Spatial model of convective solute transport in brain extracellular space does not support a "glymphatic" mechanism.

A "glymphatic system," which involves convective fluid transport from para-arterial to paravenous cerebrospinal fluid through brain extracellular space (ECS), has been proposed to account for solute clearance in brain, and aquaporin-4 water channels in astrocyte endfeet may have a role in this process. Here, we investigate the major predictions of the glymphatic mechanism by modeling diffusive and convective transport in brain ECS and by solving the Navier-Stokes and convection-diffusion equations, using realistic ECS geometry for short-range transport between para-arterial and paravenous spaces. Major model parameters include para-arterial and paravenous pressures, ECS volume fraction, solute diffusion coefficient, and astrocyte foot-process water permeability. The model predicts solute accumulation and clearance from the ECS after a step change in solute concentration in para-arterial fluid. The principal and robust conclusions of the model are as follows: (a) significant convective transport requires a sustained pressure difference of several mmHg between the para-arterial and paravenous fluid and is not affected by pulsatile pressure fluctuations; (b) astrocyte endfoot water permeability does not substantially alter the rate of convective transport in ECS as the resistance to flow across endfeet is far greater than in the gaps surrounding them; and (c) diffusion (without convection) in the ECS is adequate to account for experimental transport studies in brain parenchyma. Therefore, our modeling results do not support a physiologically important role for local parenchymal convective flow in solute transport through brain ECS

Superresolution Imaging of Aquaporin-4 Cluster Size in Antibody-Stained Paraffin Brain Sections

AbstractThe water channel aquaporin-4 (AQP4) forms supramolecular clusters whose size is determined by the ratio of M1- and M23-AQP4 isoforms. In cultured astrocytes, differences in the subcellular localization and macromolecular interactions of small and large AQP4 clusters results in distinct physiological roles for M1- and M23-AQP4. Here, we developed quantitative superresolution optical imaging methodology to measure AQP4 cluster size in antibody-stained paraffin sections of mouse cerebral cortex and spinal cord, human postmortem brain, and glioma biopsy specimens. This methodology was used to demonstrate that large AQP4 clusters are formed in AQP4−/− astrocytes transfected with only M23-AQP4, but not in those expressing only M1-AQP4, both in vitro and in vivo. Native AQP4 in mouse cortex, where both isoforms are expressed, was enriched in astrocyte foot-processes adjacent to microcapillaries; clusters in perivascular regions of the cortex were larger than in parenchymal regions, demonstrating size-dependent subcellular segregation of AQP4 clusters. Two-color superresolution imaging demonstrated colocalization of Kir4.1 with AQP4 clusters in perivascular areas but not in parenchyma. Surprisingly, the subcellular distribution of AQP4 clusters was different between gray and white matter astrocytes in spinal cord, demonstrating regional specificity in cluster polarization. Changes in AQP4 subcellular distribution are associated with several neurological diseases and we demonstrate that AQP4 clustering was preserved in a postmortem human cortical brain tissue specimen, but that AQP4 was not substantially clustered in a human glioblastoma specimen despite high-level expression. Our results demonstrate the utility of superresolution optical imaging for measuring the size of AQP4 supramolecular clusters in paraffin sections of brain tissue and support AQP4 cluster size as a primary determinant of its subcellular distribution

Stress Fractures of the Elbow in the Throwing Athlete: A Systematic Review.

Background: Stress fractures of the elbow are rare in throwing athletes and present a challenge from both a management and rehabilitation perspective. Although the incidence of stress fractures of the elbow is increasing, there is a lack of data in the literature focused on throwers. Purpose: To evaluate studies regarding the management and outcomes of stress fractures of the elbow in throwing athletes. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was conducted by searching the Scopus, PubMed, and Cochrane Library electronic databases to identify studies reporting on the management and outcomes of stress fractures in overhead-throwing athletes. Management data included nonoperative and operative modalities, and outcome data included return to play, encompassing the timing and level of activity. Studies were excluded if the stress fracture of the elbow was not a result of a sport injury attributed to throwing or if the study failed to report whether an athlete returned to play. Results: Fourteen studies met the inclusion criteria and were included in this analysis. There were 52 patients in total (50 male, 2 female) with a mean age of 19.7 years (range, 13-29.1 years). The olecranon was the most common location of the stress fracture (51 patients; 98.1%), followed by the distal humerus (1 patient; 1.9%). The majority of patients (n = 40; 76.9%) were treated operatively. Of the 40 patients who were treated surgically, 14 (35.0%) underwent a period of conservative treatment preoperatively that ultimately failed because of persistent nonunion or continued elbow pain. A total of 50 patients (96.2%) returned to sport either at or above their preinjury level. Of the 2 patients (3.8%) who did not return to sport, 1 did not return because of continued elbow pain postoperatively, and the other was lost to follow-up. Complications occurred in 9 patients (17.3%), all of whom were treated surgically. Conclusion: On the basis of this systematic review, the majority of elbow stress fractures were treated operatively and approximately one-third after a period of failed nonoperative management. The return-to-sport rate was high. Further, higher level studies are needed to optimize management and return-to-sport rates in this population

Divergence or convergence? Health inequalities and policy in a devolved Britain

Since the advent of political devolution in the UK, it has been widely reported that markedly different health policies have emerged. However, most of these analyses are based on a comparison of health care policies and, as such, only tell part of a complex and evolving story. This paper considers official responses to a shared public health policy aim, the reduction of health inequalities, through an examination of national policy statements produced in England, Scotland and Wales respectively since 1997. The analysis suggests that the relatively consistent manner in which the ‘policy problem’ of health inequalities has been framed combined with the dominance of a medical model of health have constrained policy responses. Our findings differ from existing analyses, raising some important questions about the actuality of, and scope for, policy divergence since devolution

Right to dignity and the Supreme Court

A thorough investigation of the term dignity and how it applies to the Supreme Court. By tracing different understandings of dignity from Aquinas to Kant, we can begin to define dignity. Kant's definition, like many Enlightenment ideas, had a significant impact on the Framers. The Supreme Court has provided models from the past to investigate and discover that there is a need for a "right to dignity" and the right does indeed exist. In today's court, the "right to dignity" is an individual's endowment to not have to follow a law that has meaning other than morality, since that individual has every ability to ponder his own morality. But "the right to dignity" could evolve and if it follows Justice Brennan's views one day it could mean that the "right to dignity" is the protection the individual is guaranteed from laws or government action with no purpose or externality small enough to not be worth infraction of rights

A discernable and manageable standard for partisan gerrymandering

The case of Veith v. Jubelirer (2004) challenges us to find a standard for partisan gerrymandering that is judicially discernable and manageable. Without such a standard even the most egregious partisan gerrymanders cannot be effectively challenged. However, we argue that the way to find a suitable standard is not to embark on a quest for a “new” standard. Rather it is to take the existing valid measures that science gives us, and show that these can be grounded in constitutionally protected rights. Using recent results in social choice theory, we show that the existing partisan symmetry standard can be derived from an individual right to equal protection. We also show that the existing technology for measuring partisan symmetry can provide a judicially manageable test for partisan bias

Maryland's electoral maps show how proportional representation could solve the problem of gerrymandering

This week the US Supreme Court hears a case concerning the constitutionality of partisan gerrymandering in Maryland. Examining current, past, and alternative electoral maps, Alex Keena, Michael Latner, Anthony J. McGann, and Charles Anthony Smith find that by making districts more competitive, some redistricting plans can actually work against one party or the other. Only the introduction of proportional representation with multi-member districts, they argue, would mean a truly fair electoral system for Maryland