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David H. Ellison - One of the best experts on this subject based on the ideXlab platform.
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Effect of Angiotensin II on ENaC in the Distal Convoluted Tubule and in the Cortical Collecting Duct of Mineralocorticoid Receptor Deficient Mice
Journal of the American Heart Association, 2020Co-Authors: Zhong Xiuzi Gao, Andrew S. Terker, Dan-dan Zhang, Xin Peng Duan, Dao Hong Lin, David H. EllisonAbstract:Background Angiotensin II stimulates epithelial Na+ channel (ENaC) by aldosterone‐independent mechanism. We now test the effect of angiotensin II on ENaC in the distal convoluted tubule (DCT) and c...
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Distal convoluted tubule.
Comprehensive Physiology, 2014Co-Authors: James A. Mccormick, David H. EllisonAbstract:The distal convoluted tubule (DCT) is a short nephron segment, interposed between the macula densa and collecting duct. Even though it is short, it plays a key role in regulating extracellular fluid volume and electrolyte homeostasis. DCT cells are rich in mitochondria, and possess the highest density of Na+/K+-ATPase along the nephron, where it is expressed on the highly amplified basolateral membranes. DCT cells are largely water impermeable, and reabsorb sodium and chloride across the apical membrane via electroneurtral pathways. Prominent among this is the thiazide-sensitive sodium chloride cotransporter, target of widely used diuretic drugs. These cells also play a key role in magnesium reabsorption, which occurs predominantly, via a transient receptor potential channel (TRPM6). Human genetic diseases in which DCT function is perturbed have provided critical insights into the physiological role of the DCT, and how transport is regulated. These include Familial Hyperkalemic Hypertension, the salt-wasting diseases Gitelman syndrome and EAST syndrome, and hereditary hypomagnesemias. The DCT is also established as an important target for the hormones angiotensin II and aldosterone; it also appears to respond to sympathetic-nerve stimulation and changes in plasma potassium. Here, we discuss what is currently known about DCT physiology. Early studies that determined transport rates of ions by the DCT are described, as are the channels and transporters expressed along the DCT with the advent of molecular cloning. Regulation of expression and activity of these channels and transporters is also described; particular emphasis is placed on the contribution of genetic forms of DCT dysregulation to our understanding.
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wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule
Nature Genetics, 2006Co-Authors: Maria D Lalioti, David H. Ellison, Carol Nelsonwilliams, Junhui Zhang, Heather M Volkman, Kristopher T Kahle, Kristin E Hoffmann, Hakan R Toka, Richard A Flavell, Carmen J BoothAbstract:The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4WT) or PHAII mutant (TgWnk4PHAII) Wnk4 is changed in opposite directions: TgWnk4PHAII mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4WT mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4PHAII mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.
David F Garwayheath - One of the best experts on this subject based on the ideXlab platform.
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the relationship between diurnal variations in intraocular pressure measurements and central corneal thickness and corneal hysteresis
Investigative Ophthalmology & Visual Science, 2009Co-Authors: Aachal Kotecha, David P Crabb, Alexander Spratt, David F GarwayheathAbstract:PURPOSE To examine the relationship between office-hour changes in IOP, measured with the Goldmann applanation tonometer (GAT) and dynamic contour tonometer (DCT), and the corneal characteristics central corneal thickness (CCT) and corneal hysteresis (CH). METHODS Sixty-two eyes of 62 untreated normal subjects and patients with untreated glaucoma had IOP measurements performed with the GAT (mm Hg) and DCT (mm Hg) over an 8-hour period at 2-hour intervals beginning at 9 AM. CCT (micrometers) was measured using a noncontact optical low-coherence reflectometry (OLCR) pachymeter, and CH (mm Hg) was measured with an ocular response analyzer (ORA). The associations between IOP measurements and corneal characteristics for each patient over the measurement period were assessed by using multilevel modeling. RESULTS GAT and DCT IOP and CCT changed significantly during office hours (ANOVA; GAT: F = 19.9, P < 0.001; DCT: F = 4.6, P = 0.001; CCT: F = 16.4; P < 0.001). No significant changes were observed in CH (ANOVA; F = 1.8, P = 0.13). Multilevel modeling analysis of the interrelationships between CCT, CH, and age on IOP measurements revealed that both CCT and CH changes were significantly associated with GAT IOP changes (GAT IOP/CCT slope, 0.04 mm Hg/microm; 95% confidence intervals [CIs], 0.02-0.06; GAT IOP/CH slope, 0.20 mm Hg/mm Hg; 95% CI, 0.01-0.39). CCT, but not CH, changes were significantly associated with DCT IOP changes (DCT IOP/CCT slope, 0.03 mm Hg/microm; 95% CI, 0.00-0.05). However, although the association between CCT and GAT IOP was relatively uniform between subjects, association between CCT and DCT IOP showed greater intersubject variability. Age had no effect on the diurnal variation of IOP measured with either device. CONCLUSIONS Measured IOP and corneal characteristics covary during office hours. Changes in CCT and CH are associated with changes in GAT IOP and, less consistently, with DCT IOP. The data suggest that variations in corneal characteristics explain a small proportion of the change in IOP measurements made with the GAT during office hours.
Seongjoon Park - One of the best experts on this subject based on the ideXlab platform.
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invariant chain made in escherichia coli has an exposed n terminal segment that blocks antigen binding to hla dr1 and a trimeric c terminal segment that binds empty hla dr1
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Seongjoon ParkAbstract:Invariant chain (Ii), a membrane glycoprotein, binds class II major histocompatibility complex (MHC) glycoproteins, probably via its class II-associated Ii peptide (CLIP) segment, and escorts them toward antigen-containing endosomal compartments. We find that a soluble, trimeric ectodomain of Ii expressed and purified from Escherichia coli blocks peptide binding to soluble HLA-DR1. Proteolysis indicates that Ii contains two structural domains. The C-terminal two-thirds forms an alpha-helical domain that trimerizes and interacts with empty HLA-DR1 molecules, augmenting rather than blocking peptide binding. The N-terminal one-third, which inhibits peptide binding, is proteolytically susceptible over its entire length. In the trimer, the N-terminal domains act independently with each CLIP segment exposed and free to bind an MHC class II molecule, while the C-terminal domains act as a trimeric unit.
Austin Lockwood - One of the best experts on this subject based on the ideXlab platform.
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assertive community treatment for people with severe mental disorders
Cochrane Database of Systematic Reviews, 2011Co-Authors: Max Marshall, Austin LockwoodAbstract:Background Assertive Community Treatment (ACT) was developed in the early 1970s as a response to the closing down of psychiatric hospitals. ACT is a team-based approach aiming at keeping ill people in contact with services, reducing hospital admissions and improving outcome, especially social functioning and quality of life. Objectives To determine the effectiveness of Assertive Community Treatment (ACT) as an alternative to i. standard community care, ii. traditional hospital-based rehabilitation, and iii. case management. For each of the three comparisons the main outcome indices were i. remaining in contact with the psychiatric services, ii. extent of psychiatric hospital admissions, iii. clinical and social outcome and iv. costs. Search strategy Electronic searches of CINAHL (1982-1997), the Cochrane Schizophrenia Group's Register of trials (1997), EMBASE (1980-1997), MEDLINE (1966-1997), PsycLIT (1974-1997) and SCISEARCH (1997) were undertaken. References of all identified studies were searched for further trial citations. Selection criteria The inclusion criteria were that studies should i. be randomised controlled trials, ii. have compared ACT to standard community care, hospital-based rehabilitation, or case management and iii. have been carried out on people with severe mental disorder the majority of whom were aged from 18 to 65. Studies of ACT were defined as those in which the investigators described the intervention as "Assertive Community Treatment" or one of its synonyms. Studies of ACT as an alternative to hospital admission, hospital diversion programmes, for those in crisis, were excluded. The reliability of the inclusion criteria were evaluated. Data collection and analysis Three types of outcome data were available: i. categorical data, ii. numerical data based on counts of real life events (count data) and iii. numerical data collected by standardised instruments (scale data). Categorical data were extracted twice and then cross-checked. Peto Odds Ratios and the number needed to treat (NNT) were calculated. Numerical count data were extracted twice and cross-checked. Count data could not be combined across studies for technical reasons (the data were skewed) but all relevant observations based on count data were reported in the review. Numerical scale data were subject to a quality assessment. The validity of the quality assessment was itself assessed. Numerical scale data of suitable quality were combined using the standardised mean difference statistic where possible, otherwise the data were reported in the text or 'Other data tables' of the review. Main results ACT versus standard community care Those receiving ACT were more likely to remain in contact with services than people receiving standard community care (OR 0.51, 99%CI 0.37-0.70). People allocated to ACT were less likely to be admitted to hospital than those receiving standard community care (OR 0.59, 99%CI 0.41-0.85) and spent less time in hospital. In terms of clinical and social outcome, significant and robust differences between ACT and standard community care were found on i. accommodation status, ii. employment and iii. patient satisfaction. There were no differences between ACT and control treatments on mental state or social functioning. ACT invariably reduced the cost of hospital care, but did not have a clear cut advantage over standard care when other costs were taken into account. ACT versus hospital-based rehabilitation services Those receiving ACT were no more likely to remain in contact with services than those receiving hospital-based rehabilitation, but confidence intervals for the odds ratio were wide. People getting ACT were significantly less likely to be admitted to hospital than those receiving hospital-based rehabilitation (OR 0.2, 99%CI 0.09-0.46) and spent less time in hospital. Those allocated to ACT were significantly more likely to be living independently (OR (for not living independently) 0.19, 99%CI 0.06-0.54), but there were no other significant and robust differences in clinical or social outcome. There was insufficient data on costs to permit comparison. ACT versus case management There were no data on numbers remaining in contact with the psychiatric services or on numbers admitted to hospital. People allocated to ACT consistently spent fewer days in hospital than those given case management. There was insufficient data to permit robust comparisons of clinical or social outcome. The cost of hospital care was consistently less for those allocated to ACT, but ACT did not have a clear cut advantage over case management when other costs were taken into account. Authors' conclusions ACT is a clinically effective approach to managing the care of severely mentally ill people in the community. ACT, if correctly targeted on high users of in-patient care, can substantially reduce the costs of hospital care whilst improving outcome and patient satisfaction. Policy makers, clinicians, and consumers should support the setting up of ACT teams.
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withdrawn assertive community treatment for people with severe mental disorders
Cochrane Database of Systematic Reviews, 2011Co-Authors: Max Marshall, Austin LockwoodAbstract:Background Assertive Community Treatment (ACT) was developed in the early 1970s as a response to the closing down of psychiatric hospitals. ACT is a team-based approach aiming at keeping ill people in contact with services, reducing hospital admissions and improving outcome, especially social functioning and quality of life. Objectives To determine the effectiveness of Assertive Community Treatment (ACT) as an alternative to i. standard community care, ii. traditional hospital-based rehabilitation, and iii. case management. For each of the three comparisons the main outcome indices were i. remaining in contact with the psychiatric services, ii. extent of psychiatric hospital admissions, iii. clinical and social outcome and iv. costs. Search strategy Electronic searches of CINAHL (1982-1997), the Cochrane Schizophrenia Group's Register of trials (1997), EMBASE (1980-1997), MEDLINE (1966-1997), PsycLIT (1974-1997) and SCISEARCH (1997) were undertaken. References of all identified studies were searched for further trial citations. Selection criteria The inclusion criteria were that studies should i. be randomised controlled trials, ii. have compared ACT to standard community care, hospital-based rehabilitation, or case management and iii. have been carried out on people with severe mental disorder the majority of whom were aged from 18 to 65. Studies of ACT were defined as those in which the investigators described the intervention as "Assertive Community Treatment" or one of its synonyms. Studies of ACT as an alternative to hospital admission, hospital diversion programmes, for those in crisis, were excluded. The reliability of the inclusion criteria were evaluated. Data collection and analysis Three types of outcome data were available: i. categorical data, ii. numerical data based on counts of real life events (count data) and iii. numerical data collected by standardised instruments (scale data). Categorical data were extracted twice and then cross-checked. Peto Odds Ratios and the number needed to treat (NNT) were calculated. Numerical count data were extracted twice and cross-checked. Count data could not be combined across studies for technical reasons (the data were skewed) but all relevant observations based on count data were reported in the review. Numerical scale data were subject to a quality assessment. The validity of the quality assessment was itself assessed. Numerical scale data of suitable quality were combined using the standardised mean difference statistic where possible, otherwise the data were reported in the text or 'Other data tables' of the review. Main results ACT versus standard community care Those receiving ACT were more likely to remain in contact with services than people receiving standard community care (OR 0.51, 99%CI 0.37-0.70). People allocated to ACT were less likely to be admitted to hospital than those receiving standard community care (OR 0.59, 99%CI 0.41-0.85) and spent less time in hospital. In terms of clinical and social outcome, significant and robust differences between ACT and standard community care were found on i. accommodation status, ii. employment and iii. patient satisfaction. There were no differences between ACT and control treatments on mental state or social functioning. ACT invariably reduced the cost of hospital care, but did not have a clear cut advantage over standard care when other costs were taken into account.ACT versus hospital-based rehabilitation services Those receiving ACT were no more likely to remain in contact with services than those receiving hospital-based rehabilitation, but confidence intervals for the odds ratio were wide. People getting ACT were significantly less likely to be admitted to hospital than those receiving hospital-based rehabilitation (OR 0.2, 99%CI 0.09-0.46) and spent less time in hospital. Those allocated to ACT were significantly more likely to be living independently (OR (for not living independently) 0.19, 99%CI 0.06-0.54), but there were no other significant and robust differences in clinical or social outcome. There was insufficient data on costs to permit comparison.ACT versus case management There were no data on numbers remaining in contact with the psychiatric services or on numbers admitted to hospital. People allocated to ACT consistently spent fewer days in hospital than those given case management. There was insufficient data to permit robust comparisons of clinical or social outcome. The cost of hospital care was consistently less for those allocated to ACT, but ACT did not have a clear cut advantage over case management when other costs were taken into account. Authors' conclusions ACT is a clinically effective approach to managing the care of severely mentally ill people in the community. ACT, if correctly targeted on high users of in-patient care, can substantially reduce the costs of hospital care whilst improving outcome and patient satisfaction. Policy makers, clinicians, and consumers should support the setting up of ACT teams.
Nilanka Rajapaksha - One of the best experts on this subject based on the ideXlab platform.
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a single channel architecture for algebraic integer based 8 times 8 2 d dct computation
IEEE Transactions on Circuits and Systems for Video Technology, 2013Co-Authors: Amila Edirisuriya, Arjuna Madanayake, Renato J Cintra, V S Dimitrov, Nilanka RajapakshaAbstract:An area efficient row-parallel architecture is proposed for the real-time implementation of bivariate algebraic integer (AI) encoded 2-D discrete cosine transform (DCT) for image and video processing. The proposed architecture computes 8 × 8 2-D DCT transform based on the Arai DCT algorithm. An improved fast algorithm for AI-based 1-D DCT computation is proposed along with a single channel 2-D DCT architecture. The design improves on the four-channel AI DCT architecture that was published recently by reducing the number of integer channels to one and the number of eight-point 1-D DCT cores from five down to two. The architecture offers exact computation of 8 × 8 blocks of the 2-D DCT coefficients up to the FRS, which converts the coefficients from the AI representation to fixed-point format using the method of expansion factors. Prototype circuits corresponding to FRS blocks based on two expansion factors are realized, tested, and verified on FPGA-chip, using a Xilinx Virtex-6 XC6VLX240T device. Post place-and-route results show a 20% reduction in terms of area compared to the 2-D DCT architecture requiring five 1-D AI cores. The area-time and area-time2 complexity metrics are also reduced by 23% and 22% respectively for designs with eight-bit input word length. The digital realizations are simulated up to place and route for ASICs using 45 nm CMOS standard cells. The maximum estimated clock rate is 951 MHz for the CMOS realizations indicating 7.608·109 pixels/s and a 8 × 8 block rate of 118.875 MHz.