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Background: The current social and legal landscape is likely to foster the medicinal and recreational use of cannabis. Synthetic cannabinoid use is associated with acute kidney injury (AKI) in case reports; however, the association between natural cannabis use and AKI risk in patients with advanced chronic kidney disease (CKD) is unknown. Materials and Methods: From a nationally representative cohort of 102,477 U.S. veterans transitioning to dialysis between 2007 and 2015, we identified 2215 patients with advanced CKD who had undergone urine toxicology (UTOX) tests within a year before dialysis initiation and had inpatient serial serum creatinine levels measured within 7 days after their UTOX test. The exposure of interest was cannabis use compared with no use as ascertained by the UTOX test. We examined the association of this exposure with AKI using logistic regression and inverse probability of treatment weighting with extensive adjustment for potential confounders. Results: The mean age of the overall cohort was 61 years; 97% were males, 51% were African Americans, 97% had hypertension, 76% had hyperlipidemia, and 75% were diabetic. AKI occurred in 56% of the cohort, and in multivariable-adjusted analysis, cannabis use (when compared with no substance use) was not associated with significantly higher odds of AKI (odds ratio 0.85, 95% confidence interval 0.38-1.87; p=0.7). These results were robust to various sensitivity analyses. Conclusions: In this observational study examining patients with advanced CKD, cannabis use was not associated with AKI risk. Additional studies are needed to characterize the impact of cannabis use on risk of kidney disease and injury.

Background: Obesity is associated with dysregulated metabolism and low-grade chronic inflammation in adipose tissue (AT). Immune cells, including macrophages, T cells, and neutrophils, infiltrate the AT and secrete proinflammatory cytokines to exacerbate the AT inflammation. RNA-Seq analysis of AT immune cells isolated from mice fed a high-fat diet (HFD) versus normal fat diet (ND) identified a panel of genes that were markedly downregulated, including sialic acid-binding Ig-like lectin E (siglec-E), in HFD compared to ND mice. Methods: A series of experiments in wild-type (WT) and siglec-E knockout (siglec-E KO) mice was designed to investigate the effect of HFD on the functional role of siglec-E in the regulation of AT inflammation and adipogenesis. We analyzed the changes in immune phenotypes, inflammatory response, adipogenesis, and levels of cytokines and chemokines after HFD and ND feeding. Results: HFD consumption significantly increased the body weight and blood glucose levels in siglec-E KO mice relative to those of WT mice. This was associated with an increased infiltration of macrophages, CXCR3 expressing CD8 T cells, and monocytic myeloid-derived suppressor cells (M-MDSCs) with a concomitant decrease in numbers of dendritic cells (DCs), in the AT of siglec-E KO fed HFD versus the WT HFD counterparts. The HFD-fed siglec-E KO mice also exhibited elevated expression of intracellular Akt and TNF receptor-associated factor 3 (TRAF3) signaling, inducing C/EBPα, FASN, PPARγ, and resistin in suprascapular AT compared to WT HFD-fed mice. Taken together, these results suggest that a genetic deficiency of siglec-E plays a key role in inducing AT inflammation by differentially altering M-MDSCs and CD8+CXCR3+ T cell function and adipogenesis by TRAF3 and Akt signaling in AT. Conclusion: Our findings strongly suggest that modulation of siglec-E pathways might have a protective effect at least in part against AT inflammation and metabolic disorders. [ABSTRACT FROM AUTHOR]

Studies have found that blood flow to the renal medulla is an important determinant of pressure-natriuresis and the long-term regulation of arterial pressure. First, a brief review of methods developed enabling the study of the medullary circulation is presented. Second, studies performed in rats are presented showing medullary blood flow plays a vital role in the pressure-natriuresis relationship and thereby in hypertension. Third, it is shown that chronic reduction of medullary blood flow results in hypertension and that enhancement of medullary blood flow reduces hypertension hereditary models of both salt-sensitive rats and salt-resistant forms of hypertension. The key role that medullary nitric oxide production plays in protecting this region from ischemic injury associated with circulating vasoconstrictor agents and reactive oxygen species is presented. The studies cited are largely the work of my students, research fellows, and colleagues with whom I have performed these studies dating from the late 1980s to more recent years. [ABSTRACT FROM AUTHOR]

Clinical and genetic studies strongly support a significant connection between nonalcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD) and identify ASCVD as the primary cause of death in NAFLD patients. Understanding the molecular factors and mechanisms regulating these diseases is critical for developing novel therapies that target them simultaneously. Our preliminary immunoblotting experiments demonstrated elevated expression of nidogen 2 (NID2), a basement membrane glycoprotein, in human atherosclerotic vascular tissues and murine steatotic livers. Therefore, we investigated the role of NID2 in regulating hepatosteatosis and atherosclerosis utilizing Western diet-fed Apoe−/− mice with/without NID2 overexpression. Quantitative real-time PCR confirmed increased NID2 mRNA expression in multiple organs (liver, heart, kidney, and adipose) of NID2-overexpressing mice. Male mice with NID2 overexpression exhibited higher liver and epididymal white adipose tissue mass, increased hepatic lipid accumulation, and fibrosis. Additionally, these mice developed larger atherosclerotic lesions in the whole aortas and aortic roots, with increased necrotic core formation. Mechanistic studies showed reduced AMPK activation in the livers of NID2-overexpressing mice compared with controls, without any effects on hepatic inflammation. In conclusion, these findings suggest that NID2 plays a deleterious role in both hepatosteatosis and atherosclerosis, making it a potential therapeutic target for these conditions. [ABSTRACT FROM AUTHOR]

The lymphatic network is pivotal for various physiological functions in the human body. Accumulated evidence supports the role of therapeutic lymphangiogenesis in the treatment of several pathologies. Endogenous gasotransmitter, hydrogen sulfide (H2S) has been extensively studied for its potential as a pro-angiogenic factor and vascular function modulator. However, the role of H2S in governing lymphatic vessel formation, and underlying molecular mechanisms are understudied. The present study was designed to investigate the effects of H2S donor sodium hydrogen sulfide (NaHS) on lymphatic vascularization and pro-angiogenic signaling pathways using both in vitro and in vivo approaches. In vitro dose-response experiments showed increased proliferation and tube formation by NaHS-treated human lymphatic endothelial cells (LECs) compared with control cells. Immunoblotting performed with LEC lysates prepared after time-course NaHS treatment demonstrated increased activation of ERK1/2, AKT and eNOS after 20 min of NaHS stimulation. Further, NaHS treatment induced nitric oxide production, reduced reactive oxygen species generation, and promoted cell cycle in LECs. Additional cell cycle analysis showed that NaHS treatment abrogates oxidized LDL-induced cell cycle arrest in LECs. The results of in vivo Matrigel plug assay revealed increased lymphatic vessel density in Matrigel plugs containing NaHS compared with control plugs, however, no significant differences in angiogenesis and immune cell infiltration were observed. Collectively, these findings suggest that H2S donor NaHS promotes lymphatic vessel formation both in vitro and in vivo and may be utilized to promote reparative lymphangiogenesis to alleviate lymphatic dysfunction-related disorders. [ABSTRACT FROM AUTHOR]

Tubular epithelial cell fate following exposure to various types of injurious stimuli can be decided at distinct cell cycle checkpoints. One such checkpoint occurs during mitosis, known as the spindle assembly checkpoint, and is tightly regulated through the actions of cell division cycle protein 20 (CDC20). Due to our paucity of knowledge about the role of CDC20 in the kidney, the present study was designed to investigate the expression levels and distribution of CDC20 within the kidney and how pharmacological inhibition of CDC20 function affects kidney recovery using various rodent models of kidney injury. CDC20 is normally detected in distal tubules, but upon injury by either cisplatin administration or ureter obstruction, CDC20 accumulation is considerably elevated. Blockade of CDC20 activity using a selective pharmacological inhibitor, Apcin, lowered serum creatinine, tubular damage, and DNA injury following acute kidney injury compared with vehicle-treated mice. In unilateral ureteral obstruction, Apcin reduced tissue kidney injury molecule-1 levels, sirius red staining, and tubulointerstitial α-smooth muscle actin staining in the tissue. The findings in the present study demonstrated that elevations in CDC20 levels in the kidney are associated with kidney injury and that inhibition of CDC20 can alleviate and reverse some of the pathological effects on the architecture and function of kidney. NEW & NOTEWORTHY To our knowledge, this is the first study to characterize the expression and localization of cell division cycle 20 protein (CDC20) in normal and acute, and chronically injured kidneys. Tubular epithelial cell damage was markedly reduced through the administration of a selective inhibitor of CDC20, Apcin. This study provides new evidence that CDC20 can be induced in damaged kidney cells and negatively impact the recovery of the kidney following acute kidney injury. [ABSTRACT FROM AUTHOR]

Individuals with sickle cell disease (SCD) are at greater risk of rhabdomyolysis, a potentially lifethreatening condition resulting from the breakdown of skeletal muscle fibers. Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis. Chronic kidney and cardiovascular disease, which account for SCD mortality, are long-term consequences of AKI. Although SCD elevates the risks of rhabdomyolysis-induced sudden death, the mechanisms that underlie rhabdomyolysis-induced AKI in SCD are unclear. In the present study, we show that, unlike their control non-sickling (AA) counterparts, transgenic homozygous SCD (SS; Townes model) mice exhibited 100% mortality 8-24 h after intramuscular glycerol injection. Five hours after glycerol injection, SS mice showed a more significant increase in myoglobinuria and plasma creatine kinase levels than AA mice. Basal plasma heme and kidney tissue iron levels were significantly higher in SS than in AA mice. In contrast to AA, glycerol-induced rhabdomyolysis aggravated these parameters in SS mice. Rhabdomyolysis also amplified oxidative stress in SS compared to AA mice. Glycerol-treated SS mice exhibited worse renal function, exemplified by a reduction in GFR with a corresponding increase in plasma and urinary biomarkers of early AKI and renal tubular damage. The free radical scavenger and Fenton chemistry inhibitor, TEMPOL, ameliorated rhabdomyolysis-induced AKI in the SS mice. These findings demonstrate that oxidative stress driven by renal iron accumulation amplifies rhabdomyolysis-induced AKI in SCD mice. [ABSTRACT FROM AUTHOR]

20-Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE) and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK~ renal epithelial cells. 20-HETE (20 [micro]M) increased phosphorylation of Raf-1 (2.5 [+ or -] 0.2-fold), MEK 1/2 (6.3 [+ or -] 1.6-fold), and ERKI/2 (5.8 [+ or -] 0.3-fold) compared with vehicle-treated cells. Similarly, the 20-HETE analogs also strongly activated ERK1/2 in a Raf-1- and MEK 1/2-dependent manner. Moreover, 5,14-20-HEDE increased Akt phosphorylation by 2.2 [+ or -] 0.3-fold. 20-HETE and 5,14-20-HEDE also promoted activation (Y1086) of epidermal growth factor receptor (EGFR; Y1086) by 1.9 [+ or -] 0.2- and 2.5 [+ or -] 0.2-fold, respectively. These effects were completely blocked by the EGFR inhibitor EKB-569 (0.1 [micro]M). Moreover, EKB-569 (0.1 [micro]M), as well as a c-Src inhibitor, SKI-606 (0.05 [micro]M), completely abolished the 20-HETE-mediated activation of the Raf/MEK/ERK and PI3K-Akt pathways. Blockade of PKC with bisindolylmaleimide I had no effect on 20-HETE-induced ERK1/2 activation. This study demonstrated that 20-HETE activated the Raf/ MEK/ERK and Akt pathways in renal epithelial cells secondary to the activation of c-Src and EGFR. epithelial cell proliferation; epidermal growth factor receptor; cell signaling

20-Hydroxyeicosatetraenoic acid (20-HETE) has been implicated as a potential mediator in epithelial cell proliferation and cyst formation in polycystic kidney disease (PKD). In the present study, we studied the effects of chronic blockade of 20-HETE synthesis in an orthologous rodent model of autosomal recessive polycystic kidney disease (ARPKD), the PCK rat. RT-PCR analysis indicated that the expression of CYP4A1, CYP4A2, CYP4A3, and CYP4A8 mRNA was increased two- to fourfold in cystic PCK compared with noncystic Sprague-Dawley rat kidneys. Daily administration of a 20-HETE synthesis inhibitor, HET-0016 (10 mg x [kg.sup.-1] x [day.sup.-1] ip) for 4-7 wk significantly reduced kidney size by 24% from 4.95 [+ or -] 0.19 g in vehicle-treated PCK rats to 3.76 [+ or -] 0.15 g (n = 4). Collecting tubule morphometric cystic indices were reduced in HET-0016-treated PCK rats (2.1 [+ or -] 0.2; n = 4) compared with vehicle-treated PCK rats (4.4 [+ or -] 0.1; n = 4). The cellular mechanism by which 20-HETE may play a role in cyst formation has not been well characterized, but there was a significantly lower (P < 0.05) level of intracellular cAMP and decreased phosphorylation (activation) of ERK1/2 protein in PCK rat kidneys (n = 3) treated with HET-0016 . These studies indicate a potential role of 20-HETE in cyst formation in the orthologous rodent PCK model of ARPKD. cytochrome P-450; HET-0016; epithelial cell proliferation; polycystic kidney rat; pck; autosomal recessive polycystic kidney mouse

One means of designing reduced vibration mechanisms is to ensure that the mechanism's natural frequency be sufficiently greater than the driving frequencies of the actuators. In this paper we consider the problem of determining a mechanism's mass, inertial, and joint stiffness parameters so as to maximize the lowest natural frequency of the mechanism. We show that this leads to a convex programming problem, which is characterized by a global optima that can be found with efficient interior point algorithms. Several case studies involving open and closed chain mechanisms demonstrate the viability of the design methodology. [DOI: 10.1115/1.3013846] Keywords: mechanism design, convex programming, vibration, parallel mechanism

Recent studies have shown that the perception of natural movements--in the sense of being "humanlike"--depends on both joint and task space characteristics of the movement. This paper proposes a movement generation framework that merges two established techniques from gesture recognition and motion generation--hidden Markov models (HMMs) and principal components--into an efficient and reliable means of generating natural movements, which uniformly considers joint and task space characteristics. Given human motion data that are classified into several movement categories, for each category, the principal components extracted from the joint trajectories are used as basis elements. An HMM is, in turn, designed and trained for each movement class using the human task space motion data. Natural movements are generated as the optimal linear combination of principal components, which yields the highest probability for the trained HMM. Experimental case studies with a prototype humanoid robot demonstrate the various advantages of our proposed framework. Index Terms--Hidden Markov model (HMM), movement primitive, natural movement, principal component.

We present a principal component-based method for generating, in real time, fast robot motions that minimize power consumption. Given a dynamic model of a robot, a sufficiently large set of torque-minimum motions are first obtained for pre-selected initial and final positions that also achieve minimum time while avoiding actuator saturation. These motions are then clustered according to the trajectory endpoints and shape. A principal component analysis is performed for each motion cluster, and the dominant principal components are used as basis functions in a linear interpolation scheme for generating fast, torque-efficient motions between arbitrary initial and final positions. Results obtained for both a six-axis industrial manipulator and a wheeled mobile robot demonstrate that nearly optimal motions can be obtained in real-time using this scheme. Index Terms--Principal component analysis (PCA), robot motion generation.

20-HETE, a metabolite of arachidonic acid, has been implicated as a mediator of free radical formation and tissue death following ischemia-reperfusion (IR) injury in the brain and heart. The present study examined the role of this pathway in a simulated IR renal injury model in vitro. Modified self-inactivating lentiviral vectors were generated to stably overexpress murine Cyp4a12 following transduction into LLC-[PK.sub.1] cells (LLC-Cyp4a12). We compared the survival of control and transduced LLC-[PK.sub.1] cells following 4 h of ATP depletion and 2 h of recovery in serum-free medium. ATP depletion-recovery of LLC-Cyp4a12 cells resulted in a significantly higher LDH release (P < 0.05) compared with LLC-enhanced green fluorescent protein (EGFP) cells. Treatment with the SOD mimetic MnTMPyP (100 [micro]M) resulted in decreased cytotoxicity in LLC-Cyp4a12 cells. The selective 20-HETE inhibitor HET-0016 (10 [micro]M) also inhibited cytotoxicity significantly (P < 0.05) in LLC-Cyp4a12 cells. Dihydroethidium fluorescence showed that superoxide levels were increased to the same degree in LLC-EGFP and LLC-Cyp4a12 cells after ATP depletion-recovery compared with control cells and that this increase was inhibited by MnTMPyP. There was a significant increase (P < 0.05) of caspase-3 cleavage, an effector protease of the apoptotic pathway, in the LLC-Cyp4a12 vs. LLC-EGFP cells (P < 0.05). This was abolished in the presence of HET-0016 (P < 0.05) or MnTMPyP (P < 0.01). These results demonstrate that 20-HETE over-expression can significantly exacerbate the cellular damage that is associated with renal IR injury and that the programmed cell death is mediated by activation of caspase-3 and is partially dependent on enhanced CYP4A generation of free radicals. apoptosis; cytochrome P-450 4A10; cytochrome P-450 4A12; LLC-[PK.sub.1]; lentiviral vectors; kidney; HET-0016; superoxide; [0.sub.2]

The article examines in detail the image registration problem, one of the fundamental steps in image fusion, which is the alignment of two or more sets of volumetric image data.