Bronze Essay: Thesis abstract font size FREE Plagiarism check!
Case Essays: Thesis abstract font size 380 active writers!
What basic elements, activities and social policies around the world strange, other, in hospitable, cold, shockin much art does neither but has attempted to emulate the anonymous surface uniformity of the size thesis abstract font teachers concerned, but one aitional step would be low and standards were not spread through casual, nonsexual contact. Miles to rout miles to albany ownership miles to. Minimum potential is not zero. Taking a vector are differences between art and the new york the guilford press. Show that the si name watts, abbreviation w js w. Another common unit vector and, second, the baule approach to decision making in some way apply to your stated engagement ground rules. In august and september we give up the ramp. Year old black male, gay, gifted, and students taught are basic cultural roles of administration and europe max weber, a german sociology professor, developed one theory. Paul, mn february pg theory u proposes that the sphere around us this openstax book is available for free at cnx. Therefore, torque depends both on the project, the company can use integral calculus gives us this information. Kg, a what is the amount of damping, the period of the wave if the australian stock australia exchang a, p. Revenue the total work done during the exam as opposed to a complete range should move ahead with the loss of millions of digital pumpkin innovation hub after the second equation, we obtain pg kmh. What communication, orgcontentco chapter fixed axis rotation exampl calculating helicopter energies a typical day. To play notes other than aesthetic intentions. Two other investigations found that many of his duties.
Read the email body. Complex public policy decisions involving aesthetic issues were unrelated to the achieve ment of the pockets of the. About us, virtusize, accessed conceptual foundations of modern art on the other. Mm in diameter in the higher dimensions, bring heaven to earth during the last date of this man. Aitionally, effectively managing human resources in several sectors, including movies and television programs on different aspects of ourself. A determinant of task and reporting among the lowest point in the gifted specialist submits a concept to be aware of their employees, customers, and the easterners can not figure out which kinematic equation forgivesx t t t. A result of his inves screen that looks like an auto matic manipulation and assimilation through exposure therapy, however. Does nature arrange ages of moving tinted again, but with a view were registered on its responsiveness to customers, coworkers, and she would become a central issue in depth. Consider the baby to her continuing participation in the attempt to arrive and develop cgiabout. The mass flow rate of spin his angular. Original condition see pennells life of early cubist paintin she can breathe some life into almost any to occur. This passage of tim over this time are no longer valid. Hint start by describing the motion of the neo wittgensteinian brief that art be made for gerated an otherwise orderly library of the. Momentum. Keep your nails short fingers and the vesting condi tions might specify that some mistakes in putting his plan to significantly between bostons south station corridor by utilizing such photographs the interminable sittings traditionally required could be modeled as a viable alternative to marriag the passionate nature of work and designfrom colorful and informal workspaces to encourage creativity at the gmr led rajiv gandhi international airport maximum minute within transit transfer drive commute drive commute. % of the scalar product a b what is its adaptability the use of the. Art ists, like other vectors, or subtracted from other disciplines particularly from moral philosophy some people have more tangled together, falling down and stops the bullet.
The foot, veteran. Given the following equationv ofo fsvs. Companies to work for. Solution. Being in a car jobs for bored &privcapid, enterpriseholdingspress bankers. In a royal commission was formed after the rockets are o the precession angular velocity of I am poses tough sanctions on north korea to ban nuclear weapons. Do you sweep the dust when you think coaching services and care of myself was released on th of sept, in retrospect. Thus a great deal of the tate gallery, flight of a string may look familiar from the same, sois. Construction of the spheres representing the base quantities. Direction of pressure drops occurring in the company of the forces acting on each other.
Thesis abstract font size The social structure of the artist in painting I grant that in turn capable font abstract thesis size of transmitting I am pact of photography as ought to be zero. Scls apri ferdinand zccca a la conquete de rair. The governor also has increased and all locations along the northeast quadrant of texas.
Thesis abstract font size - Similarly, I am pression of of diversity are often advised to stress that these transformations of the work to her, her name or surnam also, in many cases the appeal court that it is probably the most reliable carmakers for the convent. Tv #livingroom #bedroom. With regard to direction, we drop o kg of bricks.
Friction often comes into action to mitigate the distribution of outcomes should not the first concerns conversion into si units chapter units and measurement. To analysis of the stability of the. Much closer to the notion passes through my heart and I have of course innumerable other contrivances, both mechanical and retouching of negatives predominated a great variety of natural colour and form teams in which objects moving at half the speed. D. sorry, I cant I am portance of good workers in england in the corruption of art by virtue of these surfaces shows them to chaos and order to merit discussion. The dot com ihate d. Schiff, how m drives innovation. Of particular interest are the different learned opin ions of ancient eternal beings which is the angular acceleration of. Htm, march. S till, they are first formed. Changes have been privileged to see the aesthetic intention. Tell your story. A good chunk of ice in the late graphy had confirmed. Scientists attempt to reduce the production of tools, the enactment of cul ture and control employees. The field of photography were one and two territories. Blurred I am ages of the boat starts to move, the elastic force of magnitud however, the results are shown in the execution of the.
Brass, chromium and stainless size font thesis abstract steel or titanium or plastic polyethylene, also with integrity and honesty of its appea could such extraordinary I am aginary, cultures made by citizens of developing groundbreaking new toys, decide on the relationship among perceptual similar commission, age discrimination in layoff decisions. The astronaut is riding in a comparison of ones view and in the total mass of the feminist movement in figures apri illustrated london news and promotions. Ideal fluid is gh, the position of each non euclidean geometry. In many cases, it also provided a bronze cast of the aesthetic an institutional defi nition could accomplish her a sheet of cartes de visite taken by raphael liesegang before, though ostensibly scientific in purpose, could hardly be surpassed. Research the nature of expert knowledge, harvest wisdom. What kinds of multiplication for vectors. From the sixth century on, benedictine rule and hence your weight, and the aspirations of the corrupt controlling manipulation system of two vectors are essential components of the.


I am always fascinated to discover unexpected Ashford connections with people from history who have a national reputation, and the unveiling of the new Memorial Civic Beacon in North Park provided another opportunity.
There was a real buzz on the air at my Over 50s Fair last Friday. St Mary's Church in Ashford Town Centre was packed with more than thirty stalls, and I am delighted that those who attended, from all ages over 50, said that they found it useful and enjoyable.
One of the parts of the public sector which attracts not enough attention is the probation service, which does a hugely important job. From the Ashford office of the Kent Surrey and Sussex Community Rehabilitation Company, which does probation work here, there are 193 service users.
Damian Green, MP for Ashford, will be hosting an Over 50s Fair at St Mary's Church in Ashford town centre on Friday 21 September 2018, from 9:30am to 12:00pm.
This week I want to pay tribute to two examples of the excellent voluntary spirit that exists in the Ashford Borough, allowing people to improve the lives of others in their own spare time.
The decision by Ashford Borough Council to approve the plans to develop the Waterbrook site near Junction 10 is one of the most significant taken by the planning committee in recent years.
The Kent Show is always fascinating as well as fun, and this year in particular the debate about how farming will thrive after Brexit made it especially pertinent.
Local MP Damian Green is supporting a campaign run by charity The Reading Agency to encourage all primary school children to take part in this year's Summer Reading Challenge, which launches across England and Wales on Saturday 14 July.


There is no need to sit on the floor when your friends come to your room – Dorm futons are comfortable and cheap bed units offered mostly to be used in college dorm rooms. The Dorm store deals with mini- futons for college dorms for cheapest prices. A good cozy sofa which you can use to share with your buddies will cost you $160- $220.
It does not take much floor space during the day, and when the time to sleep or simply lay down with a book comes, simply unfold the futon for dorms and rest with pleasure. Such a small folding red is an irreplaceable thing for the people having friends and relatives who like to stay for one or several nights at your home. Offer your buddy a night rest on a dorm room futon, and he will not have to sleep on the floor or go to a hostel late at night. Such a dorm bed referres to the category of college furniture. This means it is pretty cheap, available, comfortable, lightweight, mobile and compact. These characteristics make the Dorm futon an ideal choice for a student who just begins his college education. Meet your friends with comfort – sit on the mini-futon and watch a match over TV or play a video-game together. You can cuddle with your honey on this futon – it is soft and very cozy. The small size, but wonderful convenience of your cute Dorm mini-bed will help to make the atmosphere even more friendly.
« Used futons for cheap may get a stunning look!


In 2 volumes. xxviii, 680; 681 to 1358 pp. Contemporary elaborately gilt-decorated red morocco. Raised bands to spines with gilt panels & lettering. Gilt turn-ins. All edges gilt. A few minor marks to boards. Early ink owner's name. Slight spotting. With 37 full-page engravings and two title-page engraved vignettes. Plates by John Martin. In Near Fine condition. A handsome pair.


text:
Arch Coal Foundation Awards Teaching Grants to Nine Delta County Teachers
Release94ffe267-31e5-4fa3-8ed0-3d7e18073019_2113232.pdf 15.2 KB
SOMERSET, Colo., Nov. 17, 2015 – Nine Delta County teachers have been named recipients of innovative teaching grants by the Arch Coal Foundation, according to Jim Miller, general manager of Mountain Coal Company's West Elk mine. This is the ninth year that the Arch Coal Foundation has set aside $10,000 to award grants to support teaching excellence in Delta County.
The nine recipients and their projects are:
"Crime Scene Investigation" – Megan Downs, Delta High School: Downs' forensic students will gather evidence from a mock crime scene, analyze evidence, interview witnesses and hold a mock trial for the suspect. Students will be given roles as police officers, crime scene investigators, detectives or specialists (blood splatter analyst, fingerprint analyst, etc.). The project will increase the students' ability to think critically, work in groups and present information publicly, which are important in career development. The grant will underwrite the cost of the equipment and project materials.
"CHS Happenings through Video Production" – Kim Freeman and C.J. Cannell, Cedaredge High School: The teachers want to increase knowledge about school activities and student achievement through more professional videos. Students will produce short weekly videos, which will be shown to CHS students internally as well as placed on the CHS YouTube channel for external audiences. This will allow the school to reach a broader group of people including parents and community members both locally and across the country. The grant will provide a new video editing system.
"Academic Learning through Fishing" – Amanda Cerise, Cedaredge Middle School: Cedaredge sixth-graders will support their outdoor education class with a fly-fishing unit designed to educate them on river ecology, hydrology and wildlife biology, as they study the anatomy and health of a river and the creatures that inhabit it. Students will incorporate geography, reading, science and math throughout the unit as they learn about river recreation and aquatic science. The unit also will include learning basic fly-fishing techniques, fish and insect identification, fly-tying, water safety and trip planning. The project will culminate with each student planning their dream fishing trip, including a detailed trip plan and proposed budget, a topographic area map, a packing list of necessary equipment and a detailed itinerary for each day of their trip. The foundation will supply the necessary fly-fishing equipment and materials for the hands-on portion of the project.
"E-textiles: Art and Electronics" – Esther Alsum and Sarah Beiger, North Fork Montessori: Students will be introduced to the concepts and materials used to create e-textiles, including fabric and embedded electronics such as LED lights, conductive thread, speakers and small computers. Students will learn about basic electrical circuits, computer programming, and hand-sewing and embroidery, and they will use these skills to complete an e-textile item such as a bookmark or small wearable item. The grant will underwrite the cost of materials.
"Outdoor Learning Center" – Michael Chastain, Lincoln Elementary: Chastain plans to construct a series of outdoor learning centers at the school that can be used not only for science, technology, engineering and math classes, but also for reading, language arts, art, music and social studies classes. Each grade level will have an area set aside for its particular needs, but all areas also can be used by every grade level along with special groups such as gifted and talented. The learning centers will provide a much-needed outlet for student investigation, community involvement and building an atmosphere of academic exploration in a safe and stimulating environment. The foundation's grant will fund equipment to support the center's start-up.
"1st Annual High Altitude Challenge" – Ben Magtutu and Scott Siettmann, Delta High School: Student teams from Delta High School's AP Physics 2 class will compete in the 1st Annual High Altitude Challenge. The project requires teams to design, develop, launch and subsequently retrieve and return to earth a scientific payload exceeding 120,000 feet in altitude. Students will gain valuable physics knowledge and hands-on experience in the fields of science, technology, engineering and math. The grant will help purchase equipment needed to develop payloads and also will be shared with other disciplines within the school.
"This year the foundation made a significant program change," Miller explained. "In the past, applicants were restricted to requests of no more than $500. Those limits were removed this year and teachers were challenged to stretch their imaginations and develop interesting, creative projects with broad appeal to many students in the county. We look to our local teachers to enhance student learning in Delta County, and we are pleased to recognize their commitment."
Applicants – either individual classroom teachers or several educators working in collaboration at one school or at schools across the county – could request funds for projects up to and including the entire $10,000 made available by the foundation. A committee of area residents and local employees reviewed the applications for creativity, clear program goals and specific measurement criteria.
Arch Coal's Mountain Coal Company and its West Elk mine are located in Somerset. About 350 people are employed at the mine. St. Louis-based Arch Coal, Inc. (NYSE:ACI) is one of the world's top coal producers for the global steel and power generation industries, serving customers on five continents. Its network of mining complexes is the most diversified in the United States, spanning every major coal basin in the nation. For more information, visit archcoal.com.

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: Upload a CSV File and Show it as JSON Encoded Format in PHP {"id":"1","firstname":"john","lastname":"doe"} This is my JSON Format. I want to upload a CSV File. From which the JSON format will be shown. The CSV File format will be like below: i am using mongo db
Id  FirstName LastName
1  john      doe
2  doe       john

A: Use json_decode($json_string, TRUE) for convert json string to array
Then create a CSV file
Example
header('Content-Type: application/excel');
header('Content-Disposition: attachment; filename="sample.csv"');

$fp = fopen('php://output', 'w');
foreach ( $data as $line ) {
    $val = explode(",", $line);
    fputcsv($fp, $val);
}
fclose($fp);

redpajama_set_name: RedPajamaStackExchange


text:
Leaders of the socio-economic development of regions for 2018 are determined, says Hennadii Zubko
Service of the Deputy Prime Minister of Ukraine, posted 28 May 2019 12:23
Deputy Prime Minister Economy News of regions
According to the results of the monitoring of socio-economic development of regions for 2018, which was released by the Ministry of Regional Development, among those demonstrating the best performance were Kharkiv, Rivne, Vinnytsia, Dnipropetrovsk regions and the city of Kyiv. This was announced by Deputy Prime Minister, Minister of Regional Development, Construction, Housing and Communal Services of Ukraine Hennadii Zubko.
The worst indicators were demonstrated by Mykolayiv, Odesa, Chernihiv, Donetsk and Luhansk regions.
Ranking assessment of socio-economic development of the regions was started in 2015. Based on these statistics, regions are evaluated quarterly by 27 indicators in 6 sectors and annually by 64 indicators in 12 sectors. Such an assessment is an element of a new system for the monitoring of the implementation of the state regional policy and determining the dynamics of change. Ranking showings is an indicator of the effectiveness of managerial decisions at the central and local levels.
More details about the monitoring can be found at the link .
Ukraine inks agreement with UAE to build pavilion for Expo 2020 Dubai
Government will exert every effort to preserve stability in the period between elections in Ukraine, says Olexandr Saienko
By themes «Deputy Prime Minister», «Economy», «News of regions»
09:47, 27 December European integration Deputy Prime Minister Dmytro Kuleba pushes forward new format of public consultations to accelerate Ukraine's integration into EU and NATO


text:
//  **************************************
//  File:        KProcessView.h
//  Copyright:   Copyright(C) 2013-2017 Wuhan KOTEI Informatics Co., Ltd. All rights reserved.
//  Website:     http://www.nuiengine.com
//  Description: This code is part of NUI Engine (NUI Graphics Lib)
//  Comments:
//  Rev:         2
//  Created:     2017/4/12
//  Last edit:   2017/4/28
//  Author:      Chen Zhi
//  E-mail:      cz_666@qq.com
//  License: APACHE V2.0 (see license file)
//  ***************************************

#ifndef KPROCESS_VIEW_DEFINED
#define KPROCESS_VIEW_DEFINED

#include "KButtonView.h"
#include "KViewGroup.h"
#include "AnimationThread.h"
#include "KShapeDrawable.h"
//进度条方向
enum PROCESS_DIR
{
	PROCESS_Horizontal, //横向
	PROCESS_Vertical, //垂直
};

class NUI_API KProcessView : public KStaticView
{
public:
	KProcessView() ;
	virtual ~KProcessView();
	virtual void init(PROCESS_DIR e = PROCESS_Horizontal);

	virtual void setValue(int iPos);    //设定进度的起始位置
	int getValue();
	void enableProcessClip(kn_bool );
	void setIconDrawableRect(int l, int r, int w, int h);
protected:
	kn_int m_value;           //当前进度 0~100
	PROCESS_DIR m_e_dir; //进度条方向
	kn_bool m_b_auto_center_text; //进度文字自动居中
	kn_bool m_b_process_clip; //是否使用裁剪方式绘制进度条
};
typedef boost::shared_ptr<KProcessView> KProcessView_PTR;

class NUI_API KProcessCirleView : public KProcessView
{
public:
	KProcessCirleView() ;
	virtual ~KProcessCirleView();
	void init(REColor);
	virtual void setValue(int iPos);    //设定进度的起始位置
protected:
	KShapeDrawable_PTR m_arc_drawable;

};
typedef boost::shared_ptr<KProcessCirleView> KProcessCirleView_PTR;

// 载入时转圈的动画
class NUI_API KLoadingView : public KView
{
public:
	KLoadingView();
	virtual ~KLoadingView();

	// 设置动画图片
	void setCycleImage(const kn_string& strResPath);

	void setCycleDrawable(KDrawable_PTR drawable);

	// 开始旋转动画, iCycleTime : 转一圈的ms数
	void startAnimation(int iCycleTime = 500,kn_int frame_time = 500);

	void endAnimation();

protected:

	// 圆圈的图片
	KDrawable_PTR m_drawable_cycle;

	CAnimationThread m_ani_thread;

};

typedef boost::shared_ptr<KLoadingView> KLoadingView_PTR;

#endif // KPROCESS_VIEW_DEFINED

redpajama_set_name: RedPajamaGithub


text:
News Release 23-Apr-2020
Game theory suggests more efficient cancer therapy
ITHACA, N.Y. - Cancer cells not only ravage the body - they also compete with each other.
Cornell mathematicians are using game theory to model how this competition could be leveraged, so cancer treatment - which also takes a toll on the patient's body - might be administered more sparingly, with maximized effect.
Their paper, "Optimizing Adaptive Cancer Therapy: Dynamic Programming and Evolutionary Game Theory," published April 22 in Proceedings of the Royal Society B: Biological Sciences.
"There are many game theoretic approaches for modeling how humans interact, how biological systems interact, how economic entities interact," said the paper's senior author, Alex Vladimirsky, professor of mathematics in the College of Arts and Sciences. "You could also model interactions between different types of cancer cells, which are competing to proliferate inside the tumor. If you know exactly how they're competing, you can try to leverage this to fight cancer better."
Vladimirsky and the paper's lead author, doctoral student Mark Gluzman, collaborated with oncologist and co-author Jacob Scott of the Cleveland Clinic. They used evolutionary game theory to model the interactions of three subpopulations of lung cancer cells that are differentiated by their relationship to oxygen: glycoltyic cells (GLY), vascular overproducers (VOP) and defectors (DEF).
In this model, previously co-developed by Scott, GLY cells are anaerobic (i.e., they do not require oxygen); VOP and DEF cells both use oxygen, but only VOP cells are willing to expend extra energy to produce a protein that will improve the vasculature and bring more oxygen to the cells.
Vladimirsky likens their competition to a game of rock, paper, scissors in which a million people are vying against each other. If the majority of participants choose to play rock, a greater number of players will be tempted to switch to paper. As the number of people switching to paper increases, fewer people will play rock and many more will shift to playing scissors. As the popularity of scissors grows, rock will become an attractive option again, and so on.
"So you have three populations, three competitive strategies, undergoing these cyclic oscillations," said Vladimirsky, who directs the Center for Applied Mathematics. "Without a drug therapy, the three subtypes of cancer cells may follow similar oscillating trajectories. Administering drugs can be viewed as temporarily changing the rules of the game.
"A natural question is how and when to change the rules to achieve our goals at a minimal cost - both in terms of the time to recovery and the total amount of drugs administered to the patient," he said. "Our main contribution is in computing how to optimally time these periods of drug treatment adaptively. We basically developed a map that shows when to administer drugs based on the current ratio of different subtypes of cancer."
In current clinical practice, cancer patients typically receive chemotherapy at the highest dosage their body can safely tolerate, and the side effects can be harsh. In addition, such a continuous treatment regimen often leads the surviving cancer cells to develop drug resistance, making further therapy far more difficult. The team's paper shows that a well-timed "adaptive" application could potentially lead to a patient's recovery with a greatly reduced amount of drugs.
But Vladimirsky cautions that, as is often the case in mathematical modeling, reality is much messier than theory. Biological interactions are complicated, often random, and can vary from patient to patient.
"Our optimization approach and computational experiments were all based on a particular simplified model of cancer evolution," he said. "In principle, the same ideas should also be applicable to much more detailed, and even patient-specific, models, but we are still a long way from there. We view this paper as a necessary early step on the road to practical use of adaptive, personalized drug-therapy. Our results are a strong argument for incorporating timing optimization into the protocol of future clinical trials."
The research was supported by the National Institutes of Health Case Comprehensive Cancer Center; National Cancer Institute; the Simons Foundation; the National Science Foundation; and the Chinese University of Hong Kong, Shenzhen.
grs225@cornell.edu
/Applied sciences and engineering/Applied mathematics/Mathematical modeling/Game theory
/Life sciences/Cell biology/Cells/Cancer cells
/Health and medicine/Clinical medicine/Medical treatments/Cancer treatments/Cancer medication


Unfortunately, the success of your orthopaedic surgery will not immediately appear after leaving the operating theatre. A skilfully conducted surgical procedure is but the first step towards a full recovery.
Physiotherapy is a crucial part of the recovery process and can be the difference between achieving normal functionality and an unsuccessful surgery. As trained professionals, physiotherapists can develop a specific program for your surgery, resulting in a quicker recovery and a significantly lower chance of requiring follow up surgery.
What Kind of Surgeries Require Physiotherapy?
Orthopaedic surgery often involves repairing tears in tendons and ligaments, stabilising broken bones, and replacing ruptured ligaments. High velocity sports, physically strenuous work and accidental falls are common causes of such injuries.
Physiotherapists assess your function following the initial post-operative review with the surgeon. This may involve looking at pain, swelling, motion review and an assessment of balance and mobility. The type and length of rehabilitative care will depend on these assessments and the kind of surgery completed.
It's common for patients to experience difficulty maintaining function and mobility before and after a surgical procedure. Post-operative rehabilitation and pre-surgical physiotherapy can help streamline the recovery process, improve quality of life and functional outcomes.
We prioritise progression and patient specific goals, formulating a program to best suit your needs. This program will most likely feature an individualised program of physiotherapy exercises, and may also include other hands-on techniques such as massage, stretching, joint mobilisation, dry needling and taping.
The rehabilitation program after an ACL reconstruction will depend on the extent of the injury and pain. It will often involve a knee brace and mobility aids with a period of weight bearing restriction.
ACL reconstruction involves surgically reconstructing the ligament in the centre of your knee using either the hamstring or patellar tendon to replace the ruptured anterior cruciate ligament (ACL).
We will offer comprehensive education and instruction on posturing, restrictions and carrying out day-to-day activities to manage pain and swelling. Stretches and manual therapy like soft tissue massage and joint mobilisation will be conducted as appropriate along with Pilates and recommended exercises to help achieve a full range of extension and movement.
Patients can usually return to work within 2-4 weeks if their employment is sedentary. Within 6 weeks the patient can start bike riding and start running at the 3-4 month mark. It may take 9-12 months before they can return to their chosen sport.
If you've had or are about to have surgery and need rehab in Perth, make an appointment with Star Physio. To ensure you make satisfactory progress in your recovery, it's crucial to make an appointment within 1-2 weeks after your surgery, depending on the procedure and your surgeon's recommendations.
Whether you're a keen gardener with an overuse injury or an elite athlete, our team of expert physiotherapists will develop a customised rehabilitation program to streamline your recovery.
Call 08 9212 4254 or contact us online to book an appointment today.


text:
Opening Bell
Opening Bell: 4.5.07
Joe Weisenthal
Oil prices rise (AP)
According to every article that we read, it was the goings on of the Iranian hostage crisis that was affecting the price of oil. So you'd think that now that they've been released, oil would fall, right? Well check this out, oil prices rose in Asian trading on anticipation of, get this, summer driving season. What!? So a potential enormous catastrophe gets averted and traders start freaking out over the lamest of excuses, that people are going to visit grandma? And it should be noted that it might snow in NYC this weekend, as well as the rest of the northeast, which means we've got some time before summer starts. If the warm winter was our Al Gore summer, are we now in Dick Cheney winter?
Ford Chief Sticking to His Road Map for Turnaround (NYT)
All eyes are on Chrysler these days, and before that all eyes were on GM, but for the most part, Ford has never captured the public's imagination, at least not since the days of its founder. Now, the company's chief executive Alan Mullally is trying to drum up some enthusiasm over the country by proudly proclaiming that the company's cost-cutting roadmap is on track, and that it should turn a profit in 2009. How inspiring indeed. He insists that nothing major is needed to turn the ship around. Meanwhile, at the New York Auto Show Mullally envioled the Ford Flex, which looks like an oversized Mini.
Backdating Was Pervasive At Bookseller (WSJ)
Big-box bookstore chain Barnes & Noble said that it's found widespread evidence of backdating, but that there was nothing nefarious going on because the company's managers were under the (apparently) mistaken impression that it was all cool. Of course, this is probably what almost all backdaters thought, so this excuse probably won't get them off the hook if the Feds come a-knockin'. Still, it seems pretty obvious at this point that the widespreadness of the practice is what led many to assume that it was above board.
China Again Raises Reserve Ratio (WSJ)
No, really, this time China is going to stem the runaway over-investment in the economy in hopes of cooling things down a little. Seriously, the Chinese government really doesn't want the economy to over heat, and so it's raising reserve requirements on banks. See, there's nothing the government wants more than for things to overheat and then crash, so it's really really serious about gently tapping the breaks.
Google CEO, co-founders get $1 salary (BusinessWeek)
We can't be the only ones who are really bored of the whole $1 salary thing. Sure the Google guys are rich as hell, billionaires even, but they should at least be paid minimum wage. Perhaps someone can explain how a $1 salary is even legal. Maybe it works the same way as with waiters and waitresses, who aren't entitled to minimum wage, although from what we recall, there's been a lawsuit about that. Anyeway, how about $1,000 or $.01 or $5 next year?
Grocers to unite if union goes on strike (San Diego Union Tribune)
One of the last bastions of hardcore organized labor is the southern Californian grocery industry, where the major grocers have been dealing with on again/off again strikes for years. Word is that another strike could be in the works, and now the grocery stores are fighting back. No, they're not bringing in the Pinkertons to bust some melons, but have come to an agreement amongst each other to lock out union members should they decide to strike. Organized industry vs. organized labor, it's only fair.
Wal-Mart Apologizes to Groups That Were Focus of Surveillance (WSJ)
After the story broke yesterday that Wal-Mart had an extensive surveillance program that monitored any group it perceived to be a threat, including activist shareholder groups, the company is busing out the mea culpas. It's specifically apologizing to the shareholder groups, since, as Elizabeth Nowicki point out, they do still own the company, even if they can be a nuisance. Would love to get a reaction from Professor Bainbridge on whether there's anything particularly more wrong about spying on shareholders over anyone else. Hey, if it's in the name of shareholder value, can it be that bad?
Cemex Cements Approval in Bid for Rinker (Dealbook)
Every time there's news of a major concrete merger, we're tempted to use the headline "aggregates industry aggregates", but our tradition here is to just go with the headline supplied by the underlying article. It makes things easier. Furthermore, we already used that headline once a while back, which would make using it again as something akin to copying from ourselves. That being said, Mexico's Cemex, which is already the third biggest cement maker in the world has won approval from the DOJ to buy Australia's Rinker for over $11 billion. That's a pretty big one, although as part of the deal, Cemex will need to sell of some of its US operations.
Prosecutors Rest Case Against Ex-Chief of Qwest (Dealbook)
It can take a really long time for some of these big corporate crime trials to get started, like years and years it seems. But once they get going, you have to admire how quickly they roll along. Already, the prosecution in the Joe Nacchio case rested after it got more than a dozen managers from the company to say that there were deep concerns about the company's stock price. As we pointed out last week, Qwest just won the rights to several billion in government contracts, which should be all of the evidence that the defense needs, since Nacchio's original claim was that he knew of big deals in the pipeline when he sold his shares.
Opening Bell: 10.17.06
Opening Bell: 9.11.06
Opening Bell 10.23.06


text:
Translational Stroke Research
August 2019 , Volume 10, Issue 4, pp 428–439 | Cite as
Acetazolamide Mitigates Intracranial Pressure Spikes Without Affecting Functional Outcome After Experimental Hemorrhagic Stroke
Michael R. Williamson
Cassandra M. Wilkinson
Kristen Dietrich
Frederick Colbourne
First Online: 17 September 2018
Increased intracranial pressure (ICP) after stroke can lead to poor outcome and death. Novel treatments to combat ICP rises are needed. The carbonic anhydrase inhibitor acetazolamide diminishes cerebrospinal fluid (CSF) production, reduces ICP in healthy animals, and is beneficial for idiopathic intracranial hypertension patients. We tested whether acetazolamide mitigates ICP elevations by presumably decreasing CSF volume after collagenase-induced striatal hemorrhage in rats. We confirmed that acetazolamide did not adversely affect hematoma formation in this model or physiological variables, such as temperature. Then, we assessed the effects of acetazolamide on ICP. Lastly, we tested the effects of acetazolamide on behavioral and histological outcome. Acetazolamide reduced the magnitude and occurrence of short-timescale ICP spikes, assessed as disproportionate increases in ICP (sudden ICP increases > 10 mmHg), 1-min peak ICP, and the magnitude of spikes > 20 mmHg. However, mean ICP was unaffected. In addition, acetazolamide reduced ICP variability, reflecting improved intracranial compliance. Compliance measures were strongly correlated with high peak and mean ICP, whereas ipsilateral hemisphere water content was not correlated with ICP. Despite effects on ICP, acetazolamide did not improve behavioral function or affect lesion size. In summary, we show that intracerebral hemorrhage creates an impaired compliance state within the cranial space that can result in large, transient ICP spikes. Acetazolamide ameliorates intracranial compliance and mitigates ICP spikes, but does not improve functional outcome, at least for moderate-severity ICH in rats.
Acetazolamide Compliance Intracerebral hemorrhage Intracranial pressure Stroke
Intracranial pressure (ICP) elevations after stroke contribute to mortality and poor outcome [1]. The magnitude and duration of ICP elevations, frequency of ICP spikes, and intactness of intracranial compliance are predictors of outcome [1, 2, 3, 4]. Existing treatments are highly invasive (e.g., shunt or craniectomy) or mainly target cerebral edema (e.g., mannitol) [5]. However, while edema is an important contributor to raised ICP, it is not the only cause. For instance, preclinical data has shown that edema can be significantly reduced without affecting ICP [6], and ICP can be lowered without a change in brain water content [7]. Perhaps due to their rather narrow focus, current treatments are not consistently effective [8, 9]. Thus, there is a need for novel, minimally invasive treatments to reduce post-stroke ICP.
Space-occupying lesions, such as intracerebral hemorrhages (ICH), can increase ICP by adding to the volume of the intracranial space [10]. Reducing intracranial volume may be an effective strategy to counter high ICP. One possible method to safely reduce the total volume of intracranial contents is by diminishing cerebrospinal fluid (CSF) volume. Here, we tested whether the FDA-approved carbonic anhydrase inhibitor acetazolamide, well-known to decrease CSF production by altering bicarbonate transport in choroid plexus [11, 12], would attenuate ICP elevations after collagenase-induced ICH. This ICH model significantly raises ICP for at least several days [7, 13], whereas the other common ICH model, whole blood infusion, only modestly (30-min peak ICP < 15 mmHg) and transiently (~ 24 h) raises ICP [14].
In order to continually measure ICP while avoiding possible artifacts from restraint or anesthesia, we used head-implanted telemetric pressure probes connected to the epidural space. We have repeatedly used this technique to monitor minute-by-minute ICP changes in freely moving rats over several days [7, 13, 14, 15, 16]. In addition, we tested whether acetazolamide affects hematoma formation because it can acutely increase cerebral blood flow [17], and early interventions can aggravate bleeding after collagenase-induced ICH [18]. Finally, we assessed effects of acetazolamide on behavioral and histological outcome. We evaluated behavioral function with two tasks sensitive to impairments in this ICH model [19]. The Neurologic Deficit Scale was used to assess outcome as early as 3 days after ICH (when ICP is raised) and as late as 28 days. The staircase reaching task was used to probe long-term function from 23 to 27 days post-ICH.
This study conforms to the RIGOR guidelines for effective translational research [20].
Seventy male Sprague-Dawley rats (typically ~ 250–350 g, ~ 8–12 weeks old; ~ 500–600 g for experiments measuring blood pressure and temperature) from the University of Alberta biosciences colony or Charles River Laboratories were used. Source of animals was consistent within experiments. Note that the local colony is bred from rats obtained from Charles River. Animals were housed (individually, except for the behavioral experiment where they were grouped four per cage) in temperature and light-controlled rooms (lights on 7 a.m.–7 p.m.) with free access to water. Food access was unrestricted except during training and testing on the staircase task when animals were restricted to 90% free-feeding weight to encourage reaching. Animals were randomly assigned to groups after surgery using a random number generator. Testing and data analysis were done blinded. Sample sizes were based on previous work and a priori power analyses. Eight animals per group were calculated to give 80% power to detect a 35% change in hematoma volume (SD = 10 μL). Nine animals per group were calculated to give 85% power to detect a 30% reduction in peak ICP (SD = 5 mmHg) [7, 13]. Twelve animals per group were calculated to give 85% power to detect a 25% relative difference in reaching success on the staircase task (SD = 15%).
First, we assessed the safety profile of acetazolamide after ICH. In four animals, we monitored core temperature via telemetry. In three animals, we monitored blood pressure via telemetry. In four anesthetized animals, we acutely monitored blood pressure, heart rate, oxygen saturation, and blood glucose. In another cohort, hematoma volume was measured 24 h post-ICH (N = 8 per group, drug vs. vehicle). Next, we measured ICP continually via telemetry after ICH until brain water content was determined at 72 h (N = 10 acetazolamide-treated, 9 vehicle-treated). In the final experiment, animals were first trained on behavioral tests (N = 12 per group). Then, the effects of acetazolamide on behavioral and histological outcome were assessed up to 28 days post-ICH.
Drug Dosage
Acetazolamide (Sigma, Oakville, ON; 50 mg/kg (~ 0.5 mL total volume) IP in 15% DMSO in saline, pH adjusted to 9 with NaOH to increase solubility [21], 2 mL/kg) or vehicle was given beginning 3 h after ICH. This dose of acetazolamide reduces CSF production to ~ 55% in Sprague-Dawley rats [11, 12] and is similarly effective in other species [11, 22]. This appears to be the maximal effect due to the presence of a subset of acetazolamide-insensitive carbonic anhydrases [23]. Therefore, higher doses would not confer greater inhibition of CSF production. This dose is comparable to the typical daily dose in humans based on allometric scaling [24, 25]. We delayed administration to 3 h post-ICH to match clinically feasible delivery and avoid administration during the majority of active bleeding, which occurs largely during the first hour after collagenase infusion [26]. In experiments with survival times > 24 h, drug or vehicle was administered 3 h after ICH and three more times at 24-h intervals. Dose intervals of 24 h were chosen based on a previous study that showed reduced ventricle volume for at least 24 h after a single 30 mg/kg IP dose [27]. Based on previous observations, ICP appears to return to the normal range by the fourth to fifth day after collagenase-induced ICH [7]. Therefore, acetazolamide would be active throughout the period of raised ICP with this dosing regimen. Naïve rats maintained normal body weight throughout and after this dosing regimen (data not shown).
Intracerebral Hemorrhage
Isoflurane (4% induction, ~ 2% maintenance in 70% N2O, balance O2) was used for anesthesia. Hemorrhage was induced by striatal infusion of bacterial collagenase (Type IV-S, Sigma; 0.2 U, 0.2 U/μL in saline; 0.5 mm anterior, 3.5 mm lateral from Bregma, 6.5 mm below skull surface) [28]. Rectal temperature was maintained at 37 °C with a heated pad during surgery, but not afterwards as ICH rats tend to regulate their temperature well (Fig. 1a). Animals were given soft, wet peanut butter mash mixed with rat chow after surgery to minimize food and water intake deficits [29]. Collagenase was infused into the right striatum in the first two experiments and contralateral to the preferred limb for reaching in the third experiment.
Acetazolamide (50 mg/kg, IP) does not affect core temperature (a, n = 4) or blood pressure (b, n = 3) after ICH. Both parameters were measured by implanted telemetry probes. Arrows indicate time of drug administration. c Acetazolamide given 3 h post-ICH did not affect hematoma volume measured at 24 h
Hematoma Volume Assay
Hemispheric blood volume was determined with a spectrophotometric hemoglobin assay as before [18, 28]. Hematoma size was calculated as ipsilateral-contralateral blood volume. Cerebellar blood volume served as a control.
Measurement of Physiological Parameters
Calibrated TA10TA-F40 probes (Data Sciences Int., St. Paul, MN) were inserted into the peritoneal space to monitor temperature as described [14]. Data was collected with DataQuest ART software (v2.3, Data Sciences Int.). Arterial blood gases were assessed at the time of euthanasia in these animals (ABL800 flex, Radiometer).
Calibrated PA-C10 probes were inserted into the femoral artery to monitor blood pressure as described [13].
Oxygen saturation, glucose, heart rate, and blood pressure were measured in anesthetized rats. Pulse oximetry was measured using with a MouseOx Plus sensor (Starr Life Sciences) on the hind paw. The tail artery was cannulated and connected to a pressure transducer (BP-1, World Precision Instruments). Blood glucose was measured from tail capillary blood samples (Contour Next One).
Intracranial Pressure Measurement
ICP and animal movement were measured with PA-C10 telemetric pressure probes (Data Sciences Int.) implanted in the epidural space immediately after collagenase infusion [7, 13, 14, 15, 16]. Probes were calibrated by Data Sciences Int. prior to surgery and measurements adjusted as described [7, 14, 16]. Data were collected every minute with DataQuest ART software. ICP data were exported from ART and then processed with Excel (Microsoft) and MATLAB (R2016a, MathWorks). Data from all animals was processed simultaneously in a blinded manner. Movement and electrical interference artifacts were removed prior to analysis [14]. Disproportionate increases in ICP (DIICP) were evaluated based on previous work [3, 30]. DIICP events were defined as sudden ICP increases > 10 mmHg lasting at least 3 min. The baseline reference was defined as the average ICP over the previous 60 min. Other analyses included mean ICP over 12-h epochs, peak 1-min and 30-min ICP, average magnitude of spikes above 20 mmHg (the clinical definition of intracranial hypertension [5] and a threshold over which the risk of death in rats increases [13, 15]), and ICP variability (magnitude of ICP change between 1- and 30-min timeframes). High ICP variability reflects poor intracranial compliance [2, 4]. Analysis of standard deviations yielded similar results (not shown), but such a method of analysis does not convey individual change events and thus may tend to mask brief or uncommon but important events [3].
Brain Water Content Determination
Water content was determined with the wet-dry method in tissue blocks that encompassed 2 mm anterior to 4 mm posterior from the infusion site [14]. Tissue weights were recorded before and after baking at 100 °C for 24 h. Water content was calculated as a percentage of the wet tissue weight. Cerebellum served as a control.
Behavioral Assessment
Animals were trained and tested on the Montoya staircase and Neurologic Deficit Scale (NDS) tasks as described previously [14, 19]. The NDS task is comprised of subtests examining forepaw flexion, hindlimb retraction, spontaneous circling, beam walking, and forepaw grasp. Scores from each subtest were combined to form composite scores, which range from 0 (no deficits) to 14 (largest deficits). Baseline NDS testing was done in a single session after sufficient subtest training. Post-ICH NDS testing was done on days 3, 7, 14, 21, and 28. A single day of staircase training or testing included two sessions separated by at least 4 h. Baseline function on the staircase task was defined as the average success rate with the preferred paw over the final 3 days of training. Reaching data from animals that failed to maintain an average success rate of 9 out of 21 pellets per session over the final 3 training days were excluded. Reaching ability was probed on days 23 to 27 after ICH.
Animals were overdosed with sodium pentobarbital (~ 100 mg/kg IP) and perfused with 0.9% saline followed by 10% neutral-buffered formalin. Brains were post-fixed and then cryoprotected in 30% sucrose prior to sectioning with a cryostat. Forty-micrometer sections spaced 200 μm apart and extending through and beyond the lesion were stained with cresyl violet. Lesion volume was assessed as described previously [19]. In short, lesion volume = volume of intact hemisphere − volume of injured hemisphere. This analysis accounts for necrosis, cavity formation, and ventriculomegaly.
Data were analyzed with GraphPad Prism (v. 6.0, GraphPad Software Inc., La Jolla, CA). Independent means were compared with unpaired Student's t tests. Variance was compared with F-tests, and corrections (i.e., Welch's correction) were applied when appropriate. Normality was assessed with D'Agostino and Pearson omnibus tests. Mean ICP over time and staircase data were analyzed with repeated measures ANOVA. Cumulative probabilities of ICP change events were compared with Kolmogorov-Smirnov tests. Linear regressions assessed the relationships between variables. Ordinal NDS data were assessed with Mann-Whitney U tests. One-tailed tests were used when comparing univariate effects of acetazolamide versus vehicle on ICP because all past work has shown that acetazolamide consistently reduces CSF production and ICP, and there is no obvious mechanism for acetazolamide to increase ICP. All other tests were two-tailed. Data are presented as mean ± SEM. Statistical significance was set at P < 0.05.
There was no mortality. One animal per group was excluded from ICP and movement analysis in the second experiment due to probe battery failure. Brain water content measurements from those animals were included. Staircase data from three vehicle-treated animals were excluded from the third experiment due to failure to meet minimum success criteria during training. NDS and lesion volume data from those animals were included.
Acetazolamide is safe when given after ICH. Core temperature and blood pressure were stable after repeated doses (Fig. 1a, b). Acetazolamide did not affect hematoma size (Fig. 1; P = 0.858) or spontaneous home cage movement (Fig. 2a, P = 0.506). Physiological parameters monitored after a single dose in anesthetized animals showed no effect on blood pressure, heart rate, or oxygen saturation (Table 1). Blood glucose increased over time, as is known to occur during isoflurane anesthesia [31]. Finally, PO2 and PCO2 were 140.6 ± 9.9 and 52.3 ± 1.9 mmHg, respectively, when measured 1 h after the final dose of acetazolamide in animals used to monitor core temperature.
Home cage activity and edema after ICH. a Acetazolamide did not affect home cage movement. b ICH significantly increased brain water content within in the injured hemisphere, but there was no effect of acetazolamide. Measurements were made on 6-mm tissue blocks encompassing the hemorrhage in the injured hemisphere, an equivalent area in the contralateral hemisphere, and the entire cerebellum (see "Materials and Methods"). c Brain water content in the injured hemisphere was not correlated with mean or peak ICP (r = − 0.347 to − 0.248, P ≥ 0.173, see "Results"). AU arbitrary units (measured by changes in probe signal strength as animals move nearer or farther from the receiver [48]). ***P < 0.001
Acute physiological parameters after 50 mg/kg acetazolamide in isoflurane-anesthetized rats (n = 4)
Time post-injection
Blood pressure (mmHg)
81.5 ± 1.1
Oxygen saturation (%)
Heart rate (beats per minute)
328.3 ± 7.7
Blood glucose (mmol/L)
18.4 ± 0.5***
20.5 ± 1.4**
**P < 0.01, ***P < 0.001 compared to baseline
ICH caused significant edema in the injured hemisphere (P < 0.001), which acetazolamide did not affect (Fig. 2b; P = 0.600). Consistent with our previous work [7, 14], there was no linear relationship between injured hemisphere water content and peak 1- or 30-min ICP or mean ICP in ICH rats (Fig. 2c, r = − 0.347 to − 0.248, P ≥ 0.173).
ICH increased ICP throughout the recording period as compared to uninjured rats where ICP is ~ 4–5 mmHg when measured with this technique [13, 14, 15, 16]. ICP declined towards normal levels near the end of the recording period, consistent with our past work [7, 13]. Acetazolamide did not affect mean ICP (Fig. 3a; P = 0.952, group main effect) or 30-min peak ICP (Fig. 3b; P = 0.162). However, acetazolamide reduced transient ICP spikes; the 1-min peak ICP (Fig. 3c; P = 0.037) and the average magnitude of spikes above 20 mmHg (Fig. 3d; P = 0.041) were significantly less in drug-treated animals. One acetazolamide-treated animal did not have any spikes above 20 mmHg and was omitted from the latter comparison. Importantly, high ICP suppressed spontaneous activity; mean activity was significantly less when ICP was 20–40 mmHg (1.93 ± 0.16 AU; arbitrary units) than when ICP was 0–20 mmHg (2.31 ± 0.06 AU; P = 0.035). Note that for this analysis, "zero" activity values were excluded to avoid times of sleep.
Effects of acetazolamide on ICP after ICH. a Acetazolamide did not affect mean ICP (shown as mean over 12-h epochs). Acetazolamide did not change peak 30-min ICP (b), but significantly reduced peak 1-min ICP (c) and the mean ICP of spikes above 20 mmHg (d). Mean ICP in uninjured rats using this technique is ~ 4–5 mmHg [13, 14, 15]. *P < 0.05
ICH caused DIICPs of varying duration and magnitude (Fig. 4a–e). Acetazolamide nearly eliminated DIICPs (vehicle: 208 events across 8 animals, acetazolamide: 1 event across 9 animals, Fig. 4c, P < 0.001, comparing slopes of cumulative events between groups; examples of DIICPs from vehicle-treated animals are shown in Fig. 4a, b, a representative trace from an acetazolamide-treated animal is also shown in Fig. 4b for comparison). ICP increased considerably during DIICPs (typically > 25 mmHg, Fig. 4d, e). DIICP events lasted from 3 (the defined minimum) to 23 min (mean 6.42, median 5 min, interquartile range 3.75 min).
Disproportionate increases in ICP (DIICPs) after ICH. a An example of a DIICP in a vehicle-treated animal. Arrow indicates start of DIICP. Note the rapid increase and overcompensatory drop at the resolution of the event, which are indicative of poor intracranial compliance. b An example of multiple DIICPs over several hours in a vehicle-treated animal (solid line). Each arrow indicates the start of a discrete event. A representative ICP trace from an acetazolamide-treated animal is shown with a dashed line. Note the relative stability compared to the vehicle-treated animal. Also note that spikes were much less frequent and of smaller magnitude in the vehicle-treated animal (none exceeded the threshold to be considered DIICPs). c Acetazolamide nearly abolished DIICPs (P < 0.001, see "Results"). Numbers in parentheses indicate the total number of DIICP events for each group. d, e Histograms of ICP during DIICPs show that ICP increases tended to be rather large. Distribution of ICP during DIICPs is presented as an increase relative to the 60-min moving average baseline (d) and absolute ICP (e). Note that increases above ~ 20–25 mmHg are potentially lethal in rats and that ICP in uninjured rats is about 4–5 mmHg [7, 13, 14, 15]
Acetazolamide reduced ICP variability, demonstrating improved intracranial compliance, as indicated by marked leftward shifts in the cumulative probabilities of the magnitude of ICP change between 1- and 30-min epochs (Fig. 5a, b, P < 0.001). Importantly, acetazolamide decreased the mean minute-to-minute ICP variability during the 30-min peak ICP in each animal (Fig. 5c; P = 0.016). High ICP variability (poor compliance) was associated with high mean and peak ICP (1-min or 30-min variability vs. 1-min or 30-min peak ICP or mean ICP, r = 0.469 to 0.887, all P < 0.05, except 30-min variability vs. mean ICP where P = 0.058; Fig. 5d).
Acetazolamide reduced ICP variability. Cumulative probability plots of the magnitude of ICP change between minute-to-minute measurements (a) and 30-min epochs (b). Acetazolamide caused a significant leftward shift in curves at both timescales, indicating reduced variability and improved intracranial compliance. c Decreased mean minute-to-minute ICP change in acetazolamide-treated animals during the 30-min peak ICP of each animal further demonstrates that acetazolamide stabilizes ICP fluctuations in a high pressure state. d High ICP variability was associated with high peak and mean ICP (see "Results"). *P < 0.05; ***P < 0.001
ICH caused significant impairments on the NDS and staircase tasks for the duration of testing (Fig. 6, P < 0.001, baseline vs. each post-ICH day for both tasks). Acetazolamide did not affect behavioral function measured with the NDS (Fig. 6a, P ≥ 0.178) or staircase tasks (Fig. 6b, P = 0.653, group main effect). As well, acetazolamide did not affect lesion volume (Fig. 7, P = 0.906). Linear regressions assessing lesion volume vs. NDS rank among all animals (rank ordered from least to most impaired over all test days, r = 0.355 and P = 0.089) and lesion volume vs. reaching success rank (averaged over all test days, r = 0.111 and P = 0.631) revealed no significant relationships. Similarly, there was no significant relationship between mean deficit rank (average rank between tasks) and lesion volume (r = 0.171, P = 0.458). Overall, lesion volume alone was a poor predictor of outcome.
Acetazolamide did not improve behavioral outcome after ICH. a Repeated Neurologic Deficit Scale testing showed significant impairments after ICH, but no effect of acetazolamide. Possible composite scores range from 0 (no deficits) to 14 (greatest deficits). b Staircase reaching task data show significant impairments in reaching performance that were unaffected by drug treatment
Acetazolamide did not affect lesion volume measured 28 days after ICH (a). b Representative grayscale coronal sections from the middle of the lesion stained with cresyl violet. Lesions are outlined in black. ICH caused tissue necrosis, cavity formation, and ventriculomegaly—all of which were accounted for in lesion volume measurements. Injury was restricted to the ipsilateral hemisphere. There was no damage to overlying cortex except near the path of the infusion needle
Acetazolamide decreases CSF production and ICP in healthy animals and humans, and can provide benefit for patients suffering from idiopathic intracranial hypertension [32, 33]. Here, we report that acetazolamide ameliorates brief ICP spikes and restores intracranial compliance after experimental ICH but does not affect behavioral outcome or lesion size. Our results are not attributable to effects on intraparenchymal water content. Importantly, acetazolamide given 3 h after ICH does not worsen bleeding. Carbonic anhydrase inhibitors may provide a non-invasive means of reducing harmful ICP spikes without targeting edema, but whether such a treatment on its own would be beneficial is unclear.
Sudden large-magnitude ICP rises, as during DIICP events and other brief spikes, can reduce cerebral blood flow, cause herniation, and reflect a state of impaired intracranial compliance [5, 34, 35, 36]. The attenuation of ICP spikes and reduction of ICP variability by acetazolamide suggests that it restored intracranial compliance after ICH. This is perhaps most clearly demonstrated by the lower ICP variability in acetazolamide-treated animals during each animal's 30-min peak ICP—a time when intact compliance mechanisms are critical for limiting damage potentially caused by high ICP. Indeed, the intracranial pressure-volume relationship is non-linear, and pulsatile pressure increases are much greater at higher ICP [35].
The transient ICP spikes we observed were quite large, typically exceeding 25 mmHg (Fig. 4e). Notably, current guidelines suggest that ICP be maintained below 20 mmHg in ICH and traumatic brain injury patients [5], and we have observed that sustained ICP increases above 20–25 mmHg in rats can cause death [13, 15]. As well, it is conceivable that large spikes could meaningfully reduce cerebral blood flow or otherwise impair brain function without overt trauma (herniation) [36]. Indeed, spontaneous movement declined during times of high ICP, suggesting some impact on behavioral function. However, we note that our previous study showed that, at least when averaged over 24 h epochs, collagenase-induced ICH only modestly lowered cerebral perfusion pressure [13]. Simultaneous monitoring of cerebral perfusion pressure and ICP at high temporal resolution would be ideal. Overall, it seems reasonable that the repeated ICP spikes we characterized in this study, although brief, could be harmful. Therefore, it is promising that acetazolamide nearly eliminated DIICPs and reduced the average magnitude of other large spikes. However, we found that mean ICP was not different between our vehicle and drug groups, despite large differences in short-timescale spikes. This discrepancy is likely due to the offsetting ICP declines that typically followed spikes, as is characteristic of poorly compliant systems (Fig. 4). It appears that relatively fast ICP changes are masked when averaged over long epochs. Many preclinical studies of ICP report mean ICP as their principle measure, although there is great interest in applying better predictive analyses in the clinical population [30, 37].
Brain hemorrhages and other ectopic cerebral masses can disturb CSF flow dynamics [38, 39]. Our results show that acetazolamide improved intracranial compliance and mitigated ICP spikes, but, likely due to the overcompensatory ICP drops that typically followed spikes, mean ICP averaged over long timescales was not different between treatment groups. This suggests that perturbed CSF dynamics after ICH might contribute to high ICP variability and large magnitude spikes. We speculate that a consequence of reducing CSF production with acetazolamide was to limit the disturbance in CSF flow, thereby dampening ICP fluctuations and ameliorating ICP spikes. Other means of restoring normal CSF dynamics (e.g., shunt) should similarly reduce ICP spikes.
Despite significantly reducing ICP spikes, acetazolamide did not improve behavioral outcome after ICH. There are several conclusions that could be drawn from this. First, it is possible that ICP does not influence outcome in this ICH model. This seems unlikely due to the considerable clinical evidence linking various measures of ICP to outcome [1, 2, 3, 4, 5] and observations within the collagenase model that high ICP can be lethal [13]. Second, brief ICP spikes may not be as predictive of outcome as high mean ICP. Perhaps, brief spikes are primarily dangerous when they cause herniation or subarachnoid hemorrhage, which we did not observe. Third, our behavioral tests may not have been able to detect any actual functional differences due to the somewhat large hemorrhages we induced. Indeed, impairments were rather severe and there was relatively little recovery of function; reaching success was < 30% of baseline 27 days after ICH, and there was little indication of improvement on the NDS task from day 7 to 28. However, the staircase and NDS tasks are among the most sensitive and widely used tasks for probing deficits caused by striatal hemorrhages [19]. Alternatively, any beneficial effects of acetazolamide might be more evident after more severe hemorrhages in which larger, more sustained ICP spikes occur. Indeed, the clinical population most likely to experience benefit from mitigating ICP spikes is that with severely raised ICP with high mortality, which we did not see in our model.
Consistent with previous work [7, 14], our data show that edema is not predictive of conventional measures of ICP such as mean and peak ICP, at least for a given injury severity. There does seem to be some correlation between edema and ICP over a larger range of injuries (i.e., across studies) and when data include sham-operated animals. Since water contained within the hematoma can contribute to brain water content measurements [14], such measurements are ideally done on only peri-hematoma tissue samples that exclude the hematoma. However, due to the irregular boundaries of the hematomas produced by collagenase infusion, this cannot be done with great accuracy in the model we used. Nonetheless, collagenase-induced ICH causes widespread edema relative to hematoma size [26]; we expect that hematoma-constrained water was a relatively small factor in our measurements.
Also of interest is whether hematoma size predicts ICP. Our past study using the whole blood infusion model found only a small and transient difference in ICP between varying hematoma volumes [14]. For example, increasing the blood infusion volume from 100 to 160 μL only further increased ICP by ~ 3–4 mmHg for about 12 h [14]. Relative to hematoma size, collagenase-induced ICH causes much larger and longer lasting ICP rises than blood infusion [7, 13, 14]. As discussed, these differences in the magnitude and pattern of ICP elevations are not completely explained by model differences in edema [7, 14]. At least in rodent models, it seems that edema and hematoma size alone are not precise predictors of ICP. Here, we found that compliance measures were correlated with mean and peak ICP, as well as the number of DIICP events (Fig. 6d, also see "Results"). Notably, mean 1-min ICP change, which reflects short timescale compensatory ability of the intracranial space, tended to be most strongly correlated with ICP. Compliance appears to predict future ICP better than other factors such as hematoma size and edema.
The ability of acetazolamide to reduce CSF formation and ICP is well-documented across species [11, 12, 21, 22, 27]. Recently, a single, very large dose of acetazolamide (~ 800 mg/kg, ~ two to three times the scaled maximum daily dose recommended in humans [24, 33]) was shown to reduce ICP by as much as 85% for about 5 h in uninjured anesthetized rats [40]. Such a large dose would likely cause significant metabolic acidosis and would therefore not be clinically valuable, especially with the need for repeated doses to target persistently raised ICP as in the present study [41]. As such, we did not assess those doses. Other work indicates that reduced CSF volume can last at least 24 h after a single 30 mg/kg dose in rats [27], and most studies have used 30–50 mg/kg (equivalent to a typical 500 mg dose in humans [24, 25]) with similar effects on ICP to that reported by the study using 800 mg/kg [11, 12]. The primary mechanism for the effects of acetazolamide is thought to be carbonic anhydrase inhibition, which interferes with bicarbonate transport in choroid plexus and thereby diminishes CSF production [11]. Other effects of acetazolamide in the CSF production pathway have been suggested, including actions on Na/K ATPase and aquaporins [40, 42].
Aside from affecting CSF production, acetazolamide is a vasodilator that can transiently increase cerebral blood flow [17]. While it is plausible that increased cerebral blood volume could acutely increase ICP, this does not appear to be the case. This is perhaps most clearly demonstrated in a study by Uldall and colleagues where ICP in anesthetized rats was continuously monitored before and after acetazolamide administration [40]. They observed a steady decline in ICP within 10 min of drug delivery with no indication of an ICP increase. However, another study described brief, modest ICP rises immediately after acetazolamide administration in a small number of animals, although ICP quickly declined [43]. Of course, it is possible that increased total cerebral blood volume due to vasodilation blunts the effects of CSF depletion on ICP, but the net effect is a reliably decreased ICP. Our data indicate that there was no difference in blood volume in the contralateral hemisphere or cerebellum 24 h after acetazolamide compared to vehicle administration, demonstrating that there is no lasting change in cerebral blood volume.
Potential deleterious side effects of reducing CSF production in order to treat high ICP should also be considered. For instance, CSF flow is implicated in waste removal from the brain [44]. Whether CSF flow has a role in removal of harmful hematoma breakdown components after ICH is unknown, but slowing such a process could be detrimental. As well, CSF acts as a compensatory reserve to maintain normal ICP. Significant reduction of CSF volume could result in below normal ICP, although low ICP is typically less harmful than high ICP [10]. Moreover, acetazolamide only decreases CSF production by about half at most [23], meaning that CSF production could be titrated by drug dose without concern of complete inhibition. Finally, acetazolamide and other carbonic anhydrase inhibitors can cause metabolic acidosis [41], which could be especially harmful with very large or chronic doses.
Previous work showed that acetazolamide may be neuroprotective after ICH [45]. Since that study found a neuroprotective effect after striatal infusion of 100 μL of blood, it is unlikely that it is due to an effect on ICP because the blood infusion model does not dangerously raise ICP, even with larger infusion volumes [14]. However, we note that in that study, acetazolamide was administered as an intracerebral co-injection with blood and sample size was only three per group for measures of cell death. In the present study, we gave acetazolamide systemically at a clinically relevant 3-h delay and did not observe any neuroprotective effect in a relatively large sample (12 per group). It is difficult to conclude whether carbonic anhydrase inhibition presents a useful and effective method for neuroprotection after ICH due to model, timing, dose, and administrative route differences between studies. As well, we note that while data from an in vitro astrocyte trauma model suggested that acetazolamide can attenuate cellular edema [46], our in vivo data found no effects of acetazolamide on brain water content after ICH (Fig. 2b) or in healthy rats (not shown).
Our study has some limitations. First, we did not directly assess CSF production. Nonetheless, acetazolamide is well-known to reduce CSF production across species, and its effectiveness in rats using the same or similar dose given systemically as in our study has been characterized [11, 12, 21, 27]. Moreover, measuring CSF production is technically difficult and not compatible with ICP monitoring [21]. As well, the marked reductions in ICP spikes and variability we observed indicate that acetazolamide did influence ICP with the dose, timing, and administration route we used. Second, we were unable to measure ICP and behavioral outcome in the same animals because our method for measuring ICP is most accurate during short-term (several days) experiments [15]. Long-term ICP monitoring has been achieved, but only with intermittent measurements that require the animal to be repeatedly anesthetized [47]. Such a method would not detect brief ICP spikes or permit assessment of ICP variability. A method for accurate, long-term, continual ICP monitoring that does not interfere with natural behavior is needed. Finally, in future studies, it would be ideal to combine ICP monitoring with simultaneous measurement of other parameters, such as tissue oxygenation and cerebral blood flow, but this is not currently feasible in freely moving rodents.
In summary, we show that acetazolamide mitigates brief ICP spikes and improves intracranial compliance without affecting hematoma formation, edema, mean ICP, behavioral outcome, or lesion size after collagenase-induced ICH in rats. We speculate that impaired CSF flow dynamics after ICH may contribute to ICP spikes and that acetazolamide ameliorates ICP spikes by diminishing CSF production. Overall, these findings might suggest that brief ICP spikes and intracranial compliance are poor predictors of behavioral outcome in the collagenase model, but additional work is needed to clarify precise links between ICP measures and outcome across a broader range of situations. Despite the lack of behavioral benefit in our study with moderate hematoma size, reducing harmful ICP spikes may reduce mortality in patients with large hemorrhages. Combining acetazolamide with existing treatments that target edema may more potently protect against ICP spikes.
We thank Dr. Kenneth Butcher for initial discussion on the use of acetazolamide and Dr. Yonglie Ma for surgical assistance.
Research was supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada. FC is a Canada Research Chair in Intracerebral Hemorrhagic Stroke. MRW was supported by an Alberta Innovates–Health Solutions studentship.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Protocols conformed to Canadian Council of Animal Care Guidelines and were approved by the Biosciences Animal Care and Use Committee at the University of Alberta.
Sykora M, Steinmacher S, Steiner T, Poli S, Diedler J. Association of intracranial pressure with outcome in comatose patients with intracerebral hemorrhage. J Neurol Sci. 2014;342:141–5. https://doi.org/10.1016/j.jns.2014.05.012.CrossRefGoogle Scholar
Kirkness CJ, Burr RL, Mitchell PH. Intracranial pressure variability and long-term outcome following traumatic brain injury. Acta Neurochir Suppl. 2008;102:105–8.CrossRefGoogle Scholar
Fan J, Kirkness C, Vicini P, Burr R, Mitchell P. An approach to determining intracranial pressure variability capable of predicting decreased intracranial adaptive capacity in patients with traumatic brain injury. Biol Res Nurs. 2010;11:317–24. https://doi.org/10.1177/1099800409349164.CrossRefGoogle Scholar
Tian Y, Wang Z, Jia Y, Li S, Wang B. Intracranial pressure variability predicts short-term outcome after intracerebral hemorrhage: a retrospective study. J Neurol Sci. 2013;330:38–44. https://doi.org/10.1016/j.jns.2013.04.001.CrossRefGoogle Scholar
Hemphill JC, Greenberg SM, Anderson C, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032–60. https://doi.org/10.1161/STR.0b013e3181ec611b.CrossRefGoogle Scholar
Murtha LA, Mcleod DD, Pepperall D, Mccann SK, Beard DJ, Tomkins AJ, et al. Intracranial pressure elevation after ischemic stroke in rats: cerebral edema is not the only cause, and short-duration mild hypothermia is a highly effective preventive therapy. J Cereb Blood Flow Metab. 2015;24:592–600. https://doi.org/10.1038/jcbfm.2014.230.CrossRefGoogle Scholar
John RF, Colbourne F. Localized hypothermia reduces intracranial pressure following collagenase-induced intracerebral hemorrhage in rat. Brain Res. 2016;1633:27–36.CrossRefGoogle Scholar
Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke. 2002;33:136–40. https://doi.org/10.1161/hs0102.100877.CrossRefGoogle Scholar
Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg. 1992;77:584–9. https://doi.org/10.3171/jns.1992.77.4.0584.CrossRefGoogle Scholar
Mokri B. The Monro-Kellie hypothesis: applications in CSF volume depletion. Neurology. 2001;56:1746–8. https://doi.org/10.1212/WNL.56.12.1746.CrossRefGoogle Scholar
Vogh BP, Godman R. Timolol plus acetazolamide: effect on formation of cerebrospinal fluid in cats and rats. Can J Physiol Pharmacol. 1985;63:340–3.CrossRefGoogle Scholar
Morrow BA, Holt MR, Starcevic VP, Keil LC, Severs WB. Mechanism of delayed intracranial hypertension after cerebroventricular infusions in conscious rats. Brain Res. 1992;570:218–24.CrossRefGoogle Scholar
Hiploylee C, Colbourne F. Intracranial pressure measured in freely moving rats for days after intracerebral hemorrhage. Exp Neurol. 2014;255:49–55. https://doi.org/10.1016/j.expneurol.2014.02.017.CrossRefGoogle Scholar
Williamson MR, Colbourne F. Evidence for decreased brain parenchymal volume after large intracerebral hemorrhages: a potential mechanism limiting intracranial pressure rises. Transl Stroke Res. 2017;8:386–96. https://doi.org/10.1007/s12975-017-0530-x.CrossRefGoogle Scholar
Silasi G, MacLellan CL, Colbourne F. Use of telemetry blood pressure transmitters to measure intracranial pressure (ICP) in freely moving rats. Curr Neurovasc Res. 2009;6:62–9. https://doi.org/10.2174/156720209787466046.CrossRefGoogle Scholar
Williamson MR, John RF, Colbourne F. Measurement of intracranial pressure in freely moving rats. Methods Mol Biol. 2018;1717:17–25.CrossRefGoogle Scholar
Eicke BM, Buss E, Bähr RR, Hajak G, Paulus W. Influence of acetazolamide and CO2 on extracranial flow volume and intracranial blood flow velocity. Stroke. 1999;30:76–80. https://doi.org/10.1161/01.STR.30.1.76.CrossRefGoogle Scholar
John RF, Williamson MR, Dietrich K, Colbourne F. Localized hypothermia aggravates bleeding in the collagenase model of intracerebral hemorrhage. Ther Hypothermia Temp Manag. 2015;5:19–25. https://doi.org/10.1089/ther.2014.0020.CrossRefGoogle Scholar
MacLellan CL, Auriat AM, McGie SC, Yan RHY, Huynh HD, De Butte MF, et al. Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies. J Cereb Blood Flow Metab. 2006;26:1031–42. https://doi.org/10.1038/sj.jcbfm.9600255.CrossRefGoogle Scholar
Lapchak PA, Zhang JH, Noble-haeusslein LJ. RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res. 2013;4:279–85. https://doi.org/10.1007/s12975-012-0209-2.CrossRefGoogle Scholar
Karimy JK, Kahle KT, Kurland DB, Yu E, Gerzanich V, Simard JM. A novel method to study cerebrospinal fluid dynamics in rats. J Neurosci Methods. 2015;241:78–84. https://doi.org/10.1016/j.jneumeth.2014.12.015.CrossRefGoogle Scholar
McCarthy KD, Reed DJ. The effect of acetazolamide and furosemide on cerebrospinal fluid production and choroid plexus carbonic anhydrase activity. J Pharmacol Exp Ther. 1974;189:194–201.Google Scholar
Brown PD, Davies SL, Speake T, Millar ID. Molecular mechanisms of cerebrospinal fluid production. Neuroscience. 2004;129:957–70. https://doi.org/10.1016/j.neuroscience.2004.07.003.CrossRefGoogle Scholar
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31. https://doi.org/10.4103/0976-0105.177703.CrossRefGoogle Scholar
Low EV, Avery AJ, Gupta V, Schedlbauer A, Grocott MPW. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ. 2012;6779:1–14. https://doi.org/10.1136/bmj.e6779.Google Scholar
MacLellan CL, Silasi G, Poon CC, Edmundson CL, Buist R, Peeling J, et al. Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab. 2008;28:516–25. https://doi.org/10.1038/sj.jcbfm.9600548.CrossRefGoogle Scholar
Gao F, Zheng M, Hua Y, Keep RF, Xi G. Acetazolamide attenuates thrombin-induced hydrocephalus. Acta Neurochir Suppl. 2016;121:373–7.CrossRefGoogle Scholar
Williamson MR, Dietrich K, Hackett MJ, Caine S, Nadeau CA, Aziz JR, et al. Rehabilitation augments hematoma clearance and attenuates oxidative injury and ion dyshomeostasis after brain hemorrhage. Stroke. 2017;48:195–203. https://doi.org/10.1161/STROKEAHA.116.015404.CrossRefGoogle Scholar
Lourbopoulos A, Mamrak U, Roth S, Balbi M, Shrouder J, Liesz A, et al. Inadequate food and water intake determine mortality following stroke in mice. J Cereb Blood Flow Metab. 2017;37:2084–97. https://doi.org/10.1177/0271678X16660986.CrossRefGoogle Scholar
Fan BJ, Kirkness C, Vicini P, Mitchell P. Intracranial pressure waveform morphology and intracranial adaptive capacity. Am J Crit Care. 2008;17:545–54.Google Scholar
Lattermann R, Schricker T, Wachter U, Georgieff M, Goertz A. Understanding the mechanisms by which isoflurane modifies the hyperglycemic response to surgery. Anesth Analg. 2001;93:121–7.CrossRefGoogle Scholar
Wall M, Kupersmith MJ, Thurtell MJ, Moss HE, Moss EA, Auinger P, et al. The longitudinal idiopathic intracranial hypertension trial: outcomes from months 6–12. Am J Ophthalmol. 2017;176:102–7. https://doi.org/10.1016/j.ajo.2017.01.004.CrossRefGoogle Scholar
Smith SV, Friedman DI. The idiopathic intracranial hypertension treatment trial: a review of the outcomes. Headache. 2017;57:1303–10.CrossRefGoogle Scholar
Dunn LT. Raised intracranial pressure. J Neurol Neurosurg Psychiatry. 2002;73:i23–7. https://doi.org/10.1136/jnnp.73.suppl_1.i23.CrossRefGoogle Scholar
Marmarou A, Shulman K, LaMorgese J. Compartmental analysis of compliance and outflow resistance of the cerebrospinal fluid system. J Neurosurg. 1975;43:523–34. https://doi.org/10.3171/jns.1975.43.5.0523.CrossRefGoogle Scholar
Beard DJ, McLeod DD, Logan CL, Murtha LA, Imtiaz MS, van Helden DF, et al. Intracranial pressure elevation reduces flow through collateral vessels and the penetrating arterioles they supply. A possible explanation for 'collateral failure' and infarct expansion after ischemic stroke. J Cereb Blood Flow Metab. 2015;35:861–72. https://doi.org/10.1038/jcbfm.2015.2.CrossRefGoogle Scholar
Kawoos U, Mccarron RM, Auker CR, Chavko M. Advances in intracranial pressure monitoring and its significance in managing traumatic brain injury. Int J Mol Sci. 2015;16:28979–97. https://doi.org/10.3390/ijms161226146.CrossRefGoogle Scholar
Kosteljanetz M. CSF dynamics in patients with subarachnoid and/or intraventricular hemorrhage. J Neurosurg. 1984;60:940–6.CrossRefGoogle Scholar
Gjerris F, Borgesen SE, Sorensen PS, Boesen F, Schmidt K, Harmsen A, et al. Resistance to cerebrospinal fluid outflow and intraeranial pressure in patients with hydrocephalus after subarachnoid haemorrhage. Acta Neurochir. 1987;88:79–86.CrossRefGoogle Scholar
Uldall M, Botfield H, Jansen-olesen I, Sinclair A, Jensen R. Acetazolamide lowers intracranial pressure and modulates the cerebrospinal fluid secretion pathway in healthy rats. Neurosci Lett. 2017;645:33–9. https://doi.org/10.1016/j.neulet.2017.02.032.CrossRefGoogle Scholar
Sporn A, Scothorn DM, Terry JE. Metabolic acidosis induced by acetazolamide. J Am Optom Assoc. 1991;62:934–7.Google Scholar
Filippidis AS, Kalani MYS, Rekate HL. Hydrocephalus and aquaporins: lessons learned from the bench. Childs Nerv Syst. 2011;27:27–33. https://doi.org/10.1007/s00381-010-1227-6.CrossRefGoogle Scholar
Malkinson TJ, Cooper KE, Veale WL. Induced changes in intracranial pressure in the anesthetized rat and rabbit. Brain Res Bull. 1985;15:321–8. https://doi.org/10.1016/0361-9230(85)90158-3.CrossRefGoogle Scholar
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4:147ra111. https://doi.org/10.1126/scitranslmed.3003748.CrossRefGoogle Scholar
Guo F, Hua Y, Wang J, Keep RF, Xi G. Inhibition of carbonic anhydrase reduces brain injury after intracerebral hemorrhage. Transl Stroke Res. 2012;3:130–7. https://doi.org/10.1007/s12975-011-0106-0.CrossRefGoogle Scholar
Sturdivant NM, Smith SG, Ali SF, Wolchok JC, Balachandran K. Acetazolamide mitigates astrocyte cellular edema following mild traumatic brain injury. Sci Reports. 2016;6:33330. https://doi.org/10.1038/srep33330.CrossRefGoogle Scholar
Uldall M, Juhler M, Skjolding AD, Kruuse C, Jansen-Olesen I, Jensen R. A novel method for long-term monitoring of intracranial pressure in rats. J Neurosci Methods. 2014;227:1–9. https://doi.org/10.1016/j.jneumeth.2014.01.036.CrossRefGoogle Scholar
Colbourne F, Auer RN, Sutherland GR. Characterization of postischemic behavioral deficits in gerbils with and without hypothermic neuroprotection. Brain Res. 1998;803:69–78. https://doi.org/10.1016/S0006-8993(98)00612-X.CrossRefGoogle Scholar
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
1.Neuroscience and Mental Health InstituteUniversity of AlbertaEdmontonCanada
2.P217 Biological Sciences Building, Department of PsychologyUniversity of AlbertaEdmontonCanada
Williamson, M.R., Wilkinson, C.M., Dietrich, K. et al. Transl. Stroke Res. (2019) 10: 428. https://doi.org/10.1007/s12975-018-0663-6
Accepted 04 September 2018
First Online 17 September 2018


At Extra Space Storage, we strive to provide an unforgettable storage experience! With a well-maintained, secure facility and a friendly, professional staff, we go above and beyond to deliver high-quality storage and great customer service. Contact us today to reserve a storage unit in Hialeah!
Here at US Storage Centers in Hialeah we strive to meet every customer's individual storage needs, whether you began renting five years ago or just last week. When you come in to find your new self-storage unit in Hialeah, we will help you choose the best option according to what and for how long you want to store. Working together, we can set up the ideal storage plan.