Functional MRI Assessment of Renal Fibrosis in Rat Models

poster abstractIntroduction Renal fibrosis is a common consequence of chronic kidney diseases which affects a large population. Therefore, it is important to establish imaging based noninvasive biomarkers to monitor the progression or regression of renal fibrosis instead of biopsy. Magnetic resonance imaging (MRI) could provide both high spatial resolution and excellent tissue contrast for visualization of kidney morphology. Moreover, MRI is capable of assessing pseudo perfusion (Df) and perfusion fraction (Pf) with intra-voxel incoherent motion (IVIM) imaging (1), tissue oxygenation with T2* mapping (2), macromolecular composition with T1rho imaging (3) and kidney function (eGFR) with dynamic contrast enhanced (DCE) imaging (4). This study is aimed to evaluate the sensitivity of these MRI techniques to the renal fibrotic changes in a rat model. Methods A total of 4 rats were scanned at early (2-5 days) and late (25-35 days) time points after surgical intervention (unilateral ureteral obstruction to induce renal fibrosis) on a Siemens Tim Trio 3T scanner using an 80mm inner diameter 8-channel rat body coil (RAPID, USA) under a stable anesthetized condition. Axial images of 80mm FOV, 2mm slice thick and sub-millimeter in-place resolution were acquired for different functional MRI techniques with following parameters, respectively: IVIM with10 b-values of 0 - 750 s/mm2. T2*: with 10 TEs of 8 - 66 ms; T1rho: with 9 TSL times of 5 - 80 ms; DCE: with150 dynamic measurements at a temporal resolution of 1.01 s. before and after a 15s injection of 1.1 ml GD-DTPA through rat tail with a power injector. Functional data were processed and analyzed using custom MATLAB programs or analysis tools installed in the MRI console workstation. Results Figure 1 shows an anatomical image of the obstructed (R) and healthy (L) rat kidneys. Figures 2-4 show example T1rho map, IVIM Df map, and T2* map, respectively. Quantitative results based on ROI measurements are summarized in table 1. Changes consistent with the expected progression of fibrosis were observed in the obstructed kidney (R) while the healthy kidney (L) and muscle region remained stable. Figure 5 shows the DCE-MRI images at baseline as well as 45s, 95s and 240s after contrast infusion. The timing and intensity of signal changes are clearly different between two kidneys. Quantitative results of DCE-MRI data and comparison with PET study is reported in a separate abstract. Discussion High quality anatomical and functional images of rat kidney can be obtained on a clinical 3.0T MR scanner with dedicated small animal coils and optimized imaging techniques. The findings suggest that IVIM, T2*, T1rho and DCE can be used to assess and monitor different aspects of physiological changes in kidney fibrosis

Microparticle subpopulations are potential markers of disease progression and vascular dysfunction across a spectrum of connective tissue disease

OBJECTIVE: Microparticles (MPs) are membrane-bound vesicles derived from vascular and intravascular cells such as endothelial cells (EMPs) and platelets (PMPs). We investigated EMP and PMP numbers across a spectrum of autoimmune rheumatic diseases (AIRDs) with the aim of comparing the levels of, and relationship between, EMPs and PMPs.METHODS: Patients with Systemic Lupus Erythematosus (SLE) (n = 24), Systemic Sclerosis (SSc) (n = 24), Primary Raynauds Phenomenon (RP) (n = 17) and "other CTD" (n = 15) (Primary Sjogrens Syndrome, UCTD or MCTD) as well as 15 healthy controls were recruited. EMPs and PMPs were quantified using flow cytometry. Associations between MP levels and objective functional vascular assessments were evaluated.RESULTS: SLE patients had significantly higher EMPs compared with healthy controls and SSc patients. Higher PMP levels were noted in SSc and primary RP when compared to healthy controls and 'other CTD' patients. A modest correlation was noted between EMP and PMP levels in healthy controls (Spearman r = 0.6, p = 0.017). This relationship appeared stronger in SLE (r = 0.72, p &lt; 0.0001) and other CTD patients (r = 0.75, p &lt; 0.0001). The association between EMPs and PMPs was notably less strong in SSc (r = 0.45, p = 0.014) and RP (r = 0.37, p = 0.15). A significantly lower EMP/PMP ratio was detected in SSc/RP patients in comparison to both healthy controls and SLE/other CTD patients. Higher EMP and PMP levels were associated with higher digital perfusion following cold challenge in SSc. In contrast, higher PMP (but not EMP) levels were associated with lower digital perfusion at both baseline and following cold challenge in primary RP. Higher PMP levels were associated with greater endothelial-independent dilation in patients with SLE.CONCLUSION: MP populations differ across the spectrum of AIRDS, possibly reflecting differences in vascular cell injury and activation. MP levels are associated with functional assessments of vascular function and might have a role as novel vascular biomarkers in AIRDs.SIGNIFICANCE AND INNOVATIONS: Levels of circulating endothelial and platelet microparticles differ between SSc/primary RP compared with SLE and other CTDs (UCTD, MCTD and Primary Sjogrens). MP release may occur within different vascular sites across these disease groups (macrovascular and microvascular). The association between circulating MP levels and objective assessment of macro- and microvascular dysfunction within these disease areas suggests that MPs might have a useful role as novel circulating biomarkers of vascular disease within the CTDs.</p

Examination of the comfort and pain experienced with blood flow restriction training during post-surgery rehabilitation of anterior cruciate ligament reconstruction patients: A UK National Health Service trial.

Examine the comfort and pain experienced with blow flow restriction resistance training (BFR-RT) compared to standard care heavy load resistance training (HL-RT) during anterior cruciate ligament reconstruction (ACLR) patient rehabilitation. Randomised controlled trial. United Kingdom National Health Service. Twenty eight patients undergoing unilateral ACLR surgery with hamstring autograft were recruited. Following surgery participants were block randomised to either HL-RT at 70% repetition maximum (1RM) (n = 14) or BFR-RT (n = 14) at 30% 1RM and completed 8 weeks of twice weekly unilateral leg press training on both limbs. Perceived knee pain, muscle pain and rating of perceived exertion (RPE) were assessed using Borg's (1998) RPE and pain scales during training. Knee pain was also assessed 24 h post-training. There were no adverse events. Knee pain was lower with BFR-RT during (p  0.05) for both BFR-RT and HL-RT. ACLR patients experienced less knee joint pain and reported similar ratings of perceived exertion during and following leg press exercise with BFR-RT compared to traditional HL-RT. BFR-RT may be more advantageous during the early phases of post-surgery ACLR rehabilitation. [Abstract copyright: Copyright © 2019. Published by Elsevier Ltd.

Magnetic Resonance Diffusion Tensor Imaging and Diffusion Compartmental Modeling in an Animal Model of Chronic Kidney Disease

poster abstractPurpose: According to National Health and Nutrition Examination Survey (NHANES), Chronic Kidney Disease (CKD) affects 25% of the US population over age 601. Renal fibrosis, a common pathological consequence of CKD, is a progressive process that ultimately leads to end-stage renal failure that requires dialysis or kidney transplantation2. There is a compelling need for non-invasive biomarkers that track changes in the tissue microenvironment associated with CKD. Several studies using magnetic resonance diffusion tensor imaging (DTI) have been proposed as imaging biomarkers for CKD3. In this study, in addition to DTI, we explored a diffusion-compartmental modeling technique4 to study the microstructures of hypoxia induced animal models of CKD. Method: Preparation of the animal CKD model: Experiments were performed in 4 Wistar Rats using protocols approved by the Institutional Animal Care and Use Committee (IACUC). Two days prior to the first magnetic resonance imaging (MRI) scan; surgical intervention in right renal artery was performed in all the animals to create hypoxia induced renal fibrosis. The MRI scans were repeated at an interval of approximately one month. During the imaging session, the rats were sedated and kept in head-first supine position. MRI imaging: The MRI diffusion pulse sequence was a single-shot spin-echo echo-planar imaging (SS-SE-EPI) sequence with multiple diffusion-weighting b-values (i.e. 3 shells with b-values of 150, 300 and 450 s/mm2) and multiple diffusion-weighting directions at each shell (i.e., 10, 19 and 30, respectively). Diffusion directions in each shell and in the projected sphere with all directions (i.e., total 59) were optimized for uniform diffusion sampling in the spherical space5. The repetition time (TR) is 2200 ms and echo time (TE) is 73.6 ms. A total of four signal averages was performed. The imaging parameters were field-of-view (FOV) = 128 x 64 mm, matrix size = 128 x 64, isotropic voxel size of 1 mm3, and 20 oblique coronal slices. Image data processing: DTI derived parameters including axial diffusivity (Da), radial diffusivity (Dr), mean diffusivity (MD), and fractional anisotropy (FA) were computed6. The diffusion compartmental model originally proposed for the brain called neutrite orientation dispersion and density imaging (NODDI)4 was modified to fit the water diffusivities of kidneys. The NODDI model with Watson stick framework produces the volume fraction of stick like diffusion compartment that may explain the active diffusion (transport) of water in the interstitial space between renal tubules, ellipsoid like diffusion compartment that may explain diffusion inside renal tubule, and a fast isotropic diffusion to account for the pseudo-diffusion term relating to bulk vascular flow. The normalized diffusion intensity was fit with a non-linear mathematical model given by A = (1-Viso) (VicAic+(1-Vic) Aec) + VisoAiso ; where Vic and Viso are the volume fraction of active water transport and free diffusion compartments in the kidney, respectively. Aic, Aec and Aiso are the normalized diffusion signal contribution from stick, tubule and free diffusion compartments, respectively. In the raw DW data, the b-value=0 volume clearly shows three distinct layers in the rat kidney representing the inner medulla, outer medulla and cortex (Figure1). Non-overlapping ROI's were constructed from the b-value =0 images. Figure 1: The DTI and Diffusion compartmental modeling parameter for RAT Kidney 2 days after surgical intervention. The Cortex (C), the Outer Medulla (OM) and Inner Medulla (IM) are shown in raw b0 maps. The orientation of the images follows radiology convention. Results: On post-surgical day 2, the overall water diffusivity (i.e., mean diffusivity (MD)) decreased significantly in the outer medullae and inner medullae of the surgical kidneys (Figure 2 B green bars). In the compartmental model, the volume fraction of the stick (interstitial) diffusion compartment (Vic) in right outer and inner medulla was significantly increased compared to the left (Figure 2A blue bars), whereas the volume fraction of water diffusion inside the tubules (Vec = (1-Vic)) decreased significantly. In addition, isotropic free diffusion compartment (Viso) was significantly lower in the inner medullae of the right kidneys. The axial diffusivity (Da) that may describe the diffusion parallel to the tubules decreased significantly in outer and inter medullae of the right surgical kidneys (Figure 2 B blue bars). The radial diffusivity (Dr) that may describe the water diffusion perpendicularly to the renal tubules decreased significantly in only the outer medullae of the right kidneys (Figure 2B gray bars). While FA shows high value in the inner medullae for both left and right kidneys, no significant results were found between left and right kidneys and between two time points. Over the one-month period of time, right inner medullae continued the significant changes in the diffusivity measurements (Figure 2C and D, right groups), but the diffusivities remained similar in the outer medullae (Figure 2 C and D, middle groups). No significant findings were found in the renal cortices between the right and left kidneys on post-surgical day 2 (Figure 2 A and B). Interestingly, the right renal cortices did have significant increase in Vic and decreases in Da, Dr, and MD over the one-month time period (Figure 2 C and D). Figure 2: Diffusion Compartmental (Figure 2A) and DTI (Figure 2B) parameters for Right Cortex (RC) and Left Cortex (LC), Right Outer Medulla (ROM) and Left Outer Medulla (LOM) and Right Inner Medulla (RIM) and Left Inner Medulla (LIM) on post-surgical day 2. (Figure 2C) Is the time series study of diffusion compartmental parameters and (Figure 2D) for DTI parameters for the right kidneys at post-surgical day 2 and 30, respectively. The bars represent diffusion measurements of all four rats. The overhead connecting lines represent significant statistical student t-test with p-value < 0.01. Discussions and Conclusion: The DTI and NODDI analogous diffusion compartment derived parameters are sensitive to the micro-structural changes in kidneys after surgical hypoxia intervention. The outer and inner medullae appear most sensitive to the surgical hypoxia intervention as early as post-surgical day 2. The preliminary result suggests that water diffusion decreases due to renal fibrosis, and more so inside the Henle tubules. In post-surgical day 30, renal cortices start to show changes in water diffusivities while inner medullae continue pathological changes. The NODDI compartmental model shows promising preliminary results in revealing renal microenvironments under the influences of hypoxia induced renal fibrosis. Further study is required to optimize and validate the model

Redesigning Primary Care Processes to Improve the Offering of Mammography. The use of Clinic Protocols by Nonphysicians.

OBJECTIVE: To develop, within the framework of continuous quality improvement, new processes for offering mammography and determine whether protocols executed completely by nonphysicians would increase mammography utilization. DESIGN: A prospective follow-up study with patients from an intervention clinic and two control clinics. SETTING: Three general internal medicine clinics in a large, urban teaching hospital in Detroit, Michigan. PATIENTS/PARTICIPANTS: A total of 5,934 women, aged 40 through 75 years, making 16,546 visits to one of the clinics during the study period (September 1, 1992, through November 31, 1993). INTERVENTION: Medical assistants and licensed practical nurses in the intervention clinic were trained to identify women due for screening mammography, and to directly offer and order a mammogram if patients agreed. MEASUREMENTS AND MAIN RESULTS: Patients were considered up-to-date with screening if they had a mammogram within 1 year (if age 50-75) or 2 years (if age 40-49) prior to the visit or a mammogram within 60 days after the visit. The proportion of visits each month in which a woman was up-to-date with mammography was calculated using computerized billing records. Prior to the intervention, the proportion of visits in which women were up-to-date was 68% (95% confidence interval [CI] 63%, 73%) in the intervention clinic and 66% (95% CI 61%, 71%) in each of the control clinics. At the end of the evaluation, there was an absolute increase of 9% (95% CI 2%, 16%) in the intervention clinic, and a difference of 1% (95% CI -5%, 7%) in one of the control clinics and -2% (95% CI -3%, 5%) in the other. In the intervention clinic, the proportion of visits in which women were up-to-date with mammography increased over time and was consistent with a linear trend (p = .004). CONCLUSIONS: Redesigning clinic processes to make offering of mammography by medical assistants and licensed practical nurses a routine part of the clinic encounter can lead to mammography rates that are superior to those seen in physicians\u27 usual practice, even when screening levels are already fairly high. Physicians need not be considered the sole, or even the primary, member of the health care team who can effectively deliver some preventive health measures

Surgical treatment of prosthetic valve endocarditis

AbstractFrom 1975 through 1992, we reoperated on 146 patients for the treatment of prosthetic valve endocarditis. Prosthetic valve endocarditis was considered to be early (<1 year after operation) in 46 cases and active in 103 cases. The extent of the infection was prosthesis only in 66 patients, anulus in 46, and cardiac invasion in 34. Surgical techniques evolved in the direction of increasingly radical débridement of infected tissue and reconstruction with biologic materials. All patients were treated with prolonged postoperative antibiotic therapy. There were 19 (13%) in-hospital deaths. Univariate analyses demonstrated trends toward increasing risk for patients with active endocarditis and extension of infection beyond the prosthesis; however, the only variables with a significant (p < 0.05) association with increased in-hospital mortality confirmed with multivariate testing were impaired left ventricular function, preoperative heart block, coronary artery disease, and culture of organisms from the surgical specimen. During the study period, mortality decreased from 20% (1975 to 1984) to 10% (1984 to 1992). For hospital survivors the mean length of stay was 25 days. Follow-up (mean interval 62 months) documented a late survival of 82% at 5 postoperative years and 60% at 10 years. Older age was the only factor associated (p = 0.006) with late death. Nineteen patients needed at least one further operation; reoperation-free survival was 75% at 5 and 50% at 10 postoperative years. Fever in the immediate preoperative period was the only factor associated with decreased late reoperation-free survival (p = 0.032). Prosthetic valve endocarditis remains a serious complication of valve replacement, but the in-hospital mortality of reoperations for prosthetic valve endocarditis has declined. With extensive débridement of infected tissue and postoperative antibiotic therapy, the extent and activity of prosthetic valve endocarditis does not appear to have a major impact on late outcome, and the majority of patients with this complication survive for 10 years after the operation. (J THORAC CARDIOVASC SURG 1996;111:198-210

Development of Hydrocephalus in Mice Expressing the Gi-Coupled GPCR Ro1 RASSL Receptor in Astrocytes

We developed a transgenic mouse line that expresses the

Assessment of the Draft AIAA S-119 Flight Dynamic Model Exchange Standard

An assessment of a draft AIAA standard for flight dynamics model exchange, ANSI/AIAA S-119-2011, was conducted on behalf of NASA by a team from the NASA Engineering and Safety Center. The assessment included adding the capability of importing standard models into real-time simulation facilities at several NASA Centers as well as into analysis simulation tools. All participants were successful at importing two example models into their respective simulation frameworks by using existing software libraries or by writing new import tools. Deficiencies in the libraries and format documentation were identified and fixed; suggestions for improvements to the standard were provided to the AIAA. An innovative tool to generate C code directly from such a model was developed. Performance of the software libraries compared favorably with compiled code. As a result of this assessment, several NASA Centers can now import standard models directly into their simulations. NASA is considering adopting the now-published S-119 standard as an internal recommended practice