Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordThere is another record in ORE for this publication: http://hdl.handle.net/10871/33419The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.We thank D.R. Alessi (Dundee) and R.P. Lifton (Rockefeller) for their support. K.T.K. is supported by the March of Dimes Basil O'Connor Award, a Simons Foundation SFARI Grant, the Hydrocephalus Association Innovator Award, and the NIH (4K12NS080223-05). J.M.S. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (NS060801; NS061808) and the US Department of Veterans Affairs (1BX002889); R.M. is supported by the Howard Hughes Medical Institute

Increased Small Conductance Calcium-Activated Potassium Type 2 Channel-Mediated Negative Feedback on N-methyl-D-aspartate Receptors Impairs Synaptic Plasticity Following Context-Dependent Sensitization to Morphine

This paper addresses the comparison between two techniques for the optimization under parametric uncertainty of multiproduct batch plants integrating design and production planning decisions. This problem has been conceived as a two-stage stochastic mixed integer linear programming (MILP) in which the first-stage decisions consist of design variables that allow determining the batch plant structure, and the second-stage decisions consist of production planning continuous variables in a multiperiod context. The objective function maximizes the expected net present value. In the first solving approach, the problem has been tackled through mathematical programming considering a discrete set of scenarios. In the second solving approach, the multi-scenario MILP problem has been reformulated by adopting a simulation-based optimization scheme to accommodate the variables belonging to different management levels. Advantages and disadvantages of both approaches are demonstrated through a case study. Results allow concluding that a simulation-based optimization strategy may be a suitable technique to afford two-stage stochastic programming problems.Sociedad Argentina de Informática e Investigación Operativ

Association of Baseline Frailty Status and Age with Postoperative Morbidity and Mortality Following Intracranial Meningioma Resection

PURPOSE: Although numerous studies have established advanced patient age as a risk factor for poor outcomes following intracranial meningioma resection, large-scale evaluation of frailty for preoperative risk assessment has yet to be examined. METHODS: Weighted discharge data from the National Inpatient Sample were queried for adult patients undergoing benign intracranial meningioma resection from 2015 to 2018. Complex samples multivariable logistic regression models and receiver operating characteristic curve analysis were performed to evaluate adjusted associations and discrimination of frailty, quantified using the 11-factor modified frailty index (mFI), for clinical endpoints. RESULTS: Among 20,250 patients identified (mean age 60.6 years), 35.4% (n = 7170) were robust (mFI = 0), 34.5% (n = 6985) pre-frail (mFI = 1), 20.1% (n = 4075) frail (mFI = 2), and 10.0% (n = 2020) severely frail (mFI ≥ 3). On univariable analysis, these sub-cohorts stratified by increasing frailty were significantly associated with the development of Clavien-Dindo grade IV (life-threatening) complications (inclusive of those resulting in mortality) (1.3% vs. 3.1% vs. 6.5% vs. 9.4%, p \u3c 0.001) and extended length of stay (eLOS) (15.4% vs. 22.5% vs. 29.3% vs. 37.4%, p \u3c 0.001). Following multivariable analysis, increasing frailty (aOR 1.40, 95% CI 1.17, 1.68, p \u3c 0.001) and age (aOR 1.20, 95% CI 1.05, 1.38, p = 0.009) were both independently associated with development of life-threatening complications or mortality, whereas increasing frailty (aOR 1.20, 95% CI 1.10, 1.32, p \u3c 0.001), but not age, was associated with eLOS. Frailty (by mFI-11) achieved superior discrimination in comparison to age for both endpoints (AUC 0.69 and 0.61, respectively). CONCLUSION: Frailty may be more accurate than advanced patient age alone for prognostication of adverse events and outcomes following intracranial meningioma resection

IUI+mLPS increases proteolytic activity and decreases collagen IV immunoreactivity.

<p><b>A–C</b>: <i>In situ</i> zymography (A,B), with quantification (C), of coronal sections from naïve control (CTR) and 24 hours after dual prenatal pro-angiogenic stimuli (PS) of IUI+mLPS, shown at low (A) and at high (B) magnification; the subventricular zone is shown in (B); nuclei stained with DAPI (blue); scale bars, 1 mm (A), 25 μm (B); 3 pups per group; *, <i>p</i><0.05; **, <i>p</i><0.01. <b>D,E</b>: Images of vessels identified by immunolabeling for RECA (red), that show proteolytic activity on <i>in situ</i> zymography (green); merged images are shown on the right; nuclei stained with DAPI (blue); scale bars, 50 μm. <b>F</b>: Immunolabeling for collagen IV (<i>left</i>), with quantification (<i>right</i>), on P0 in naïve controls (CTR), after IUI alone, after mLPS alone, and after the dual pro-angiogenic stimuli of IUI+mLPS (PS), in all cases after vaginal delivery, in coronal brain sections; 5 pups per group; tissues from the IUI alone group were from a previous study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171163#pone.0171163.ref020" target="_blank">20</a>].</p

The effect of cerebral microbleeds on neurological function.

<p><b>A</b>: Performance on the righting reflex and on the negative geotaxis test on P3–14 in naïve pups with vaginal delivery (CTR-VD), pups following prenatal pro-angiogenic stimuli with vaginal delivery (PS-VD), and pups following prenatal pro-angiogenic stimuli with abdominal delivery (PS-AD). <b>B</b>: Performance on the open field test at P24, the elevated plus maze at P31, and on thigmotaxis at P35, in CTR-VD pups, PS-VD pups, and PS-AD pups. <b>C</b>: Spontaneous rearing at P31, performance on the beam balance test at P31, and grip strength at P31 in CTR-VD pups, PS-VD pups, and PS-AD pups. <b>D</b>: Incremental spatial learning on P35–39, performance on the memory probe at P40, and on the rapid learning test at P42 in CTR-VD pups, PS-VD pups, and PS-AD pups. For all panels, 19–25 pups/group; * and **, <i>p</i><0.05 and 0.01, respectively, comparing CTR-VD and PS-VD; §§, <i>p</i>< 0.01comparing PS-VD and PS-AD.</p

qPCR primers used in this study.

<p>qPCR primers used in this study.</p

The effect of cerebral microbleeds on myelination.

<p><b>A–D</b>: Representative images (A–C), with quantification (D), of LFB staining (A) and MBP immunolabeling (B,C) at P52 in naïve pups with vaginal delivery (CTR-VD), pups following prenatal pro-angiogenic stimuli with vaginal delivery (PS-VD), and in pups following prenatal pro-angiogenic stimuli with abdominal delivery (PS-AD); arrows in (A) point to clumped myelinated fibers; arrows in (C) point to poorly myelinated fibers above corpus callosum; rectangles show ROI’s that were quantified; 7 rats/group; **, <i>p</i><0.01 comparing CTR-VD and PS-VD; §§, <i>p</i><0.01 comparing PS-VD and PS-AD; bars, 1 mm (A), 500 μm (B), 250 μm (C). <b>E</b>: Immunoblot (<i>left</i>), with quantification (<i>right</i>), of all bands of MBP at P52 in CTR-VD, PS-VD, and PS-AD rats; HSC70 used as loading control; 3 rats per group.</p

Cerebral microbleeds are linked to pro-angiogenic stimuli <i>in utero</i> followed by vaginal delivery.

<p><b>A,B</b>: H&E-stained sections of P0 brains showing representative microbleeds (<i>arrows</i>) in pup following prenatal pro-angiogenic stimuli with vaginal delivery (PS-VD) (A, <i>left panel</i>; B, <i>all panels</i>) but not following prenatal pro-angiogenic stimuli with abdominal delivery (PS-AD) (A, <i>right panel</i>); scale bars, 1 and 0.25 mm in (A) and (B), respectively. <b>C</b>: Maps showing the locations and sizes of microbleeds identified in the coronal section 2.5 mm from the rostral extent of the lateral ventricle, on P0 in PS-VD pups (<i>left panel</i>) and in PS-AD pups (<i>right panel</i>); data from the right and left hemispheres of 10 pups are superimposed; scale bar, 1 mm. <b>D</b>: Averages of the total area occupied by hemorrhages in 9 coronal sections (see <i>inset</i>) in CTR-VD pups, PS-VD pups, and in PS-AD pups; 10 pups per group; **, <i>p</i><0.01 comparing CTR-VD and PS-VD; §§, <i>p</i><0.01 comparing PS-VD and PS-AD. <b>E</b>: Histogram showing the frequency distribution of microbleeds by size in the 3 groups; same coronal plane as in (C); inset shows the data plotted with an extended abscissa and the ordinate in log scale.</p

The effect of cerebral microbleeds on axonal development.

<p><b>A,B</b>: Representative images (A), with quantification (B), of immunolabeling for SIM-312 at P52 in naïve pups with vaginal delivery (CTR-VD), pups following prenatal pro-angiogenic stimuli with vaginal delivery (PS-VD), and in pups following prenatal pro-angiogenic stimuli with abdominal delivery (PS-AD); rectangle and oval show regions of interest (ROI) that were quantified; 7 rats/group; **, <i>p</i><0.01 comparing CTR-VD and PS-VD; §§, <i>p</i><0.01 comparing PS-VD and PS-AD; bar, 500 μm (A). <b>C</b>: Immunoblot (<i>left</i>), with quantification (<i>right</i>), of SIM-312 at P52 in CTR-VD, PS-VD, and PS-AD rats; HSC70 used as loading control; 3 rats per group.</p