Citations

Obesity-metabolic disorders (ObM) often accompany renal artery stenosis (RAS). We hypothesized that the coexistence of ObM and RAS magnifies inflammation and microvascular remodeling in the stenotic kidney (STK) and aggravates renal scarring. Twenty-eight obesity-prone Ossabaw pigs were studied after 16 wk of a high-fat/high-fructose diet or standard chow including ObM-sham, ObM-RAS, Lean-RAS, or Lean-sham (normal control) groups. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed by multidetector computed tomography (CT), renal oxygenation and tubular transport capability by blood-oxygen-level-dependent MRI, and microcirculation by micro-CT for vessel density, and Western blotting for protein expressions of angiogenic factors (VEGF/FLK-1). Renal vein and inferior vena cava levels of inflammatory cytokines were measured to evaluate systemic and kidney inflammation. Macrophage (MØ) infiltration and subpopulations, fat deposition in the kidney, and inflammation in perirenal and abdominal fat were also examined. GFR and RBF were decreased in Lean-STK but relatively preserved in ObM-STK. However, ObM-STK showed impaired tubular transport function, suppressed microcirculation, and stimulated glomerulosclerosis. ObM diet interacted with RAS to blunt angiogenesis in the STK, facilitated the release of inflammatory cytokines, and led to greater oxidative stress than Lean-STK. The ObM diet also induced fat deposition in the kidney and infiltration of proinflammatory M1-MØ, as also in perirenal and abdominal fat. Coexistence of ObM and RAS amplifies renal inflammation, aggravates microvascular remodeling, and accelerates glomerulosclerosis. Increased adiposity and MØ-accentuated inflammation induced by an ObM diet may contribute to structural injury in the post-STK kidney.

Objective— Endothelial outgrowth cells (EOC) decrease inflammation and improve endothelial repair. Inflammation aggravates kidney injury in renal artery stenosis (RAS), and may account for its persistence upon revascularization. We hypothesized that EOC would decrease inflammatory (M1) macrophages and improve renal recovery in RAS. Approach and Results— Pigs with 10 weeks of RAS were studied 4 weeks after percutaneous transluminal renal angioplasty (PTRA+stenting) or sham, with or without adjunct intrarenal delivery of autologous EOC (10×10 6 ), and compared with similarly treated normal controls (n=7 each). Single-kidney function, microvascular and tissue remodeling, inflammation, oxidative stress, and fibrosis were evaluated. Four weeks after PTRA, EOC were engrafted in injected RAS-kidneys. Stenotic-kidney glomerular filtration rate was restored in RAS+EOC, RAS+PTRA, and RAS+PTRA+EOC pigs, whereas stenotic-kidney blood flow and angiogenesis were improved and fibrosis attenuated only in EOC-treated pigs. Furthermore, EOC increased cell proliferation and decreased the ratio of M1 (inflammatory)/M2 (reparative) macrophages, as well as circulating levels and stenotic-kidney release of inflammatory cytokines. Cultured-EOC released microvesicles in vitro and induced phenotypic switch (M1-to-M2) in cultured monocytes, which was inhibited by vascular endothelial growth factor blockade. Finally, a single intrarenal injection of rh-vascular endothelial growth factor (0.05 μg/kg) in 7 additional RAS pigs also restored M1/M2 ratio 4 weeks later. Conclusions— Intrarenal infusion of EOC after PTRA induced a vascular endothelial growth factor–mediated attenuation in macrophages inflammatory phenotype, preserved microvascular architecture and function, and decreased inflammation and fibrosis in the stenotic kidney, suggesting a novel mechanism and therapeutic potential for adjunctive EOC delivery in experimental RAS to improve PTRA outcomes.

Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.

KCNJ13 encodes Kir7.1, an inwardly rectifying K+ channel that is expressed in multiple ion-transporting epithelia. A mutation in KCNJ13 resulting in an arginine-to-tryptophan change at residue 162 (R162W) of Kir7.1 was associated with snowflake vitreoretinal degeneration, an inherited autosomal-dominant disease characterized by vitreous degeneration and mild retinal degeneration. We used the Xenopus laevis oocyte expression system to assess the functional properties of the R162W (mutant) Kir7.1 channel and determine how wild-type (WT) Kir7.1 is affected by the presence of the mutant subunit. Recordings obtained via the two-electrode voltage-clamp technique revealed that injection of oocytes with mutant Kir7.1 cRNA resulted in currents and cation selectivity that were indistinguishable from those in water-injected oocytes, suggesting that the mutant protein does not form functional channels in the plasma membrane. Coinjection of oocytes with equal amounts of mutant and WT Kir7.1 cRNAs resulted in inward K+ and Rb+ currents with amplitudes that were ∼17% of those in oocytes injected with WT Kir7.1 cRNA alone, demonstrating a dominant-negative effect of the mutant subunit. Similar to oocytes injected with WT Kir7.1 cRNA alone, coinjected oocytes exhibited inwardly rectifying Rb+ currents that were more than seven times larger than K+ currents, indicating that mutant subunits did not alter Kir7.1 channel selectivity. Immunostaining of Xenopus oocytes or Madin-Darby canine kidney cells expressing mutant or WT Kir7.1 demonstrated distribution of both proteins primarily in the plasma membrane. Our data suggest that the R162W mutation suppresses Kir7.1 channel activity, possibly by negatively impacting gating by membrane phosphadidylinositol 4,5-bisphosphate.

BackgroundOctogenarians (>80 years) have been underrepresented in clinical trials of cardiac resynchronization therapy (CRT).ObjectiveTo determine the benefit of CRT with or without a defibrillator in older elderly patients.MethodsWe retrospectively studied consecutive patients who received CRT at our institution from 2002 through 2008. New York Heart Association (NYHA) class and echocardiographic parameters were assessed before and after CRT. Thirty‐day complications after device implant were collected. Survival data were obtained from the national death and location database. Data were compared between those 80 years and younger and those older than 80 years.ResultsOf 728 patients identified, 90 (12.4%) were older than 80 years. After CRT, older and younger patients had similar improvements in NHYA class (P = 0.41), ejection fraction (P = 0.48), and mitral valve regurgitation (MR) severity (P = 0.42). In the older patients, defibrillator implantation was associated with comparable improvement in NYHA class, ejection fraction, and MR grade severity (P > 0.05), as in those without a defibrillator. Overall survival was worse in octogenarians than in the younger patients by Kaplan‐Meier estimates (P = 0.001). Multivariate analysis showed similar survival between the younger and older subjects (hazard ratio, 1.23; 95% confidence interval, 0.83–1.84; P = 0.31). The observed complication rate in all study subjects was 12.2%, with no difference between the two age groups.ConclusionOctogenarian patients who received CRT with or without a defibrillator for advanced heart failure had similar clinical benefits as younger patients. CRT should not be withheld from octogenarians meeting current selection guidelines.

ABSTRACT The diagnosis of coccidioidomycosis relies heavily on serologic test results in addition to clinical history, physical examination, and radiographic findings. Use of the enzyme immunoassay (EIA) has increased because it is rapidly performed and does not require referral to a reference laboratory, as do complement fixation and immunodiffusion tests. However, interpretation of immunoglobulin M (IgM) reactivity by EIA in the absence of immunoglobulin G (IgG) reactivity has been problematic. We conducted a retrospective medical record review of all patients with such IgM reactivity at our institution to identify situations where the finding was more likely to be clinically specific for coccidioidal infection. From 1 January 2004 through 31 December 2008, a total of 1,117 patients had positive EIA coccidioidal serology or EIA IgM-only reactivity; of these, 102 patients (9%) had EIA IgM-only reactivity. Among the 102 patients with EIA IgM-only reactivity, 60 were tested to evaluate symptomatic illness, 13 for follow-up of previously abnormal serology, and 29 for screening purposes. Of the 102 patients, 80 (78%) had positive serologic findings by other methods or had positive culture or histology. Fifty-four (90%) of the 60 patients whose serology was performed to evaluate symptomatic illness had coccidioidal infection, whereas 13 (45%) of 29 patients whose serology was performed for screening purposes had coccidioidal infection. Of the 102 patients with isolated IgM reactivity by EIA, 12 later seroconverted to IgG and IgM reactivity. The use of EIA for screening in 29 asymptomatic persons was associated with unconfirmable results in 13 (45%). Although the majority of patients in our study with isolated IgM reactivity by EIA had probable or confirmed coccidioidomycosis, this result must be interpreted with caution for asymptomatic patients.

AbstractObjectivesPatient perception of healthcare quality is of growing interest. It has been shown that patient satisfaction is associated with compliance with medical advice and clinical outcome. The 3‐fold purpose of this study was to identify which attributes of the patient–physician interaction most strongly correlated with patients' perceptions of provider quality of care, to identify key drivers that move patients' perception of overall provider quality from “very good” to “excellent,” and to identify features of the pain clinic experience that were most important to patients but were simultaneously perceived as lacking.MethodsRandomized patient satisfaction survey conducted via telephone approximately 3 weeks after the patient's pain clinic visit.ResultsA total of 999 patients participated in the survey over 5 years (estimated response rate 60.2%). Thoroughness, listening, and time spent with the provider were the 3 attributes most strongly associated with the patients' perceptions of provider quality of care, while thoroughness, listening, punctuality, and clear instructions were the drivers of “very good” vs. “excellent” patient perceived overall provider quality. Areas identified for clinic improvement include thoroughness, providing adequate explanations and instructions, and including patient preferences in decision making.ConclusionsThese results may guide pain clinic physicians as they seek to improve patient perceptions of their care and ultimately patient outcomes.