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Minami S.S.,University of California at San Francisco | Farese R.V.,Jr
Nature Medicine | Year: 2014

Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

OBJECTIVE—: Aptamers are oligonucleotides targeting protein–protein interactions with pharmacokinetic profiles and activity reversal options. Although P-selectin and von Willebrand factor (vWF) have been implicated in the development of venous thrombosis (VT), no studies have directly compared aptamer efficacy with standard of care in VT. In this study, ARC5692, an anti-P-selectin aptamer, and ARC15105, an anti-vWF aptamer, were compared with low–molecular-weight heparin, enoxaparin, to test the efficacy of P-selectin or vWF inhibition in promoting thrombus resolution and preventing vein wall fibrosis, in a baboon model of VT.APPROACH AND RESULTS—: Groups were as follows: treatment arm: animals received P-selectin or vWF aptamer inhibitors or enoxaparin (n=3 per group). Controls received no treatment (n=3). Prophylactic arm: animals received P-selectin inhibitor (n=4) or vWF inhibitor (n=3). Treatment arm: P-selectin-inhibitor demonstrated a significant improvement in vein recanalization by magnetic resonance venography (73% at day 21), and significantly decreased vein wall collagen, compared with all groups. Anti–P-selectin equaled enoxaparin in maintaining valve competency by ultrasound. All control animals had compromised valve competency post thrombosis. Prophylactic arm: animals receiving P-selectin and vWF inhibitors demonstrated improved vein recanalization by magnetic resonance venography versus controls (80% and 85%, respectively, at day 21). Anti–P-selectin protected iliac valve function better than anti-vWF, and both improved valve function versus controls. No adverse bleeding events were observed.CONCLUSIONS—: The P-selectin inhibitor aptamer promoted iliac vein recanalization, preserved valve competency, and decreased vein wall fibrosis. The results of this work suggest that P-selectin inhibition maybe an ideal target in the treatment and prophylaxis of deep VT, warranting clinical trials. © 2015 American Heart Association, Inc.

Hori D.,Johns Hopkins University | Hogue C.W.,Jr.
Anesthesia and Analgesia | Year: 2015

BACKGROUND:: Individualizing mean arterial blood pressure (MAP) based on cerebral blood flow (CBF) autoregulation monitoring during cardiopulmonary bypass (CPB) holds promise as a strategy to optimize organ perfusion. The purpose of this study was to evaluate the accuracy of cerebral autoregulation monitoring using microcirculatory flow measured with innovative ultrasound-tagged near-infrared spectroscopy (UT-NIRS) noninvasive technology compared with transcranial Doppler (TCD). METHODS:: Sixty-four patients undergoing CPB were monitored with TCD and UT-NIRS (CerOx™). The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of TCD-measured CBF velocity and MAP. The cerebral flow velocity index (CFVx) was calculated as a similar coefficient between slow waves of cerebral flow index measured using UT-NIRS and MAP. When MAP is outside the autoregulation range, Mx is progressively more positive. Optimal blood pressure was defined as the MAP with the lowest Mx and CFVx. The right- and left-sided optimal MAP values were averaged to define the individual optimal MAP and were the variables used for analysis. RESULTS:: The Mx for the left side was 0.31 ± 0.17 and for the right side was 0.32 ± 0.17. The mean CFVx for the left side was 0.33 ± 0.19 and for the right side was 0.35 ± 0.19. Time-averaged Mx and CFVx during CPB had a statistically significant “among-subject” correlation (r = 0.39; 95% confidence interval [CI], 0.22–0.53; P < 0.001) but had only a modest agreement within subjects (bias 0.03 ± 0.20; 95% prediction interval for the difference between Mx and CFVx, −0.37 to 0.42). The MAP with the lowest Mx and CFVx (“optimal blood pressure”) was correlated (r = 0.71; 95% CI, 0.56–0.81; P < 0.0001) and was in modest within-subject agreement (bias −2.85 ± 8.54; 95% limits of agreement for MAP predicted by Mx and CFVx, −19.60 to 13.89). Coherence between ipsilateral middle CBF velocity and cerebral flow index values averaged 0.61 ± 0.07 (95% CI, 0.59–0.63). CONCLUSIONS:: There was a statistically significant correlation and agreement between CBF autoregulation monitored by CerOx compared with TCD-based Mx. © 2015 International Anesthesia Research Society.

Lopes B.,Rio Of Janeiro Corneal Tomography And Biomechanics Study Group | Ambrosio R.,Jr
Cornea | Year: 2014

PURPOSE:: The aim of this study was to compare corneal densitometry measured by Scheimpflug tomography in normal and keratoconic eyes and to assess the differences in densitometry values among the stages of keratoconus.METHODS:: Keratoconic and normal corneas were examined using the Pentacam. Corneal densitometry was measured over a 12-mm diameter area, divided by annular concentric zones and depths. Keratoconus was classified according to the topographic keratoconus classification.CONCLUSIONS:: The densitometry map reveals that light backscatter was higher in the central portion of the anterior keratoconic cornea than in the normal cornea. The densitometry level is higher in more advanced stages.RESULTS:: We enrolled 1 eye randomly selected from each of 172 patients with normal corneas (N) and 98 patients with bilateral keratoconus (KC). There were significant differences between the groups for densitometry measurements in 2 annuli: central 2.0 mm in diameter (N = 16.85 ± 2.42, KC = 18.93 ± 2.78, P = 0.0001) and annulus 2.0 to 6.0 mm in diameter (N = 15.18 ± 2.18, KC = 16.16 ± 1.71, P = 0.005), and total diameter (N = 24.89 ± 6.18, KC = 16.71 ± 2.3, P = 0.033). Divided by layers, the inner parts of anterior (120 μm), central (from 120 μm to the last 60 μm), and posterior (last 60 μm) layers were also higher in the KC group (P < 0.001). There were differences according to the stages of KC for corneal densitometry of the central annuli at total thickness, anterior and central layers. More advanced cases presented a higher backscatter (P < 0.05). The anterior layer presented the smallest overlap between groups and KC stages. © 2014 by Lippincott Williams & Wilkins.

Suri R.S.,Center Hospitalier Of Luniversite Of Montreal | Lockridge R.S.,Jr.
Clinical Journal of the American Society of Nephrology | Year: 2014

Background and objectives Patients receiving hemodialysis often perceive their caregivers are overburdened. We hypothesizethat increasinghemodialysis frequencywould resultin higherpatient perceptionsofburden on their unpaid caregivers. Design, setting, participants, & measurements In two separate trials, 245 patients were randomized to receive in-center daily hemodialysis (6 days/week) or conventional hemodialysis (3 days/week) while 87 patients were randomized to receive home nocturnal hemodialysis (6 nights/week) or home conventional hemodialysis for 12 months. Changes in overall mean scores over time in the 10-question Cousineau perceived burden scale were compared. Results In total, 173 of 245 (70%) and 80 of 87 (92%) randomized patients in the Daily and Nocturnal Trials, respectively, reported having an unpaid caregiver at baseline or during follow-up. Relative to in-center conventional dialysis, the 12-month change in mean perceived burden score with in-center daily hemodialysis was -2.1 (95% confidence interval, -9.4 to +5.3; P=0.58). Relative to home conventional dialysis, the 12-month change in mean perceived burden score with home nocturnal dialysis was +6.1 (95% confidence interval, -0.8 to +13.1; P=0.08). After multiple imputation for missing data in the Nocturnal Trial, the relative difference between home nocturnal and home conventional hemodialysis was +9.4(95% confidence interval, +0.55 to +18.3; P=0.04). In the Nocturnal Trial, changes in perceived burden were inversely correlated with adherence to dialysis treatments (Pearson r=-0.35; P=0.02). Conclusion Relative to conventional hemodialysis, in-center daily hemodialysis did not result in higher perceptions of caregiver burden. There was a trend to higher perceived caregiver burden among patients randomized to home nocturnal hemodialysis. These findings may have implications for the adoption of and adherence to frequent nocturnal hemodialysis. © 2014 by the American Society of Nephrology.

Salem N.,Jr. | Eggersdorfer M.,DSM Nutritional Products Inc.
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2015

PURPOSE OF REVIEW: To delineate the available sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for human consumption and to determine if the available supply is capable of supplying the nutrient levels recommended by expert bodies. RECENT FINDINGS: There are converging opinions among experts, professional organizations and health professionals that a recommendation for a daily individual consumption of 500 mg of EPA/DHA would provide health benefits, and this translates to an annual human consumption of 1.3 million metric tons. Current human consumption of EPA/DHA is estimated to be only a small fraction of this amount and many people may suffer from suboptimal health as a result of low intake. EPA and DHA originate in the phytoplankton and are made available in the human food chain mainly through fish and other seafood. SUMMARY: The fish catch is not elastic and in fact has long since reached a plateau. Aquaculture has grown rapidly, but most of the fish oil produced is currently being used to support aquaculture feed and so this would appear to limit aquaculture growth - or at least the growth in availability of fish sources of EPA/DHA. Vegetable oil-derived alpha-linolenic acid, though relatively plentiful, is converted only at a trace level in humans to DHA and not very efficiently to EPA, and so cannot fill this gap. Microbial EPA/DHA production can in the future be increased, although this oil is likely to remain more expensive than fish oil. Plant sources of EPA and DHA have now been produced in the laboratory via transgenic means and will eventually clear regulatory hurdles for commercialization, but societal acceptance remains in question. The purpose of this review is to discuss the various sources of omega-3 fatty acids within the context of the potential world demand for these nutrients. In summary, it is concluded that fish and vegetable oil sources will not be adequate to meet future needs, but that algal oil and terrestrial plants modified genetically to produce EPA and DHA could provide for the increased world demand. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Joyal J.-S.,McGill University | Gobeil F.,Jr
Nature Medicine | Year: 2014

Neurons have an important role in retinal vascular development. Here we show that the G protein–coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulation, F2rl1 in retinal ganglion cells translocates from the plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). At the nucleus, F2rl1 facilitates recruitment of the transcription factor Sp1 to trigger Vegfa expression and, in turn, neovascularization. In contrast, classical plasma membrane activation of F2rl1 leads to the expression of distinct genes, including Ang1, that are involved in vessel maturation. Mutant versions of F2rl1 that prevent nuclear relocalization but not plasma membrane activation interfere with Vegfa but not Ang1 expression. Complementary angiogenic factors are therefore regulated by the subcellular localization of a receptor (F2rl1) that governs angiogenesis. These findings may have implications for the selectivity of drug actions based on the subcellular distribution of their targets.

Olah A.,Petz Aladar Teaching Hospital | Romics L.,Jr.
World Journal of Gastroenterology | Year: 2014

The use of enteral feeding as part of the management of acute pancreatitis dates back almost two decades. This review describes the indications for and limitations of enteral feeding for the treatment of acute pancreatitis using up-to-date evidence-based data. A systematic review was carried out to analyse current data on the use of enteral nutrition in the management of acute pancreatitis. Relevant literature was analysed from the viewpoints of enteral vs parenteral feeding, early vs delayed enteral nutrition, nasogastric vs nasojejunal feeding, and early oral diet and immunonutrition, particularly glutamine and probiotic supplementation. Finally, current applicable guidelines and the effects of these guidelines on clinical practice are discussed. The latest meta- Analyses suggest that enteral nutrition significantly reduces the mortality rate of severe acute pancreatitis compared to parenteral feeding. To maintain gut barrier function and prevent early bacterial translocation, enteral feeding should be commenced within the first 24 h of hospital admission. Also, the safety of nasogastric feeding, which eases the administration of enteral nutrients in the clinical setting, is likely equal to nasojejunal feeding. Furthermore, an early low-fat oral diet is potentially beneficial in patients with mild pancreatitis. Despite the initial encouraging results, the current evidence does not support the use of immuno-enhanced nutrients or probiotics in patients with acute pancreatitis. © 2014 Baishideng Publishing Group Inc.

Spaide R.F.,Vitreous | Ryan E.H.,Jr.
American Journal of Ophthalmology | Year: 2015

Purpose To evaluate potential accumulation of fluid in the outer choroid in eyes with central serous chorioretinopathy. Design Retrospective observational case series. Methods Patients in 2 community-based retinal practices were evaluated for hyporeflective areas in the outer choroid consistent with collections of fluid using enhanced depth imaging optical coherence tomography. Eligible patients were examined over the preceding 2 years, had a history of central serous chorioretinopathy, and did not have a history of choroidal neovascularization or photodynamic therapy. Results In the New York group there were 131 eyes of 70 patients who had a mean age of 56.3 (± 12.5) years, and 88 (67.2%) had hyporeflective regions consistent with posterior loculation of fluid in the macular region. In the Minnesota data set there were 91 eyes of 48 patients who had a mean age of 47.9 (± 9.9) years and hyporeflective regions consistent with posterior loculation of fluid was present in 59 (64.8%). In the entire group the mean subfoveal choroidal thickness of those without loculated fluid was 344 μm, as compared with 498 μm with loculated fluid (P <.001). The areas of loculated fluid were hyporeflective, were larger topographically than the large choroidal vessels, had an angular inner border, and did not have a bounding vascular wall. Conclusions Posterior loculation of fluid is a common finding in central serous chorioretinopathy, but it has a different pattern and distribution than do collections of fluid in the outer choroid and suprachoroidal space as seen in other forms of choroidal effusion. © 2015 Elsevier Inc.

Kenna K.P.,University of Massachusetts Medical School | Brown R.H.,Jr
Nature Genetics | Year: 2016

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

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