Cell volume regulation in the proximal tubule of rat kidney proximal tubule cell volume regulation

We developed a dynamic model of a rat proximal convoluted tubule cell in order to investigate cell volume regulation mechanisms in this nephron segment. We examined whether regulatory volume decrease (RVD), which follows exposure to a hyposmotic peritubular solution, can be achieved solely via stimulation of basolateral K^+ and Cl^− channels and Na^+–HCO₃^− cotransporters. We also determined whether regulatory volume increase (RVI), which follows exposure to a hyperosmotic peritubular solution under certain conditions, may be accomplished by activating basolateral Na^+/H^+ exchangers. Model predictions were in good agreement with experimental observations in mouse proximal tubule cells assuming that a 10% increase in cell volume induces a fourfold increase in the expression of basolateral K+ and Cl− channels and Na+–HCO₃^− cotransporters. Our results also suggest that in response to a hyposmotic challenge and subsequent cell swelling, Na^+–HCO₃^− cotransporters are more efficient than basolateral K^+ and Cl^− channels at lowering intracellular osmolality and reducing cell volume. Moreover, both RVD and RVI are predicted to stabilize net transcellular Na^+ reabsorption, that is, to limit the net Na^+ flux decrease during a hyposmotic challenge or the net Na^+ flux increase during a hyperosmotic challenge.This research was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, via grant R01DK106102 to AT Layton. (R01DK106102 - National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases)Accepted manuscrip

Adaptive changes in GFR, tubular morphology, and transport in subtotal nephrectomized kidneys: modeling and analysis

Removal of renal mass stimulates anatomical and functional adaptations in the surviving nephrons, including elevations in single-nephron glomerular filtration rate (SNGFR) and tubular hypertrophy. A goal of this study is to assess the extent to which the concomitant increases in filtered load and tubular transport capacity preserve homeostasis of water and salt. To accomplish that goal, we developed computational models to simulate solute transport and metabolism along nephron populations in a uninephrectomized (UNX) rat and a 5/6-nephrectomized (5/6-NX) rat. Model simulations indicate that nephrectomy-induced SNGFR increase and tubular hypertrophy go a long way to normalize excretion, but alone are insufficient to fully maintain salt balance. We then identified increases in the protein density of Na+-K+-ATPase, Na+-K+-2Cl- cotransporter, Na+-Cl- cotransporter, and epithelial Na+ channel, such that the UNX and 5/6-NX models predict urine flow and urinary Na+ and K+ excretions that are similar to sham levels. The models predict that, in the UNX and 5/6-NX kidneys, fractional water and salt reabsorption is similar to sham along the initial nephron segments (i.e., from the proximal tubule to the distal convoluted tubule), with a need to further reduce Na+ reabsorption and increase K+ secretion primarily along the connecting tubules and collecting ducts to achieve balance. Additionally, the models predict that, given the substantially elevated filtered and thus transport load among each of the surviving nephrons, oxygen consumption per nephron segment in a UNX or 5/6-NX kidney increases substantially. But due to the reduced nephron population, whole animal renal oxygen consumption is lower. The efficiency of tubular Na+ transport in the UNX and 5/6-NX kidneys is predicted to be similar to sham.This research was supported by the Department of Veterans Affairs (to V. Vallon) and by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-56248 (to V. Vallon), R01-DK-106102 (A. T. Layton and V. Vallon), and the University of Alabama at Birmingham/ University of California San Diego O'Brien Center for Acute Kidney Injury Research NIH-P30-DK-079337 (to V. Vallon). (Department of Veterans Affairs; R01-DK-56248 - National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; R01-DK-106102 - National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; NIH-P30-DK-079337 - University of Alabama at Birmingham/ University of California San Diego O'Brien Center for Acute Kidney Injury Research)Accepted manuscrip

Renal potassium handling in rats with subtotal nephrectomy: modeling and analysis

We sought to decipher the mechanisms underlying the kidney's response to changes in K+ load and intake, under physiological and pathophysiological conditions. To accomplish that goal, we applied a published computational model of epithelial transport along rat nephrons in a sham rat, an uninephrectomized (UNX) rat, and a 5/6-nephrectomized (5/6-NX) rat that also considers adaptations in glomerular filtration rate and tubular growth. Model simulations of an acute K+ load indicate that elevated expression levels and activities of Na+/K+-ATPase, epithelial sodium channels, large-conductance Ca2+-activated K+ channels, and renal outer medullary K+ channels, together with downregulation of sodium-chloride cotransporters (NCC), increase K+ secretion along the connecting tubule, resulting in a >6-fold increase in urinary K+ excretion in sham rats, which substantially exceeds the filtered K+ load. In the UNX and 5/6-NX models, the acute K+ load is predicted to increase K+ excretion, but at significantly reduced levels compared with sham. Acute K+ load is accompanied by natriuresis in sham rats. Model simulations suggest that the lesser natriuretic effect observed in the nephrectomized groups may be explained by impaired NCC downregulation in these kidneys. At a single-nephron level, a high K+ intake raises K+ secretion along the connecting tubule and reabsorption along the collecting duct in sham, and even more in UNX and 5/6-NX. However, the increased K+ secretion per tubule fails to sufficiently compensate for the reduction in nephron number, such that nephrectomized rats have an impaired ability to excrete an acute or chronic K+ load.This research was supported by the Department of Veterans Affairs (V. Vallon), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants R01-DK-112042 (V. Vallon) and R01-DK-106102 (A. T. Layton and V. Vallon), and University of Alabama at Birmingham-University of California San Diego O'Brien Center for Acute Kidney Injury Research (NIDDK Grant P30-DK-079337; V. Vallon). (Department of Veterans Affairs; R01-DK-112042 - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); P30-DK-079337 - University of Alabama at Birmingham-University of California San Diego O'Brien Center for Acute Kidney Injury Research (NIDDK Grant))Accepted manuscrip

Measurement of distortion product otoacoustic emissions in South African gold miners at risk for noise-induced hearing loss.

Background The noise-exposed population in the mining industry in South Africa poses unique problems to the occupational audiologist working in this environment, due to the broad linguistic and cultural diversity in the audiology and mining environment. Unfortunately, the problems are also exacerbated by a high incidence of pseudohypacusis within this population who are incentivised by compensation for NIHL. A solution to these specific problems would be the reliable and valid use of an objective test of function such as the DPOAE. The rationale for the study therefore was to extend the body of knowledge about the use of DPOAEs in the noise-exposed mining population. Methodology The current study was divided into two phases: phase one’s objectives entailed the investigation of the characteristics of DPOAEs in a noise-exposed mining population; phase two aimed to develop a multivariate regression model that would facilitate the prediction of the hearing threshold levels from the DPOAE levels in this population. Objectives The objectives in phase one of the study were to investigate the bivariate correlations between DPOAE levels and air-conduction hearing threshold levels in noise-exposed gold miners, for the three stimulus procedures. The study also aimed to investigate the bivariate correlations between various pure-tone averages (PTA) and the DPOAE averages of f2 frequencies closest to those pure-tone frequencies. Similarly, the Speech Recognition Thresholds (SRT) were correlated with DPOAE averages of f2 frequencies closest to the PTA. xx The study further aimed to investigate the characteristics of DPOAEs in noiseexposed gold miners by comparing the average DPOAE levels for different age category groups, different ethnic groups and for different occupation types. Finally, phase one aimed to describe the characteristics of emission level and noise floor differences (DP-NF) in a DPOAE database of a noise-exposed gold mining population. Phase two of the study had the objective of developing a multivariate prediction model using stepwise regression analysis to identify which of the DPOAE frequencies produced the best prediction of the audiogram frequencies when multivariate inputs were used for each stimulus procedure. The objective was also to evaluate the use of the predicted audiograms’ calculated percentage loss of hearing (PLH) with that of the actual PLH. This retrospective record review used an audiological database from a mine in the North West province of South Africa that contained 4800 records. The required sample size to be representative of the population was statistically determined. The records were randomly selected resulting a sample size for the FB2-S group of 161, for the FB1-S group of 177 and the FB1-S group of 155 respectively. The hearing loss characteristics in the samples ranged from normal to profound losses with the majority being mild to moderate hearing losses. Results The findings of phase one showed negative correlations ranging from -0.327 to -0.573 for Frequency Band 1- Replicated (FB1-R) between DPOAE levels and air conduction hearing threshold levels. Similarly, Frequency Band 1-Single (FB1-S) and Frequency Band 2-Single (FB2-S) also showed negative correlations (ranging from -0.203 to -0.609 and -0.274 to -0.738 respectively). These correlation strengths have been confirmed previously by other published studies. xxi Correlations between groups of frequencies on an audiogram and averaged match groups of DPOAE frequencies by intensity levels, both for PTA and SRT, ranged between -0.323 and -0.661. No statistically significant differences were found between the DPOAE measurements and ethnic groups of African and Caucasian (Sample size of 175 for FB1-S, 137 for FB1-R and 161 for FB2-S). No differences were found between the DPOAE levels and the occupation types of mining team members, stopers and drillers. There was, however, a relational finding of a progressive decrement of DPOAE intensity levels by decade of age increase (Sample size of 37 for FB1-S, 45 for FB1-R and 155 for FB2-S). Mean DP levels in this population ranged from 1.5 to -14 dB SPL, and mean NF levels in the sample ranged from 0.1 to -16.8 dB SPL with the mean DP-NF difference ranges form 0.4 to 9.3 dBSPL. More than 60% of the data collected resulted in a DP-NF of less than 10 dB SPL. The simple correlation relationship between hearing threshold levels and DPOAEs did not sufficiently explain the variance within the sample and due to the fact that a number of the independent variables in the sample were highly correlated, there was a call to use a method that allows for multicolinearity (i.e. stepwise regression analysis) in order to develop a prediction model. Consequently, phase two of the study was able to compare actual air-conduction hearing threshold levels with those calculated with the prediction model, and then calculate predicted percentage loss of hearing (PLH) with actual PLH found in the noise-exposed gold miners. In phase two, with the use of the predictive models, the predicted hearing threshold levels were found to differ from the actual thresholds by no more than 7dB HL across all frequencies (average of 5 dB HL for FB1-R, 2 dB HL for FB1-S and 3 dB HL for FB2-S). The differences for each audiogram frequency between the actual and the predicted thresholds are represented on scatter plots in phase two of the thesis. The PLH of the predicted audiograms was calculated using the weighted xxii tables prescribed by the Compensation for Occupational Diseases and Injuries Act (COIDA). A comparison of the predicted PLH with the actual PLH indicated that the predicted PLH ranged between minus 1.3% PLH and plus 6.7% PLH of the actual PLH. Results of the study are discussed with regards to the clinical implications, and the implications for training occupational audiologists in South Africa. The results of this study will improve and inform practice in the mining environment and in the field of compensation for NIHL. By developing a reliable prediction tool which is implemented on an objective test proven to document the extent of damage incurred from noise-exposure, a clinician will gain greater confidence in an accurate diagnosis, thereby further safeguarding a vulnerable population. The results from this study are highly relevant to the mining industry and will add value to the industrial development of South Africa by informing the policy on hearing conservation and compensation, thereby increasing the awareness of the need for improved occupational health and safety conditions and sustainable development in the mining industry

Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability

Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability. Am J Physiol Renal Physiol 313: F174 –F183, 2017. First published March 29, 2017; doi:10.1152/ajprenal.00482.2016.—The goals of this study were to 1) develop a computational model of solute transport and oxygenation in the kidney of the female spontaneously hypertensive rat (SHR), and 2) apply that model to investigate sex differences in nitric oxide (NO) levels in SHR and their effects on medullary oxygenation and oxidative stress. To accomplish these goals, we first measured NO synthase (NOS) 1 and NOS3 protein expression levels in total renal microvessels of male and female SHR. We found that the expression of both NOS1 and NOS3 is higher in the renal vasculature of females compared with males. To predict the implications of that finding on medullary oxygenation and oxidative stress levels, we developed a detailed computational model of the female SHR kidney. The model was based on a published male kidney model and represents solute transport and the biochemical reactions among O2, NO, and superoxide (O2 ) in the renal medulla. Model simulations conducted using both male and female SHR kidney models predicted significant radial gradients in interstitial fluid oxygen tension (PO2) and NO and O2 concentration in the outer medulla and upper inner medulla. The models also predicted that increases in endothelial NO-generating capacity, even when limited to specific vascular segments, may substantially raise medullary NO and PO2 levels. Other potential sex differences in SHR, including O2 production rate, are predicted to significantly impact oxidative stress levels, but effects on NO concentration and PO2 are limited.This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-106102 to A. T. Layton, and by American Heart Association Grant 14GRNT20480199 to J. C. Sullivan. (R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases; 14GRNT20480199 - American Heart Association)Accepted manuscrip

A phenomenological case study of the therapeutic impact of imagery: Rescripting of memories of a rape and episodes of childhood abuse and neglect

This is a systematic case study of the assessment and treatment of Anna (43), a woman presenting with posttraumatic stress disorder (PTSD) following a drug-facilitated sexual assault that occurred over twenty years earlier. She was also diagnosed with avoidant personality disorder. Treatment with cognitive therapy for PTSD and social phobia was supplemented by imagery rescripting (IR) of memories of childhood trauma within a schema therapy approach. The study documents how her intrusive memories of the rape were potentiated by early maladaptive schemas that developed in response to abusive and neglectful parenting. Within a broader narrative, three examples of IR are described which show how, as an emotion-focused intervention, this approach discloses deeper memories and emotional states that are distressing and traumatic and allows them to be transformed through a healing process that is organic and displays what Bohart and Tallman (2010) call “self-organizing wisdom.

AN APPROACH TO EXAMINE THE EFFECT OF TAPER ANGLE AND THREADING ON PERIPROSTHETIC BONE REMODELING FROM BONE-ANCHORED AMPUTATION PROSTHESES

INTRODUCTION The most common problems experienced by transfemoral amputees using socket prostheses are soft tissue pain and a limited range of motion around the hip joint [1].  Recently, intraosseous transcutaneous amputation prostheses (ITAP) have been developed as an alternative to the standard socket prostheses for amputees.  A current shortcoming of ITAP is the change in the local mechanical loading at the bone-implant interface leading to bone resorption.  The clinical consequences of this bone loss are increased risks of bone fracture and implant loosening [2].  The purpose of this study was to develop a finite element modeling approach to examine the effect of ITAP fixture threading and taper angle on femoral bone remodeling. METHODS An intact femoral geometry was generated using Mimics software (Materialise, Leuven, Belgium) from CT scans obtained from the VAHKUM database [3]. Twelve ITAP (six threaded and six unthreaded) implants of varying taper angles were designed using SolidWorks (Waltham, MA). Implants were registered and aligned within the femoral diaphysis, and the implant-femur assembly was meshed with quadratic tetrahedral elements; elements at the bone-implant interface shared identical nodes to represent full osseointegration.  Bone elements were assigned inhomogeneous linear-elastic material properties based on CT Hounsfield units. Implant material was modeled as titanium alloy Ti6Al4V (E=114 GPa, ν=0.3), which is commonly used for prostheses due to its superior strength and biocompatibility. Boundary conditions and loads applied to the finite element models were taken from Tomaszewski et al. [4], which were linearly scaled to correspond to an individual with a mass of 70.1 kg and a height of 170 cm.  All models were solved using ABAQUS Standard v6.1 (Providence, RI). Strain energy density was calculated for each implanted femur and compared to those of an intact femur. RESULTS Considerable energy was transferred to the ITAP (Figure 1). Consequently, the periprosthetic cortical bone in the implanted femur had a significantly lower strain energy density than that of the intact femur (Figure 1). DISCUSSION AND CONCLUSIONS It is critical that implant geometry is optimized to decrease periprosthetic bone resorption and reduce the incidence of bone fracture and implant loosening.  Changes in strain energy density following prosthetic implantation is a driving stimulus for bone remodeling, and our future work will incorporate adaptive bone remodeling algorithms into our simulations

Development of a teaching tool to encourage high school students to study aerospace technical subjects

This report details the efforts to develop a design competition aimed at high school students which will encourage them to study aerospace technical subjects. It has been shown that such competitions - based on an industry simulation game - are valuable ways to energize high school students to study in this area. Under the grant, a new competition scenario was developed, in keeping with NASA-Dryden's mission to develop aircraft and foster knowledge about aeronautics. Included are preliminary background materials and information which, if the grant is continued, would form the basis of a national competition for high school students, wherein they would design an Aerospaceport in a future year, taking into consideration the requirements of aircraft, spacecraft- ground transportation systems, passengers who use the facility, and employees who operate it. Many of the Competition methods were studied and tested during two existing local competitions in the disadvantaged communities of Lancaster and Victorville, California

Increasing Capacity for Knowledge Translation: Understanding How Some Researchers Engage Policy-makers

The potential for research to influence policy, and for researchers to influence policy actors, is significant. The purpose of this qualitative study was to explore the experiences of health services researchers engaging in (or not able to engage in) policy-relevant research. Semi-structured telephone interviews were completed with 23 experienced researchers.The results paint a complex and dynamic picture of the policy environment and the relationship between government officials and academic researchers. Elements of this complexity included diverse understandings of the nature of policy and how research relates to policy; dealing with multiple stakeholders in the policy-making process; and identifying strategies to manage the different cultures of government and academia

Smoothing of sandpile surfaces after intermittent and continuous avalanches: three models in search of an experiment

We present and analyse in this paper three models of coupled continuum equations all united by a common theme: the intuitive notion that sandpile surfaces are left smoother by the propagation of avalanches across them. Two of these concern smoothing at the `bare' interface, appropriate to intermittent avalanche flow, while one of them models smoothing at the effective surface defined by a cloud of flowing grains across the `bare' interface, which is appropriate to the regime where avalanches flow continuously across the sandpile.Comment: 17 pages and 26 figures. Submitted to Physical Review