwan I.; Richter, Johan; Zsigmond, Peter; Wårdell, Karin

    2008-06-01

    Diffuse reflectance spectroscopy as a method for improving intracerebral guidance during functional neurosurgery has been investigated. An optical probe was developed for measurements during stereotactic and functional neurosurgery in man. The aim of the study was to investigate the spectral differences between white and grey matter and between white matter and functional targets. Diffuse reflectance spectroscopy measurements in ten patients were recorded at incremental steps towards and in three different functional targets (STN, GPi and Zi). The recorded spectra along the trajectory were sorted into white or grey matter, based on preoperative MRI images or the recorded spectral shape and intensity. The difference between tissue types was calculated as a quotient. Significant intensity differences between white and grey matter were found to be at least 14% (p < 0.05) and 20% (p < 0.0001) for MRI and spectral-sorted data respectively. The reflectance difference between white matter and the functional targets of GPi was higher than for STN and Zi. The results indicate that diffuse reflectance spectroscopy has a potential to be developed to a suitable complement to other intracerebral guidance methods.

  19. Defining the neurocircuitry of exercise hyperpnoea

    PubMed Central

    Paterson, David J

    2014-01-01

    One hundred years ago in this journal, Krogh and Lindhard published a seminal paper highlighting the importance of the brain in the control of breathing during exercise. This symposium report reviews the historical developments that have taken place since 1913, and attempts to place the detailed neurocircuitry thought to underpin exercise hyperpnoea into context by focusing on key structures that might form the command network. With the advent of enhanced neuroimaging and functional neurosurgical techniques, a unique window of opportunity has recently arisen to target potential circuits in humans. Animal studies have identified a priori sites of interest in mid-brain structures, in particular the subthalamic locomotor region (subthalamic nucleus, STN) and the periaqueductal grey (PAG), which have now been recorded from in humans during exercise. When all data are viewed in an integrative manner, the PAG, in particular the lateral PAG, and aspects of the dorsal lateral PAG, appear to be key communicating circuitry for ‘central command’. Moreover, the PAG also fulfils many requirements of a command centre. It has functional connectivity to higher centres (dorsal lateral prefrontal cortex) and the basal ganglia (in particular, the STN), and receives a sensory input from contracting muscle, but, importantly, it sends efferent information to brainstem nuclei involved in cardiorespiratory control. PMID:23918772

  20. Pallidal gap junctions-triggers of synchrony in Parkinson's disease?

    PubMed Central

    Schwab, Bettina C; Heida, Tjitske; Zhao, Yan; van Gils, Stephan A; van Wezel, Richard J A

    2014-01-01

    Although increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in Parkinson's disease (PD), how this synchrony arises, propagates through the basal ganglia, and changes under dopamine replacement remains unknown. Gap junctions could play a major role in modifying this synchrony, because they show functional plasticity under the influence of dopamine and after neural injury. In this study, confocal imaging was used to detect connexin-36, the major neural gap junction protein, in postmortem tissues of PD patients and control subjects in the putamen, subthalamic nucleus (STN), and external and internal globus pallidus (GPe and GPi, respectively). Moreover, we quantified how gap junctions affect synchrony in an existing computational model of the basal ganglia. We detected connexin-36 in the human putamen, GPe, and GPi, but not in the STN. Furthermore, we found that the number of connexin-36 spots in PD tissues increased by 50% in the putamen, 43% in the GPe, and 109% in the GPi compared with controls. In the computational model, gap junctions in the GPe and GPi strongly influenced synchrony. The basal ganglia became especially susceptible to synchronize with input from the cortex when gap junctions were numerous and high in conductance. In conclusion, connexin-36 expression in the human GPe and GPi suggests that gap junctional coupling exists within these nuclei. In PD, neural injury and dopamine depletion could increase this coupling. Therefore, we propose that gap junctions act as a powerful modulator of synchrony in the basal ganglia. PMID:25124148