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Thursday, November 30, 2017
This Months Highlights
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Surprising Enhancement of Fibrosis by Tubule-Specific Deletion of the TGF-{beta} Receptor: A New Twist on an Old Paradigm
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Obesity-Related CKD: When Kidneys Get the Munchies
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Prescription Opioids for Pain Management in Patients on Dialysis
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Calcineurin Inhibitors in the Treatment of Lupus Nephritis: A Hare Versus Turtle Story?
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Developing Tools for Analysis of Renal Genomic Data: An Invitation to Participate
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Dialysate Potassium, Dialysate Magnesium, and Hemodialysis Risk
One of the fundamental goals of the hemodialysis prescription is to maintain serum potassium levels within a narrow normal range during both the intradialytic and interdialytic intervals. Considering the extraordinarily high rate of cardiovascular mortality in the hemodialysis population, clinicians are obligated to explore whether factors related to dialytic potassium removal can be modified to improve clinical outcomes. Observational studies and circumstantial evidence suggest that extreme concentrations of serum and dialysate potassium can trigger cardiac arrest. In this review, we provide an overview of factors affecting overall potassium balance and factors modulating potassium dialysate fluxes in dialysis, and we review data linking serum and dialysate potassium concentrations with arrhythmias, cardiovascular events, and mortality. We explore potential interactions between serum and dialysate magnesium levels and risks associated with dialysate potassium levels. Finally, we conclude with proposed dialytic and novel nondialytic approaches to optimize outcomes related to potassium homeostasis in patients on hemodialysis. Dialysis clinicians need to consider changes in the overall clinical scenario when choosing dialysate potassium concentrations, and an effective change in practice will require more frequent serum potassium monitoring and responsive dialysis care teams.
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New Ultrasound Techniques Promise Further Advances in AKI and CKD
AKI and CKD are important clinical problems because they affect many patients and the associated diagnostic and treatment paradigms are imperfect. Ultrasound is a cost-effective, noninvasive, and simple imaging modality that offers a multitude of means to improve the diagnosis, monitoring, and treatment of both AKI and CKD, especially considering recent advances in this technique. Ultrasound alone can attenuate AKI and prevent CKD by stimulating the splenic cholinergic anti-inflammatory pathway. Additionally, microbubble contrast agents are improving the sensitivity and specificity of ultrasound for diagnosing kidney disease, especially when these agents are conjugated to ligand-specific mAbs or peptides, which make the dynamic assessment of disease progression and response to treatment possible. More recently, drug-loaded microbubbles have been developed and the load release by ultrasound exposure has been shown to be a highly specific treatment modality, making the potential applications of ultrasound even more promising. This review focuses on the multiple strategies for using ultrasound with and without microbubble technology for enhancing our understanding of the pathophysiology of AKI and CKD.
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Assessing Microvascular Function in Humans from a Chronic Disease Perspective
Microvascular dysfunction (MVD) is considered a crucial pathway in the development and progression of cardiometabolic and renal disease and is associated with increased cardiovascular mortality. MVD often coexists with or even precedes macrovascular disease, possibly due to shared mechanisms of vascular damage, such as inflammatory processes and oxidative stress. One of the first events in MVD is endothelial dysfunction. With the use of different physiologic or pharmacologic stimuli, endothelium-dependent (micro)vascular reactivity can be studied. This reactivity depends on the balance between various mediators, including nitric oxide, endothelin, and prostanoids, among others. The measurement of microvascular (endothelial) function is important to understand the pathophysiologic mechanisms that contribute to MVD and the role of MVD in the development and progression of cardiometabolic/renal disease. Here, we review a selection of direct, noninvasive techniques for measuring human microcirculation, with a focus on methods, interpretation, and limitations from the perspective of chronic cardiometabolic and renal disease.
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BPI Fold-Containing Family A Member 2/Parotid Secretory Protein Is an Early Biomarker of AKI
AKI is a major cause of morbidity and mortality and an important contributor to the development and progression of CKD. Molecular biomarkers that improve the detection and prognostication of AKI are therefore required. We assessed the utility as such of BPI fold-containing family A member 2 (BPIFA2), also known as parotid secretory protein, which we identified via a multiplex quantitative proteomics screen of acutely injured murine kidneys. In physiologic conditions, BPIFA2 is expressed specifically in the parotid glands and is abundant in salivary secretions. In our study, AKI induced Bpifa2 expression in the kidneys of mice within 3 hours. Furthermore, we detected BPIFA2 protein in plasma and urine in these models as early as 6 hours after injury. However, renal injury did not induce the expression of Bpifa2 in mice lacking Nur77, an immediate early gene expressed in the kidneys during AKI. Notably, patients with AKI had higher blood and urine levels of BPIFA2 than did healthy individuals. Together, our results reveal that BPIFA2 is a potential early biomarker of AKI.
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Interference with Gs{alpha}-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage
Intracellular cAMP, the production of which is catalyzed by the α-subunit of the stimulatory G protein (Gsα), controls renin synthesis and release by juxtaglomerular (JG) cells of the kidney, but may also have relevance for the physiologic integrity of the kidney. To investigate this possibility, we generated mice with inducible knockout of Gsα in JG cells and monitored them for 6 months after induction at 6 weeks of age. The knockout mapped exclusively to the JG cells of the Gsα-deficient animals. Progressive albuminuria occurred in Gsα-deficient mice. Compared with controls expressing wild-type Gsα alleles, the Gsα-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gsα-deficient animals featured endothelial gaps, thickened basement membrane, and fibrin-like intraluminal deposits, which are classic signs of thrombotic microangiopathy. Additionally, we found endothelial damage in peritubular capillaries and vasa recta. Because deficiency of vascular endothelial growth factor (VEGF) results in thrombotic microangiopathy, we addressed the possibility that Gsα knockout may result in impaired VEGF production. We detected VEGF expression in JG cells of control mice, and cAMP agonists regulated VEGF expression in cultured renin-producing cells. Our data demonstrate that Gsα deficiency in JG cells of adult mice results in kidney injury, and suggest that JG cells are critically involved in the maintenance and protection of the renal microvascular endothelium.
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Blocking TGF-{beta} and {beta}-Catenin Epithelial Crosstalk Exacerbates CKD
The TGF-β and Wnt/β-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF-β has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF-β signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF-β type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF-β receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF-β receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/β-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF-β receptor impaired β-catenin activity in vitro and in vivo. Genetically restoring β-catenin activity in proximal tubules lacking the TGF-β receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF-β receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of β-catenin activity or an indirect effect of β-catenin interacting with other growth factors. In conclusion, blocking TGF-β and β-catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.
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Sexual Dimorphic Pattern of Renal Transporters and Electrolyte Homeostasis
Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did. Compared with the proximal tubule of males, the proximal tubule of females had greater phosphorylation of Na+/H+ exchanger isoform 3 (NHE3), distribution of NHE3 at the base of the microvilli, and less abundant expression of Na+/Pi cotransporter 2, claudin-2, and aquaporin 1. These changes associated with less bicarbonate reabsorption and higher lithium clearance in females. The distal nephrons of females had a higher abundance of total and phosphorylated Na+/Cl– cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na+ channel (ENaC) α and subunits, which associated with a lower baseline plasma K+ concentration. A K+-rich meal increased the urinary K+ concentration and decreased the level of renal phosphorylated NCC in females. Notably, we observed similar abundance profiles in female versus male C57BL/6 mice. These results define sexual dimorphic phenotypes along the nephron and suggest that lower proximal reabsorption in female rats expedites excretion of a saline load and enhances NCC and ENaC abundance and activation, which may facilitate K+ secretion and set plasma K+ at a lower level.
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Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD
Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.
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Renal Tubular Cell-Derived Extracellular Vesicles Accelerate the Recovery of Established Renal Ischemia Reperfusion Injury
Ischemic renal injury is a complex syndrome; multiple cellular abnormalities cause accelerating cycles of inflammation, cellular damage, and sustained local ischemia. There is no single therapy that effectively resolves the renal damage after ischemia. However, infusions of normal adult rat renal cells have been a successful therapy in several rat renal failure models. The sustained broad renal benefit achieved by relatively few donor cells led to the hypothesis that extracellular vesicles (EV, largely exosomes) derived from these cells are the therapeutic effector in situ. We now show that EV from adult rat renal tubular cells significantly improved renal function when administered intravenously 24 and 48 hours after renal ischemia in rats. Additionally, EV treatment significantly improved renal tubular damage, 4-hydroxynanoneal adduct formation, neutrophil infiltration, fibrosis, and microvascular pruning. EV therapy also markedly reduced the large renal transcriptome drift observed after ischemia. These data show the potential utility of EV to limit severe renal ischemic injury after the occurrence.
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Kindlin-2 Association with Rho GDP-Dissociation Inhibitor {alpha} Suppresses Rac1 Activation and Podocyte Injury
Alteration of podocyte behavior is critically involved in the development and progression of many forms of human glomerular diseases. The molecular mechanisms that control podocyte behavior, however, are not well understood. Here, we investigated the role of Kindlin-2, a component of cell-matrix adhesions, in podocyte behavior in vivo. Ablation of Kindlin-2 in podocytes resulted in alteration of actin cytoskeletal organization, reduction of the levels of slit diaphragm proteins, effacement of podocyte foot processes, and ultimately massive proteinuria and death due to kidney failure. Through proteomic analyses and in vitro coimmunoprecipitation experiments, we identified Rho GDP-dissociation inhibitor α (RhoGDIα) as a Kindlin-2–associated protein. Loss of Kindlin-2 in podocytes significantly reduced the expression of RhoGDIα and resulted in the dissociation of Rac1 from RhoGDIα, leading to Rac1 hyperactivation and increased motility of podocytes. Inhibition of Rac1 activation effectively suppressed podocyte motility and alleviated the podocyte defects and proteinuria induced by the loss of Kindlin-2 in vivo. Our results identify a novel Kindlin-2–RhoGDIα–Rac1 signaling axis that is critical for regulation of podocyte structure and function in vivo and provide evidence that it may serve as a useful target for therapeutic control of podocyte injury and associated glomerular diseases.
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Endothelial Epas1 Deficiency Is Sufficient To Promote Parietal Epithelial Cell Activation and FSGS in Experimental Hypertension
FSGS, the most common primary glomerular disorder causing ESRD, is a complex disease that is only partially understood. Progressive sclerosis is a hallmark of FSGS, and genetic tracing studies have shown that parietal epithelial cells participate in the formation of sclerotic lesions. The loss of podocytes triggers a focal activation of parietal epithelial cells, which subsequently form cellular adhesions with the capillary tuft. However, in the absence of intrinsic podocyte alterations, the origin of the pathogenic signal that triggers parietal epithelial cell recruitment remains elusive. In this study, investigation of the role of the endothelial PAS domain-containing protein 1 (EPAS1), a regulatory α subunit of the hypoxia-inducible factor complex, during angiotensin II–induced hypertensive nephropathy provided novel insights into FSGS pathogenesis in the absence of a primary podocyte abnormality. We infused angiotensin II into endothelial-selective Epas1 knockout mice and their littermate controls. Although the groups presented with identical high BP, endothelial-specific Epas1 gene deletion accentuated albuminuria with severe podocyte lesions and recruitment of pathogenic parietal glomerular epithelial cells. These lesions and dysfunction of the glomerular filtration barrier were associated with FSGS in endothelial Epas1-deficient mice only. These results indicate that endothelial EPAS1 has a global protective role during glomerular hypertensive injuries without influencing the hypertensive effect of angiotensin II. Furthermore, these findings provide proof of principle that endothelial-derived signaling can trigger FSGS and illustrate the potential importance of the EPAS1 endothelial transcription factor in secondary FSGS.
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Targeting Phospholipase D4 Attenuates Kidney Fibrosis
Phospholipase D4 (PLD4), a single-pass transmembrane glycoprotein, is among the most highly upregulated genes in murine kidneys subjected to chronic progressive fibrosis, but the function of PLD4 in this process is unknown. Here, we found PLD4 to be overexpressed in the proximal and distal tubular epithelial cells of murine and human kidneys after fibrosis. Genetic silencing of PLD4, either globally or conditionally in proximal tubular epithelial cells, protected mice from the development of fibrosis. Mechanistically, global knockout of PLD4 modulated innate and adaptive immune responses and attenuated the upregulation of the TGF-β signaling pathway and α1-antitrypsin protein (a serine protease inhibitor) expression and downregulation of neutrophil elastase (NE) expression induced by obstructive injury. In vitro, treatment with NE attenuated TGF-β–induced accumulation of fibrotic markers. Furthermore, therapeutic targeting of PLD4 using specific siRNA protected mice from folic acid–induced kidney fibrosis and inhibited the increase in TGF-β signaling, decrease in NE expression, and upregulation of mitogen-activated protein kinase signaling. Immunoprecipitation/mass spectrometry and coimmunoprecipitation experiments confirmed that PLD4 binds three proteins that interact with neurotrophic receptor tyrosine kinase 1, a receptor also known as TrkA that upregulates mitogen-activated protein kinase. PLD4 inhibition also prevented the folic acid–induced upregulation of this receptor in mouse kidneys. These results suggest inhibition of PLD4 as a novel therapeutic strategy to activate protease-mediated degradation of extracellular matrix and reverse fibrosis.
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Macrophage Migration Inhibitory Factor Limits Renal Inflammation and Fibrosis by Counteracting Tubular Cell Cycle Arrest
Renal fibrosis is a common underlying process of progressive kidney diseases. We investigated the role of macrophage migration inhibitory factor (MIF), a pleiotropic proinflammatory cytokine, in this process. In mice subjected to unilateral ureteral obstruction, genetic deletion or pharmacologic inhibition of MIF aggravated fibrosis and inflammation, whereas treatment with recombinant MIF was beneficial, even in established fibrosis. In two other models of progressive kidney disease, global Mif deletion or MIF inhibition also worsened fibrosis and inflammation and associated with worse kidney function. Renal MIF expression was reduced in tubular cells in fibrotic compared with healthy murine and human kidneys. Bone marrow chimeras showed that Mif expression in bone marrow-derived cells did not affect fibrosis and inflammation after UUO. However, Mif gene deletion restricted to renal tubular epithelial cells aggravated these effects. In LPS-stimulated tubular cell cultures, Mif deletion led to enhanced G2/M cell-cycle arrest and increased expression of the CDK inhibitor 1B (p27Kip1) and of proinflammatory and profibrotic mediators. Furthermore, MIF inhibition reduced tubular cell proliferation in vitro. In all three in vivo models, global Mif deletion or MIF inhibition caused similar effects and attenuated the expression of cyclin B1 in tubular cells. Mif deletion also resulted in reduced tubular cell apoptosis after UUO. Recombinant MIF exerted opposing effects on tubular cells in vitro and in vivo. Our data identify renal tubular MIF as an endogenous renoprotective factor in progressive kidney diseases, raising the possibility of pharmacologic intervention with MIF pathway agonists, which are in advanced preclinical development.
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Serum Iron Protects from Renal Postischemic Injury
Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients (n=169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury–associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF-B and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants.
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Targeting Anti-TGF-{beta} Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach
Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF-β. After systemic injection of the bispecific TGF-β + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF-β mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF-β mAb (1–10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF-β mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis.
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Variations in MicroRNA-25 Expression Influence the Severity of Diabetic Kidney Disease
Diabetic nephropathy is characterized by persistent albuminuria, progressive decline in GFR, and secondary hypertension. MicroRNAs are dysregulated in diabetic nephropathy, but identification of the specific microRNAs involved remains incomplete. Here, we show that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of microRNA-25 (miR-25) compared with those of their nondiabetic counterparts. Furthermore, treatment with high glucose decreased the expression of miR-25 in cultured kidney cells. In db/db mice, systemic administration of an miR-25 agomir repressed glomerular fibrosis and reduced high BP. Notably, knockdown of miR-25 in normal mice by systemic administration of an miR-25 antagomir resulted in increased proteinuria, extracellular matrix accumulation, podocyte foot process effacement, and hypertension with renin-angiotensin system activation. However, excessive miR-25 did not cause kidney dysfunction in wild-type mice. RNA sequencing showed the alteration of miR-25 target genes in antagomir-treated mice, including the Ras-related gene CDC42. In vitro, cotransfection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the CDC42 3' untranslated region. In conclusion, these results reveal a role for miR-25 in diabetic nephropathy and indicate a potential novel therapeutic target for this disease.
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C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients
Iron deficiency (ID) is independently associated with an increased risk of death in renal transplant recipients (RTRs). ID promotes production and cleavage of intact fibroblast growth factor 23 (iFGF23) into C-terminal fibroblast growth factor 23 (cFGF23), elevated levels of which are also prospectively associated with adverse outcomes. We hypothesized that in RTRs, the relationship between ID and mortality is mediated by FGF23. We measured plasma iFGF23 and cFGF23 levels in 700 stable RTRs at a median of 5.4 years after transplant. RTRs with ID had median (interquartile range) cFGF23 concentrations higher than those of RTRs without ID (223 [131–361] versus 124 [88–180] RU/ml; P<0.001), whereas iFGF23 concentrations were similar between groups. In multivariable-adjusted Cox regression analyses, ID associated with increased mortality (81 events; hazard ratio, 1.95; 95% confidence interval, 1.22 to 3.10; P<0.01). However, this association lost significance after additional adjustment for cFGF23 levels (hazard ratio, 1.45; 95% confidence interval, 0.87 to 2.51; P=0.15). In further mediation analysis, cFGF23 explained 46% of the association between ID and mortality, whereas iFGF23 did not mediate this association. In conclusion, we found that cFGF23 levels are increased in iron-deficient RTRs and that the underlying biologic process driving production and cleavage of iFGF23, or alternatively the increased level of cFGF23 fragments, probably is an important mediator of the association between ID and mortality. Our results underline the strong relationship between iron and FGF23 physiology, and provide a potential mechanism explaining the relationship between ID and adverse outcome in RTRs.
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Use and Outcomes of Kidneys from Donation after Circulatory Death Donors in the United States
Donation after circulatory death (DCD) donors are an important source of kidneys for transplantation, but DCD donor transplantation is less common in the United States than in other countries. In this study of national data obtained between 2008 and 2015, recovery of DCD kidneys varied substantially among the country’s 58 donor service areas, and 25% of DCD kidneys were recovered in only four donor service areas. Overall, 20% of recovered DCD kidneys were discarded, varying from 3% to 33% among donor service areas. Compared with kidneys from neurologically brain dead (NBD) donors, DCD kidneys had a higher adjusted odds ratio of discard that varied from 1.25 (95% confidence interval [95% CI], 1.16 to 1.34) in kidneys with total donor warm ischemic time (WIT) of 10–26 minutes to 2.67 (95% CI, 2.34 to 3.04) in kidneys with total donor WIT >48 minutes. Among the 12,831 DCD kidneys transplanted, kidneys with WIT≤48 minutes had survival similar to that of NBD kidneys. DCD kidneys with WIT>48 minutes had a higher risk of allograft failure (hazard ratio, 1.23; 95% CI, 1.07 to 1.41), but this risk was limited to kidneys with cold ischemia time (CIT) >12 hours. We conclude that donor service area–level variation in the recovery and discard of DCD kidneys is large. Additional national data collection is needed to understand the potential to increase DCD donor transplantation in the United States. Strategies to minimize cold ischemic injury may safely allow increased use of DCD kidneys with WIT>48 minutes.
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Opioid Prescription, Morbidity, and Mortality in United States Dialysis Patients
Aggressive pain treatment was advocated for ESRD patients, but new Centers for Disease Control and Prevention guidelines recommend cautious opioid prescription. Little is known regarding outcomes associated with ESRD opioid prescription. We assessed opioid prescriptions and associations between opioid prescription and dose and patient outcomes using 2006–2010 US Renal Data System information in patients on maintenance dialysis with Medicare Part A, B, and D coverage in each study year (n=671,281, of whom 271,285 were unique patients). Opioid prescription was confirmed from Part D prescription claims. In the 2010 prevalent cohort (n=153,758), we examined associations of opioid prescription with subsequent all-cause death, dialysis discontinuation, and hospitalization controlled for demographics, comorbidity, modality, and residence. Overall, >60% of dialysis patients had at least one opioid prescription every year. Approximately 20% of patients had a chronic (≥90-day supply) opioid prescription each year, in 2010 usually for hydrocodone, oxycodone, or tramadol. In the 2010 cohort, compared with patients without an opioid prescription, patients with short-term (1–89 days) and chronic opioid prescriptions had increased mortality, dialysis discontinuation, and hospitalization. All opioid drugs associated with mortality; most associated with worsened morbidity. Higher opioid doses correlated with death in a monotonically increasing fashion. We conclude that opioid drug prescription is associated with increased risk of death, dialysis discontinuation, and hospitalization in dialysis patients. Causal relationships cannot be inferred, and opioid prescription may be an illness marker. Efforts to treat pain effectively in patients on dialysis yet decrease opioid prescriptions and dose deserve consideration.
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Multitarget Therapy for Maintenance Treatment of Lupus Nephritis
Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2–3 mg/d; mycophenolate mofetil, 0.50–0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; P=0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; P<0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; P=0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.
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The Clinical and Economic Effect of Vascular Access Selection in Patients Initiating Hemodialysis with a Catheter
Patients in the United States frequently initiate hemodialysis with a central venous catheter (CVC) and subsequently undergo placement of a new arteriovenous fistula (AVF) or arteriovenous graft (AVG). Little is known about the clinical and economic effects of initial vascular access choice. We identified 479 patients starting hemodialysis with a CVC at a large medical center (during 2004–2012) who subsequently had an AVF (n=295) or AVG (n=105) placed or no arteriovenous access (CVC group, n=71). Compared with patients receiving an AVG, those receiving an AVF had more frequent surgical access procedures per year (1.01 [95% confidence interval, 0.95 to 1.08] versus 0.62 [95% confidence interval, 0.55 to 0.70]; P<0.001) but a similar frequency of percutaneous access procedures per year. Patients receiving an AVF had a higher median annual cost (interquartile range) of surgical access procedures than those receiving an AVG ($4857 [$2523–$8835] versus $2819 [$1411–$4274]; P<0.001), whereas the annual cost of percutaneous access procedures was similar in both groups. The AVF group had a higher median overall annual access-related cost than the AVG group ($10,642 [$5406–$19,878] versus $6810 [$3718–$13,651]; P=0.001) after controlling for patient age, sex, race, and diabetes. The CVC group had the highest median annual overall access-related cost ($28,709 [$11,793–$66,917]; P<0.001), largely attributable to the high frequency of hospitalizations due to catheter-related bacteremia. In conclusion, among patients initiating hemodialysis with a CVC, the annual cost of access-related procedures and complications is higher in patients who initially receive an AVF versus an AVG.
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Tubulointerstitial Nephritis with IgM-Positive Plasma Cells
Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3–-Cl– anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell–tubulointerstitial nephritis.
from Journal of the American Society of Nephrology current issue http://ift.tt/2BC751Z
Relationship of Kidney Injury Biomarkers with Long-Term Cardiovascular Outcomes after Cardiac Surgery
Clinical AKI, measured by serum creatinine elevation, is associated with long-term risks of adverse cardiovascular (CV) events and mortality in patients after cardiac surgery. To evaluate the relative contributions of urine kidney injury biomarkers and plasma cardiac injury biomarkers in adverse events, we conducted a multicenter prospective cohort study of 968 adults undergoing cardiac surgery. On postoperative days 1–3, we measured five urine biomarkers of kidney injury (IL-18, NGAL, KIM-1, L-FABP, and albumin) and five plasma biomarkers of cardiac injury (NT-proBNP, H-FABP, hs-cTnT, cTnI, and CK-MB). The primary outcome was a composite of long-term CV events or death, which was assessed via national health care databases. During a median 3.8 years of follow-up, 219 (22.6%) patients experienced the primary outcome (136 CV events and 83 additional deaths). Compared with patients without postsurgical AKI, patients who experienced AKI Network stage 2 or 3 had an adjusted hazard ratio for the primary composite outcome of 3.52 (95% confidence interval, 2.17 to 5.71). However, none of the five urinary kidney injury biomarkers were significantly associated with the primary outcome. In contrast, four out of five postoperative cardiac injury biomarkers (NT-proBNP, H-FABP, hs-cTnT, and cTnI) strongly associated with the primary outcome. Mediation analyses demonstrated that cardiac biomarkers explained 49% (95% confidence interval, 1% to 97%) of the association between AKI and the primary outcome. These results suggest that clinical AKI at the time of cardiac surgery is indicative of concurrent CV stress rather than an independent renal pathway for long-term adverse CV outcomes.
from Journal of the American Society of Nephrology current issue http://ift.tt/2kcvLKa
The Association of Sleep Duration and Quality with CKD Progression
Evidence suggests that sleep disorders are common in individuals with CKD, but the influence of sleep duration and quality on CKD progression is unknown. We examined the association of habitual sleep duration and quality with CKD progression in 431 Chronic Renal Insufficiency Cohort (CRIC) Study participants, of whom 48% were women and 50% had diabetes (mean age of 60 years old, mean eGFR =38 ml/min per 1.73 m2, and median urine protein-to-creatinine ratio [UPCR] =0.20 g/g). We assessed sleep duration and quality by 5–7 days of wrist actigraphy and self-report. Primary outcomes were incident ESRD, eGFR slope, log-transformed UPCR slope, and all-cause death. Participants slept an average of 6.5 hours per night; mean sleep fragmentation was 21%. Over a median follow-up of 5 years, we observed 70 ESRD events and 48 deaths. In adjusted analyses, greater sleep fragmentation associated with increased ESRD risk (hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.07 per 1% increase in fragmentation). In adjusted mixed effects regression models, shorter sleep duration (per hour less) and greater sleep fragmentation (per 1% more) each associated with greater eGFR decline (–1.12 and –0.18 ml/min per 1.73 m2 per year, respectively; P=0.02 and P<0.01, respectively) and greater log UPCR slope (0.06/yr and 0.01/yr, respectively; P=0.02 and P<0.001, respectively). Self-reported daytime sleepiness associated with increased risk for all-cause death (hazard ratio, 1.11; 95% confidence interval, 1.02 to 1.20 per one-point increase in the Epworth Sleepiness Scale score). These findings suggest that short and poor-quality sleep are unrecognized risk factors for CKD progression.
from Journal of the American Society of Nephrology current issue http://ift.tt/2BBbgLs
Without Obamacare Mandate, ‘You Open the Floodgates’ for Skimpy Health Plans
By REED ABELSON from NYT Health http://ift.tt/2Bz9WIN
FOX NEWS: UMass Amherst declares meningitis outbreak after 2 confirmed cases
UMass Amherst declares meningitis outbreak after 2 confirmed cases
A Massachusetts university has declared a meningitis outbreak after two students tested positive for the bacterial illness.
FOX NEWS: US says patient charity helped drugmakers, revokes approval
US says patient charity helped drugmakers, revokes approval
One of the largest U.S. patient assistance charities may close after the federal government revoked its authorization, citing findings that the group, mainly funded by pharmaceutical companies, enabled drugmakers to influence prescriptions.
FOX NEWS: Bodybuilding products sold online may be mislabeled or unsafe
Bodybuilding products sold online may be mislabeled or unsafe
Many bodybuilding products sold online are mislabeled and contain unapproved drugs and other ingredients that may not be safe, a new study suggests.
FOX NEWS: Forecast predicts over half of US children will be obese by age 35
Forecast predicts over half of US children will be obese by age 35
Nearly three in five children in the U.S. today are destined to be obese when they reach their 35th birthday, according to a new projection.
FOX NEWS: Weirdest health stories of 2017
Weirdest health stories of 2017
From hospital mix-ups to cases that left doctors baffled, 2017 had it's fair share of wacky medical drama.
FOX NEWS: Man claims he contracted eye-eating parasite from amusement park water ride
Man claims he contracted eye-eating parasite from amusement park water ride
A Pennsylvania man and his wife have filed a lawsuit against an amusement park over claims that he contracted an eye-eating parasite after going on one of the water rides.
FOX NEWS: Wackiest health stories of 2017
Wackiest health stories of 2017
From hospital mix-ups to cases that left doctors baffled, 2017 had it's fair share of wacky medical drama.
FOX NEWS: Inspiration behind 'ice bucket challenge' dead at 46
Inspiration behind 'ice bucket challenge' dead at 46
The man who inspired the “ALS Ice Bucket Challenge” died on Saturday after a 14-year long battle with the disease.
Wednesday, November 29, 2017
FOX NEWS: Woman photographed breast-feeding son at Disneyland goes viral
Woman photographed breast-feeding son at Disneyland goes viral
A photo of a California woman breastfeeding her child at Disneyland has gone viral and received some support but also some negative reactions.
FOX NEWS: Dog bone treats could be deadly for pets, FDA warns
Dog bone treats could be deadly for pets, FDA warns
Store-bought bone treats may be a dog’s favorite snack, but they could make pets seriously ill and even result in death, the Food and Drug Administration has warned.
FOX NEWS: CDC: HIV diagnoses improving, but progress varies
CDC: HIV diagnoses improving, but progress varies
Delays in the time between becoming infected with HIV and getting a diagnosis are shortening, helped by efforts to increase testing for the virus that causes AIDS, U.S. health officials said.
FOX NEWS: Utah hepatitis A outbreak hits 95 cases
Utah hepatitis A outbreak hits 95 cases
The Utah Department of Health is grappling with a growing hepatitis A outbreak that has reached 95 cases, with over 60 percent of patients requiring hospitalization.
FOX NEWS: Judge: Doctor who doesn't use computer can't regain license
Judge: Doctor who doesn't use computer can't regain license
A New Hampshire judge has denied an 84-year-old doctor's request to regain her license to practice, which she had surrendered partly over her inability to use a computer.
FOX NEWS: Radio contest helps 11-year-old battling brain cancer get Christmas tree
Radio contest helps 11-year-old battling brain cancer get Christmas tree
A local radio contest is helping to bring cheer to one Indiana family whose 11-year-old sibling is battling stage four brain cancer.
Tuesday, November 28, 2017
FOX NEWS: Study finds commonality in 61 percent of opioid deaths
Study finds commonality in 61 percent of opioid deaths
As the staggering toll—in terms of bodies, emotions, money, and our life expectancy—of the opioid epidemic comes into sharper focus, the idea of those who are most at risk is crystallizing, too, thanks to research out of Columbia University Medical Center.
FOX NEWS: Mom walks out of hospital days after breaking vertebrae in freak gymnastics accident
Mom walks out of hospital days after breaking vertebrae in freak gymnastics accident
A Utah mother said doctors told her family members there was a 96 percent chance she would be a quadriplegic or dead after they discovered her C-1 vertebrae fractured in four separate places.
FOX NEWS: Massachusetts baby gets life-saving liver transplant from New Hampshire police officer
Massachusetts baby gets life-saving liver transplant from New Hampshire police officer
Sloane St. James’ parents said they noticed something was amiss with their baby girl when she was around 4 months old.
FOX NEWS: CDC urges consumers who drank raw milk product to seek treatment
CDC urges consumers who drank raw milk product to seek treatment
Health officials are urging anyone who has consumed raw milk within the last six months to seek medical attention after a New Jersey woman was infected with a rare bacteria earlier this year.
FOX NEWS: Confused VA failed to report potentially dangerous doctors, may have put lives at risk, watchdog says
Confused VA failed to report potentially dangerous doctors, may have put lives at risk, watchdog says
The Department of Veterans Affairs is under fire for possibly putting lives at risk after a government watchdog report revealed that it failed to report 90 percent of potentially dangerous medical providers in recent years.
FOX NEWS: Tens of thousands dying from $30B fake drugs trade, WHO says
Tens of thousands dying from $30B fake drugs trade, WHO says
One in 10 drugs sold in developing countries is fake or substandard, leading to tens of thousands of deaths, many of them of African children given ineffective treatments for pneumonia and malaria, health officials said on Tuesday.
Monday, November 27, 2017
FOX NEWS: Boy born without arms or legs walks for first time in viral video
Boy born without arms or legs walks for first time in viral video
“Cambden, I’m so proud of you buddy.”
Therapy for Sexual Misconduct? It’s Mostly Unproven
By BENEDICT CAREY from NYT Health http://ift.tt/2AeZHZQ
Gene Therapy Hits a Peculiar Roadblock: A Virus Shortage
By GINA KOLATA from NYT Health http://ift.tt/2i8bYuz
FOX NEWS: Disabled veteran helps deliver daughter on sidewalk
Disabled veteran helps deliver daughter on sidewalk
The birth of a baby is a momentous occasion for any family, but for one disabled veteran and his fiancé where and how their daughter was born has made it all the more special.
FOX NEWS: Patient undergoes emergency surgery after dentist drops metal file down throat
Patient undergoes emergency surgery after dentist drops metal file down throat
A grandfather has spoken of his horror after ending up in hospital to have a serrated metal file removed from his stomach following a routine dental procedure.
FOX NEWS: Man complaining of abdominal pain has 263 coins, 100 nails removed from stomach
Man complaining of abdominal pain has 263 coins, 100 nails removed from stomach
Surgeons treating a man with suspected food poisoning were stunned to discover 263 coins and 100 nails in his stomach.
FOX NEWS: Brain damage from football concussions varies by position and career duration
Brain damage from football concussions varies by position and career duration
Football players may experience different degrees of brain damage after concussions depending on what position they play and how long they stick with the sport, a small U.S. study suggests.
Sunday, November 26, 2017
As Health Care Changes, Insurers, Hospitals and Drugstores Team Up
By REED ABELSON from NYT Health http://ift.tt/2AAvgR6
FOX NEWS: Indiana ‘Night Nurse’ whose tweet about white women sparked investigation 'no longer' with hospital
Indiana ‘Night Nurse’ whose tweet about white women sparked investigation 'no longer' with hospital
A nurse at one of the largest hospital systems in the nation who sparked an internal investigation after posting a controversial tweet reportedly "is no longer an employee" at Indiana University Health.
FOX NEWS: Indiana ‘Night Nurse’ says white women raising sons who are ‘rapists’ and ‘killers,’ sparking probe
Indiana ‘Night Nurse’ says white women raising sons who are ‘rapists’ and ‘killers,’ sparking probe
A controversial tweet allegedly posted Friday by a nurse at one of the largest hospital systems in the nation has sparked an internal investigation.
Saturday, November 25, 2017
FOX NEWS: Couple gets wedding reception do-over after bride's health scare
Couple gets wedding reception do-over after bride's health scare
A New Jersey couple who had to leave their wedding reception early after the bride suffered an allergic reaction is getting a second celebration for free.
Friday, November 24, 2017
FOX NEWS: Why many pregnant women aren't screened for deadly skin cancers
Why many pregnant women aren't screened for deadly skin cancers
A new report finds that swaths of pregnant women are having to wait too long for treatment of deadly melanoma. The lag puts not just one, but two lives at risk.
Thursday, November 23, 2017
FOX NEWS: Abortion rates in US hit historic low, CDC report finds
Abortion rates in US hit historic low, CDC report finds
Abortion rates in the United States have fallen to a historic low, according to the latest data compiled by the Centers for Disease Control and Prevention.
FOX NEWS: Paramedics grant patient's last wish: one final beach day
Paramedics grant patient's last wish: one final beach day
A palliative care patient in Queensland, Australia, had a final wish: to see the ocean one more time before she died.
FOX NEWS: How to avoid listeria and other diseases while flying for the holidays
How to avoid listeria and other diseases while flying for the holidays
Close to 50 million Americans traveled for Thanksgiving last year. If you're on a plane for the holidays, here's some tips on how to avoid getting sick
Wednesday, November 22, 2017
Thanks a Lot! New Reasons Not to Eat Cookie Dough
By JAN HOFFMAN from NYT Health http://ift.tt/2jh2t8X
FOX NEWS: Toddler receives kidney transplant after initial procedure stalled over dad's probation violation, family says
Toddler receives kidney transplant after initial procedure stalled over dad's probation violation, family says
A toddler who was born without kidneys finally received a life-saving transplant on Wednesday, more than a month after his initial procedure was stalled when his father – a perfect match for him – violated his probation, the boy’s mother revealed.
Abnormal Proteins Discovered in Skin of Patients With Rare Brain Disease
By DENISE GRADY from NYT Health http://ift.tt/2zeNovo
FOX NEWS: Mom, boyfriend gave baby marijuana after she broke her leg, police say
Mom, boyfriend gave baby marijuana after she broke her leg, police say
Tessa Rose Murray and Nerrell McCoy of Muncie, Ind., were arrested Monday after they failed to seek treatment for their infant daughter’s broken leg and instead gave her marijuana to treat the pain.
FOX NEWS: Baby born 5 weeks early shares birthday with mom, grandma
Baby born 5 weeks early shares birthday with mom, grandma
A newborn’s Nov. 19 arrival marked a special date in his family’s calendar for a number of reasons, including that he now shares a birth with his mother and maternal grandmother.
FOX NEWS: Health company fires 69 employees over refusal to get flu shots, report says
Health company fires 69 employees over refusal to get flu shots, report says
A Minnesota-based health care company has fired 69 employees who failed to comply with its flu shot mandate by the Nov. 10 deadline.
Estradiol and Age-Related Bone Loss in Men
from Physiological Reviews current issue http://ift.tt/2zqNFPP
Endothelial Cell Metabolism
Endothelial cells (ECs) are more than inert blood vessel lining material. Instead, they are active players in the formation of new blood vessels (angiogenesis) both in health and (life-threatening) diseases. Recently, a new concept arose by which EC metabolism drives angiogenesis in parallel to well-established angiogenic growth factors (e.g., vascular endothelial growth factor). 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3-driven glycolysis generates energy to sustain competitive behavior of the ECs at the tip of a growing vessel sprout, whereas carnitine palmitoyltransferase 1a-controlled fatty acid oxidation regulates nucleotide synthesis and proliferation of ECs in the stalk of the sprout. To maintain vascular homeostasis, ECs rely on an intricate metabolic wiring characterized by intracellular compartmentalization, use metabolites for epigenetic regulation of EC subtype differentiation, crosstalk through metabolite release with other cell types, and exhibit EC subtype-specific metabolic traits. Importantly, maladaptation of EC metabolism contributes to vascular disorders, through EC dysfunction or excess angiogenesis, and presents new opportunities for anti-angiogenic strategies. Here we provide a comprehensive overview of established as well as newly uncovered aspects of EC metabolism.
from Physiological Reviews current issue http://ift.tt/2mPGtXP
Spaceflight-Induced Intracranial Hypertension and Visual Impairment: Pathophysiology and Countermeasures
Visual impairment intracranial pressure (VIIP) syndrome is considered an unexplained major risk for future long-duration spaceflight. NASA recently redefined this syndrome as Spaceflight-Associated Neuro-ocular Syndrome (SANS). Evidence thus reviewed supports that chronic, mildly elevated intracranial pressure (ICP) in space (as opposed to more variable ICP with posture and activity on Earth) is largely accounted for by loss of hydrostatic pressures and altered hemodynamics in the intracranial circulation and the cerebrospinal fluid system. In space, an elevated pressure gradient across the lamina cribrosa, caused by a chronic but mildly elevated ICP, likely elicits adaptations of multiple structures and fluid systems in the eye which manifest themselves as the VIIP syndrome. A chronic mismatch between ICP and intraocular pressure (IOP) in space may acclimate the optic nerve head, lamina cribrosa, and optic nerve subarachnoid space to a condition that is maladaptive to Earth, all contributing to the pathogenesis of space VIIP syndrome. Relevant findings help to evaluate whether artificial gravity is an appropriate countermeasure to prevent this seemingly adverse effect of long-duration spaceflight.
from Physiological Reviews current issue http://ift.tt/2zqW9GP
FOX NEWS: FDA approves first 2-drug HIV regimen
FDA approves first 2-drug HIV regimen
The U.S. Food and Drug Administration on Tuesday approved the first two-drug regimen to treat HIV, the virus that causes AIDS, aimed at easing the side effects for long-term patients who are on the standard treatment involving three or more drugs.
FOX NEWS: VA study shows parasite from Vietnam may be killing vets
VA study shows parasite from Vietnam may be killing vets
A half century after serving in Vietnam, hundreds of veterans have a new reason to believe they may be dying from a silent bullet — test results show some men may have been infected by a slow-killing parasite while fighting in the jungles of Southeast Asia.
FOX NEWS: Holiday party leftovers: What to keep and what to toss
Holiday party leftovers: What to keep and what to toss
Q&A with Dr. Manny: I just had a big holiday party, are there any leftovers I shouldn’t keep to avoid getting sick?
Estradiol and Age-Related Bone Loss in Men
from Physiological Reviews recent issues http://ift.tt/2zqNFPP
Endothelial Cell Metabolism
Endothelial cells (ECs) are more than inert blood vessel lining material. Instead, they are active players in the formation of new blood vessels (angiogenesis) both in health and (life-threatening) diseases. Recently, a new concept arose by which EC metabolism drives angiogenesis in parallel to well-established angiogenic growth factors (e.g., vascular endothelial growth factor). 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3-driven glycolysis generates energy to sustain competitive behavior of the ECs at the tip of a growing vessel sprout, whereas carnitine palmitoyltransferase 1a-controlled fatty acid oxidation regulates nucleotide synthesis and proliferation of ECs in the stalk of the sprout. To maintain vascular homeostasis, ECs rely on an intricate metabolic wiring characterized by intracellular compartmentalization, use metabolites for epigenetic regulation of EC subtype differentiation, crosstalk through metabolite release with other cell types, and exhibit EC subtype-specific metabolic traits. Importantly, maladaptation of EC metabolism contributes to vascular disorders, through EC dysfunction or excess angiogenesis, and presents new opportunities for anti-angiogenic strategies. Here we provide a comprehensive overview of established as well as newly uncovered aspects of EC metabolism.
from Physiological Reviews recent issues http://ift.tt/2mPGtXP
Spaceflight-Induced Intracranial Hypertension and Visual Impairment: Pathophysiology and Countermeasures
Visual impairment intracranial pressure (VIIP) syndrome is considered an unexplained major risk for future long-duration spaceflight. NASA recently redefined this syndrome as Spaceflight-Associated Neuro-ocular Syndrome (SANS). Evidence thus reviewed supports that chronic, mildly elevated intracranial pressure (ICP) in space (as opposed to more variable ICP with posture and activity on Earth) is largely accounted for by loss of hydrostatic pressures and altered hemodynamics in the intracranial circulation and the cerebrospinal fluid system. In space, an elevated pressure gradient across the lamina cribrosa, caused by a chronic but mildly elevated ICP, likely elicits adaptations of multiple structures and fluid systems in the eye which manifest themselves as the VIIP syndrome. A chronic mismatch between ICP and intraocular pressure (IOP) in space may acclimate the optic nerve head, lamina cribrosa, and optic nerve subarachnoid space to a condition that is maladaptive to Earth, all contributing to the pathogenesis of space VIIP syndrome. Relevant findings help to evaluate whether artificial gravity is an appropriate countermeasure to prevent this seemingly adverse effect of long-duration spaceflight.
from Physiological Reviews recent issues http://ift.tt/2zqW9GP
Tuesday, November 21, 2017
FOX NEWS: Formerly conjoined twins at Philadelphia hospital released before holidays
Formerly conjoined twins at Philadelphia hospital released before holidays
Formerly conjoined twins who had spent more than a year at a hospital in Pennsylvania were discharged Tuesday, just in time to be home for Thanksgiving.
FOX NEWS: Salmonella poisoning symptoms and warning signs
Salmonella poisoning symptoms and warning signs
Eating food that’s contaminated with salmonella bacteria may cause you to be ill and experience discomfort for several days.
