text:
Olney is a census-designated place and unincorporated community in Flathead County, Montana, United States. Its population was 191 as of the 2010 census. Olney has a post office with ZIP code 59927.  The most recent 2020 census states the population is 146 according to census.gov.   The community is located along U.S. Route 93.

The post office opened in 1907.

It is near Lower Stillwater Lake.

Demographics

References

Census-designated places in Flathead County, Montana
Unincorporated communities in Flathead County, Montana


A petition was filed in the Supreme Court on Monday for a SIT (Special Investigation Team) probe into the alleged Punjab National Bank scam to the tune of Rs 11,500 crores.
The apex court has neither fixed nor given any date for hearing the plea of lawyer Manohar Lal Sharma.
But it is expected that the matter would come up for hearing within one-two weeks, as per the Supreme Court registry.
Mr Sharma contended that the PNB scam allegedly to the tune of Rs 11,500 crores approximately should be investigated by a SIT.
Keeping in view the magnitude and the enormity of the alleged involvement of accused persons in the case, only a SIT probe can unearth the truth, Mr Sharma contended.
The SIT should incorporate a retired Supreme Court judge, and be under the supervision of the apex court and must be monitored by it, Mr Sharma submitted in his 13-page petition.


Holy Family will host the Philadelphia pre-release screening of the feature documentary film "The Anonymous People" at 7 pm on Thursday, May 23 in the University's Campus Center. Tickets to see the film are $15 in advance, $20 at the door. A panel discussion with the filmmakers will follow the screening.
The documentary is about the 23.5 million Americans living in long-term recovery, and the emerging public recovery movement that will transform how alcohol and other drug problems are dealt with in our communities.
"The Anonymous People" is told through the faces and voices of citizens, leaders, volunteers, corporate executives, public figures, and celebrities who are laying it all on the line to save the lives of others just like them. This passionate new public recovery movement aims to transform public opinion, engage communities and elected officials, and finally shift public policy toward lasting solutions.
A catered VIP Reception will be held prior to the screening at 6 pm and will offer attendees an opportunity to talk with business leaders, legislators, experts in the field, the filmmaker and others.
Tickets to VIP Reception and film are $75. To purchase tickets for the reception or the film, go to https://www.councilsepa.org.


AS-IS. Seller to make no repairs. Property will not qualify for financing and will require a cash purchase. Purchaser cannot re-sell, convey-This 4BR, 2BA home features a living room, dining area and den w/FP. Property is being sold or otherwise transfer title to property within 60 days of Grantor's execution of deed.
Back on Market! Great investment property, located at the end of a private gravel road. Convenient location. ALL OFFERS WILL BE SUBJECT TO A 10 DAY UPSET BID PERIOD AND COURT APPROVAL. Property being sold "as is". Inspections must be done prior to the 10-day upset bid period.


text:
import PropTypes from "react";

const Form = ({ className, children }) => (
  <form
    className={` ${className}`}
  >
    {children}
  </form>
);

Form.propTypes = {
  className: PropTypes.string,
  children: PropTypes.string,
};

export default Form;

export const FieldSet = ({ className, children }) => (
  <fieldset
    className={` ${className}`}
  >
    {children}
  </fieldset>
);

FieldSet.propTypes = {
  className: PropTypes.string,
  children: PropTypes.string,
};

export const Legend = ({ className, children }) => (
  <legend
    className={` ${className}`}
  >
    {children}
  </legend>
);

Legend.propTypes = {
  className: PropTypes.string,
  children: PropTypes.string,
};

export const FormButton = ({ className, children }) => (
  <button
    className={`icon ${className}`}
  >
    {children}
  </button>
);

FormButton.propTypes = {
  className: PropTypes.string,
  children: PropTypes.string,
};

redpajama_set_name: RedPajamaGithub


I have taken the images of this project were taken in Dagoretti, gigantic slum on the outskirts of Nairobi, capital of Kenya. They tell the poverty and distress of the 300 thousand people who live there, but also the beauty of the Children in Need project promoted by the NGO AMREF here. Children in Need aims to recover the "street children": children and teenagers left to fend for themselves in this slum, easy prey to drugs, prostitution, despair. AMREF seeks to restore hope to these shoots, helping them to leave the street and offering them a path - that of socialization, educational activities, painting, acting - that will help them to acquire esteem and self-confidence, to build a future that is not more despair and self-destruction, but of growth.
The last picture is that of a large house of cards. Some cards show images of the Dagoretti slums of Africa and the poorest who suffer. More pictures tell us the luxury of Western consumer society. Apparently, there are two ways the polar opposite, separated in an absolute way. But this separation is a sad illusion. Our Western prosperity rests on fragile papers of the poverty of others, and if the base of the castle gives the whole palace collapses on itself, even dragging us into this precipice.
Bella installazione, lodevole il progetto, grazie che ci fai riflettere sui valori della vita!


After Alanis McLachlin inherits her estranged mother's shop, the White Magic Five & Dime, in Berdache, Arizona she tries to track down and make things right with old customers her mother has conned. After sort of adopting an abused wife that was one of those customers, Alanis then needs to find the real killer of Martha's husband when Martha is arrested for his murder. In only a few short weeks since hitting town, Alanis is once again smack in the middle of a murder investigation. She barely survived her last nose poking. Will she be so lucky this time?
I have to say, I'm loving this series. Alanis is a different kind of "heroine." She doesn't fit any kind of mold. In fact, she may have broken the mold. She goes about things in a way I never expect and it's all because of the way she grew up. I can't even begin to imagine her childhood, so she keeps me on my toes. The murder mystery kept me guessing and there are great secondary characters. All-in-all an excellent way to spend an afternoon.


Enhanced ROS production by NADPH oxidase is correlated to changes in antioxidant enzyme activity in human heart failure.
Nitric oxide/reactive oxygen species generation and nitroso/redox imbalance in heart failure: from molecular mechanisms to therapeutic implications.
The role of reactive oxygen species in the pathophysiology of cardiovascular diseases and the clinical significance of myocardial redox.
Angiotensin II and oxidative stress in the failing heart.
Improved heart failure by Rhein lysinate is associated with p38MAPK pathway.
Lessons from the Hamster: Cricetulus griseus Tissue and CHO Cell Line Proteome Comparison.
NADPH oxidase signaling and cardiac myocyte function.
Right ventricular function in cardiovascular disease, part I: Anatomy, physiology, aging, and functional assessment of the right ventricle.
Role of NADPH oxidase in H9c2 cardiac muscle cells exposed to a simulated ischemia-reperfusion.
Serotonin-mediated protein carbonylation in the right heart.
Tricuspid annular motion as a predictor of severe right ventricular failure after left ventricular assist device implantation.
Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies.
T. Kartes C. Maack, H. Kilter, G. Nickenig, U.
J . Card . Fail .
The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.


From the moment you step through the front door, we hope.
We believe downstairs in the Sandarah is all about living and.
With four generous bedrooms, two bathrooms, two secluded leisure areas, an.
With five large bedrooms, four bathrooms and a vast, open kitchen.
The grandeur of the Esperance will captivate you from the moment.
From the welcoming entry that leads you into this MBA national.
The safety under the shade of the grand outdoor living area.
Dreaming of a home that delivers cherished family memories and rooms.
The Murano has been designed with the large family and entertaining.
The Trevi Lido is a family home which offers plenty of.


text:
Aldi to phase out plastic packaging in a number of stores
Aldi stores across Plymouth are phasing out black plastic trays used for fresh food produce.
A couple of stores in Bradford are also receiving the treatment. This follows Aldi's promise to ensure all of its packaging is recyclable, reusable or compostable by 2025.
The replacement trays will save up to 265 tonnes of plastic a year. Frequently, black plastic packaging ends up in landfill because it cannot be identified by machinery that sorts through usual household waste items.
Fritz Walleczek, Managing Director of Corporate Responsibility at Aldi UK, said: "Cutting waste is part of Aldi's DNA and we have a longstanding commitment to minimise our impact on the environment. One part of that is to prevent plastic going to landfill by using materials that are easier to recycle – like these clear trays – but also to ensure that there is a demand for recycled plastic by using it in products like our pasta pots."
Aldi are also scraping the packaging of its plastic pasta pots instead using 95 per cent recycled materials, this wall save a further 139 tonnes of plastic a year.
The supermarket chain join several other companies in a bid to reduce plastic pollution, a key issue in the UK currently. Theresa May has recently been reported to be introducing a proposal to increase the plastic bag levy to further crackdown on what she termed Britain's 'throwaway culture'.
Aldi is the UK's fifth largest and fastest-growing supermarket and is a continuous frontrunner in leading the way for environmental protection.
In August, the supermarket also pledged to become carbon neutral by 2019.

redpajama_set_name: RedPajamaCommonCrawl


This entry was posted in Book Launches, Book Unboxings, The Legends Chronicles and tagged acas, along came a spider, book launch, book unboxing, k.m. robinson, legends chronicles, surprise book. Bookmark the permalink.


text:
{% load static_dbg %}
{% load bootstrap3 %}

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  <meta http-equiv="X-UA-Compatible" content="IE=edge">
  <meta name="viewport" content="width=device-width, initial-scale=1">
  <script src="https://ajax.googleapis.com/ajax/libs/jquery/2.2.4/jquery.min.js"></script>
  {% bootstrap_css %}
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Are you looking for a beautiful and sacred location to host a Yoga Retreat, a Meditation Retreat, a Wellness Retreat or a Spiritual Retreat or simply looking for a place to chill and rejuvenate?
We will work with you to build a package that meets your specific needs, either as a group or as an individual.
Packages can include guest room, en-suite shower, breakfast, beverages, meals, treatments, transportation, tours, Yoga & Meditation classes, workshops, courses and more. Venue hire fees are Priced On Application based upon the components you require. Your programme can be designed based upon your stay of 1-6 days, 7 days, 10 days or long-term rentals. Rates are available for group hires and individual stays.
You are able to hire the entire Ashok Tree Centre with full use of the facilities and en-suite room accommodations for up to 32 people. If you want a "closer to nature" experience, you can pitch tents, which would extend the number of people you can host into the hundreds.
All prices are provided in GBP/£ but actual fees can be paid in other currencies as agreed.
To check availability and to design your Ashok Tree stay, please provide details in the form at bottom of page.


Karah's workshop at the Residency of the North, Power of the Personal, focuses on these aspects of her documentary style of photographic storytelling. Karah will be discussing her style & working process, talking about personal projects & how they can improve you as a photographer, personal driven photographs and making sure there are no gaps in your clients family album.
"From the moment I realised I had a space under my bed, I began to collect tangible memories and started archiving my personal collections in boxes next to my slippers. Layers of small Christmas tags complete with spider handwriting, tops from empty bottles of beer, postcards, love letters, napkins and drawings. Theatre tickets, bus passes, magazine cuttings, party invites, birthday cards and of course photographs.
Those shoeboxes filled with items started my longing to preserve my backstories visually with photography. I went from having a need to save addressed envelopes to having a burning desire to capture moments on film, instant polaroid and then over the years, digitally.
I learnt that my favourite images from my childhood were not the flash studio shots, but the real life emotions caught just at the right time. The images of the ones I love, but with younger faces in rooms I grew in. Holding these photographs in my hand, I am transported back to a time that's no longer accessible physically, but once seen and soaked up – I'm there. Right back there.
I never found school easy and even though I worked hard whilst I was there, academically I didn't tick all the boxes. When the time came to leave and go onto further education , it was the most amazing time to really absorb myself in the subjects that I was good at. At the age of 16, I was offered a place at university to study Fine Art and over a 5 year period I achieved a BTEC, 2 A Art Levels and a BA Hons Degree. Whilst studying I became hooked on film photography and all my time was spent in the darkroom. I enjoyed everything about the medium and it became the base for many hours of experimenting and developing my own professional practice. Whilst I attended Portsmouth University, my passion for research and learning was ignited and I clearly remember purchasing a photo essay book by Duane Michals and feeling this ripple within. I still have that book and equally, I still get that feeling when making photos and learning.
For me nothing feels as good as photographing your own. Nothing. I am highly motivated about the obvious relation photography has with the passing of time and how it preserves slices of importance into tiny rectangles. Family life is ever changing, nothing lasts or stays the same. People die, situations transform and what we call 'home ' is forever morphing into something new. Some may look at my work and feel it is simply snapshots, but to photograph the ones you love, it burns. The layers of emotional connection, the back stories, the intimate surroundings, it isn't always easy and the thing is, it shouldn't be. When we photograph the ones we love, we can never outgrow those images or feelings, the story in front of the lens and the story which one day will only be available in printed tangible items, will be our most cherished tale.
What makes you so passionate about the work you do?
When photographing clients I really try hard to record them in the same approach I photograph my own. I really love giving them professional images of their beautiful ordinary moments and highlighting to them, that their life as it is, is picture perfect.
I shoot all my digital work on Fuji gear. It ticks all my boxes and most importantly gives me crazy amounts of joy! The ergonomics are perfect, the weight and size is amazing, it's discreet and packs a punch in the fast style I work in. I've recently purchased a small film camera, Olympus XA2, that is the same model my Grandmother used to photograph my childhood and I'm seriously excited about using that more.
Other than your camera – what one piece of kit can you not live without?
I may have a crazy obsession with SD cards. I'm addicted to them! I always dual shoot, so I find I can go through an awful lot in a month – and I'm not the fastest photographer when it comes to editing. I equally couldn't live without my handmade cord camera straps, they are so comfortable to wear for long periods of time.
What advice would you give to any aspiring photographer?
Find your creative tribe. Never be scared to ask for help. Don't copy others, listen to what gets your juices going. Make personal work your future self will thank you for. It's okay to be different.
Finally, what one thing would you love to photograph more than anything else?
I would love the chance to photograph more births . Birth photography is on the rise and I don't think there is anything more wonderful than to celebrate new life in such a visual way. Photography during this momentous time not only locks down memories, they can help to heal and give us something we may need without knowing it.


Paul McCartney and Heather Mills are said to be close to reaching an agreement over a divorce deal, claimed to be worth as much as £60m, following a secret meeting at the High Court in London.
McCartney and Mills are said to be at the first stage of a mediation process that is designed to find common ground between the two parties over the financial value of the settlement.
The couple arrived separately and were accompanied by their lawyers yesterday (October 11) before a hearing in Court 16.
The final deal could be the biggest contested divorce settlement to date.
McCartney is expected to consent to a structured settlement, which would provide Mills with a lump sum on top of further payments for the care and support of their daughter Beatrice until she reaches the age of 18.


text:
Earth Syst. Dynam., 5, 67–87, 2014
https://doi.org/10.5194/esd-5-67-2014
Seasonality of the hydrological cycle in major South and Southeast Asian river basins as simulated by PCMDI/CMIP3 experiments
S. Hasson1,2, V. Lucarini1,3,4, S. Pascale1, and J. Böhner2 S. Hasson et al. S. Hasson1,2, V. Lucarini1,3,4, S. Pascale1, and J. Böhner2
1KlimaCampus, Meteorological Institute, University of Hamburg, Hamburg, Germany
2KlimaCampus, Institute of Geography, University of Hamburg, Hamburg, Germany
4Walker Institute for Climate System Research, University of Reading, Reading, UK
Received: 05 Jul 2013 – Discussion started: 30 Jul 2013 – Revised: 04 Dec 2013 – Accepted: 16 Dec 2013 – Published: 04 Feb 2014
Abstract. In this study, we investigate how PCMDI/CMIP3 general circulation models (GCMs) represent the seasonal properties of the hydrological cycle in four major South and Southeast Asian river basins (Indus, Ganges, Brahmaputra and Mekong). First, we examine the skill of the GCMs by analysing their performance in simulating the 20th century climate (1961–2000 period) using historical forcing (20c3m experiment), and then we analyse the projected changes for the corresponding 21st and 22nd century climates under the SRESA1B scenario. The CMIP3 GCMs show a varying degree of skill in simulating the basic characteristics of the monsoonal precipitation regimes of the Ganges, Brahmaputra and Mekong basins, while the representation of the hydrological cycle over the Indus Basin is poor in most cases, with a few GCMs not capturing the monsoonal signal at all. While the model outputs feature a remarkable spread for the monsoonal precipitation, a satisfactory representation of the western mid-latitude precipitation regime is instead observed. Similarly, most of the models exhibit a satisfactory agreement for the basin-integrated runoff in winter and spring, while their spread is large for the runoff during the monsoon season. For the future climate scenarios, most models foresee a decrease in the winter P − E over all four basins, while agreement is found on the decrease of the spring P − E over the Indus and Ganges basins only. Such decreases in P − E are mainly due to the decrease in precipitation associated with the western mid-latitude disturbances. Consequently, for the Indus and Ganges basins, the runoff drops during the spring season while it rises during the winter season. Such changes indicate a shift from rather glacial and nival to more pluvial runoff regimes, particularly for the Indus Basin. Furthermore, the rise in the projected runoff, along with the increase in precipitation during summer and autumn, indicates an intensification of the summer monsoon regime for all study basins.
How to cite: Hasson, S., Lucarini, V., Pascale, S., and Böhner, J.: Seasonality of the hydrological cycle in major South and Southeast Asian river basins as simulated by PCMDI/CMIP3 experiments, Earth Syst. Dynam., 5, 67–87, https://doi.org/10.5194/esd-5-67-2014, 2014.


text:
Q: Angular Service Worker ngsw-config.json S3/Cloudflare Image Caching CORS Error In an Angular 9 app, when I add this image caching snippet to ngsw-config.json, I get a CORS error and images don't display. If I remove this snippet the app works correctly (with no errors).

Access to fetch at 'https://assets.myurl.net/images/banner.jpg' from
origin 'https://localhost:8100' has been blocked by CORS policy: No
'Access-Control-Allow-Origin' header is present on the requested
resource. If an opaque response serves your needs, set the request's
mode to 'no-cors' to fetch the resource with CORS disabled.

ngsw-config.json (snippet):
"assetGroups": [{
    "name": "cdn",
    "installMode": "lazy",
    "updateMode": "lazy",
    "resources": {
        "urls": [
            "https://assets.myurl.net/**"
        ]
    }
}]

Images are stored in an AWS S3 bucket with CORS configuration:
<?xml version="1.0" encoding="UTF-8"?>
<CORSConfiguration xmlns="http://s3.amazonaws.com/doc/2006-03-01/">
<CORSRule>
    <AllowedOrigin>*</AllowedOrigin>
    <AllowedMethod>GET</AllowedMethod>
</CORSRule>
</CORSConfiguration>

*

*Cloudflare is being used as a CDN (and DNS).

*The app is on the latest 9.x releases: @angular 9.2.1, @angular/service-worker
9.1.12.

*Adding crossorigin="anonymous" to img and picture tags didn't seem to help.

Steps to consistently reproduce the error in Chrome/PC:

*

*Clear browser cache

*Open browser private/incognito

*Go to website -- images show okay

*Click refresh -- images no longer show - CORS errors in browser console

UPDATE
Based on this post (S3 not returning Access-Control-Allow-Origin headers?) the issue appears to be that the service worker does not send an Origin in the request header (so S3 doesn't send access-control headers).
Service Worker Request (copied from Chrome console):
Request URL: https://assets.myurl.net/images/banner.jpg
Referrer Policy: strict-origin-when-cross-origin
Provisional headers are shown
Referer: https://localhost:8100/
User-Agent: Mozilla/5.0 (Windows NT 10.0; Win64; x64) AppleWebKit/537.36 (KHTML, like Gecko) Chrome/85.0.4183.83 Safari/537.36

First of all, make sure an Origin header with every request. If no Origin header is
sent, S3 won't send access-control headers, as S3 deems them
irrelevant (and typically, they are). A browser (for which the CORS
mechanism is meant) will automatically send an Origin header when
doing cross-origin HTTP requests through XMLHTTPRequest.

Based on this post (S3 - Access-Control-Allow-Origin Header) the S3 cors script has been updated to include:
<AllowedMethod>HEAD</AllowedMethod>
<AllowedHeader>*</AllowedHeader>

Adding crossorigin="anonymous" to img tags doesn't change the service worker request header. So this doesn't fix the problem.
Cloudflare cache has been purged.
This obscure post (https://community.cloudflare.com/t/access-control-allow-origin-headers-stripped/158102/2) includes:

If you add or change CORS configuration at your origin web server,
purging the Cloudflare cache by URL does NOT update the CORS headers.

I cache busted the banner.jpg image by adding a random querystring (i.e. banner.jpg?q=abc). The banner image always displays correctly (while the other images still show cors errors). The service worker cache in Chrome console Application Tab > Cache Storage shows that the image as cached. Cloudflare caching configuration "Caching Level" = Standard "delivers a different resource each time the query string changes".

However, if I upload a new image to S3 banner01.jpg (i.e. not already cached by Cloudflare) I do get a cors error showing this image. I tried this three additional times by uploading different image names and did not get a cors error. Interestingly, an hour later even the new images are showing cors errors.
A curl command (that does not specify Origin in header) runs successfully on my local PC. The response does not contain CORS headers. e.g.
curl -v "https://assets.myurl.net/images/banner.jpg"

Adding origin to the curl command does return CORS headers. e.g.
curl -v --header "Origin: https://www.example.com" "https://assets.myurl.net/images/banner.jpg"

access-control-allow-origin: https://www.example.com
access-control-allow-methods: GET, HEAD
access-control-allow-credentials: true

UPDATE 2
I can't explain why, but Chrome now returns cors headers in the Angular Service Worker fetch response. The request does NOT include an Origin header.
accept-ranges: bytes
access-control-allow-methods: GET, HEAD
access-control-allow-origin: *

However, Safari does not. All browsers appear to be working okay but Safari still shows cors errors.

A: Go to your S3 bucket. Click on Permissions, then CORS configuration.
If you have a CORS configuration, change the allowed origin from this:
<AllowedOrigin>*</AllowedOrigin>

TO
<AllowedOrigin>http://*</AllowedOrigin>
<AllowedOrigin>https://*</AllowedOrigin>

If you don't have a CORS configuration, add a config like this:
<CORSConfiguration>
<CORSRule>
    <AllowedOrigin>http://*</AllowedOrigin>
    <AllowedOrigin>https://*</AllowedOrigin>
    <AllowedMethod>PUT</AllowedMethod>
    <AllowedMethod>POST</AllowedMethod>
    <AllowedMethod>DELETE</AllowedMethod>
    <AllowedMethod>GET</AllowedMethod>
    <AllowedHeader>*</AllowedHeader>
</CORSRule>
<CORSRule>
    <AllowedOrigin>*</AllowedOrigin>
    <AllowedMethod>GET</AllowedMethod>
</CORSRule>
</CORSConfiguration>

redpajama_set_name: RedPajamaStackExchange


On Saturday the 30th of March, dad and I went to Hugh Fearnley Whittingstall's River Cottage Canteen and Deli for lunch. We made reservations which was a great decision because it was packed when we got there and others had been turned away. We were sat very quickly and provided with water.
As you can see from the menu it says '30th March, Lunch'. This is because the dishes change literally day to day. Not week to week, but day to day. I looked at a menu from the Tuesday of the same week (trying to plan what I was going to have) but the menu had changed (luckily to something better)!
I was kind of expecting more of a canteen lay out - long tables with benches rather than chairs, but I thought the decor was nice anyways. I liked the miss-matched chairs and door-tables. In the right photo is the deli - lots of local cheeses, homemade pastry picnic foods and local produce.
The kitchen was right on the front and you could see all of the dishes being prepared, made and organised whilst you waited. I thought that was a good touch because I'm quite a nosey foodie anyways! Our waitress was the loveliest girl ever. She was very busy but also very attentive and so polite - when I took the tea bags out of our teapot and popped them on the side of my saucer, she noticed within two seconds and offered to take the plate and give me a new one. We also didn't have to sit with our dirty plates in front of us for more than two minutes.
We both opted for the Braised beef brisket with wild garlic mash, buttered greens and a red wine sauce.
It was absolutely delicious. Although the mash is green, the garlic wasn't over powering. The beef was incredibly soft, moist and flavourful and the red wine sauce really packed a punch. I would definitely eat this again and if you go, I definitely recommend it to you, it was delicious!
As it was for lunch we didn't opt for anything else - and I was full for a rather long time following this! I would certainly return to Hugh's canteen to try some of the other dishes out, you're definitely spoiled for choice! My only downfall would be on the price of drinks - wine was £4 a glass and over. I wasn't drinking but I'd be put off if I wanted one. Have you ever been? What did you have?
it was a lovely day too, so we went for a walk. Such a good location for the restaurant.


Messaging app WhatsApp now averages more than one billion daily users each day, according to parent company Facebook. Facebook made this revelation in its Q2 2017 earnings report, stating that WhatsApp users now send 55 billion messages and 4.5 billion photos daily.
According to Facebook, WhatsApp has 1.3 billion active monthly users, supports 50 languages, with users sharing more than one billion videos daily.
WhatsApp is popular among users, mostly because of the promise of end-to-end encryption and the imagination of privacy afforded through the use of the platform. WhatsApp was acquired by Facebook in 2014 for $19 billion, a hefty price tag, even in a world of expensive startup acquisitions. At the time, the platform had 350 million daily users, and 450 million monthly users. The platform had one billion total monthly users in the first quarter of 2016.
"As we celebrate this milestone, we're committed more than ever to bringing you more useful features to enjoy, while delivering the reliability, simplicity, and security you expect with WhatsApp," said WhatsApp CEO Jan Koum in a blog post.


Friend of mine was willing to part with his '94 Miata. I sold my Mazda6 last week and got the NA yesterday. There's a small list of mods he's done to the car, most which just make it a more raw driving experience. So far it's been a blast to drive. Awesome little machine. All I've got to do is become more proficient and driving a manual.


Amy Grant is not only a Christian artist, she's also a peddlar of pure pop. With a distinguished career that stretches back to the 70's she has seen trends come and go and has managed to reinvent herself in the changing landscape. One thing that doesn't change though is her love for making Christmas music, a passion that has seen her release 3 full-length festive recordings, the first of which, 'A Christmas Album', was made when she was just 22 in 1983. 'A Christmas Album' is a fine mix of secular and traditional songs, 4 of which Grant wrote herself. Other contributors included popular Christian artist Michael W. Smith who is a big fan of the season of the goodwill himself. 'A Christmas Album' is never overwhelming with delicate arrangements countered with expressions of heavenly outpourings like on the climatic 'Hark! The Herald Angels Sing'. The album does sound dated in places with songs like 'Emmanuel' and 'Little Town' completely of their time. But for the majority of the 11 tracks Amy Grant proves she can do Christmas without ever slipping into formulaic. A fine example is her version of Nat King Cole's 'The Christmas Song' which save for a lonely piano features Grant's expressive and emotive vocals.
It took a full 9 years for Amy Grant to follow up on her wonderful first Christmas album and on 1992's 'Home For Christmas' she went back to basics. 'Home For Christmas' has soft homely outlook with Grant sprinkling traditional classics like 'Have Yourself A Merry Little Christmas' and 'Winter Wonderland' with a collection of new songs she wrote for the occasion. Standouts include 'Have Yourself A Merry Little Christmas' which features lush orchestration with Grant providing equally grandiose vocals. 'Joy To The World/For Unto Us A Child Is Born' is equally impressive, as rich of sonic delights as you're going to get outside of spending time in the music halls of Vienna. Of the Grant penned tracks the understated 'Emmanuel, God With Us' is probably the pick of the bunch, sounding as it does effortlessly economical in its delivery beside the rich arrangements found elsewhere on the album.
Amy Grant's most recent Christmas album from 1999 proved that the singer had not lost her Christmas groove and like its predecessors 'A Christmas To Remember' was split between new tracks and covers of classic Christmas songs. This was Grant's third holiday album and again it scored well on both the Billboard and Christmas charts. The title track was an ambitious opener that referenced all the things that make Christmas such a memorable time of the year. It contrasted well with Grant's take on 'Silent Night' that took the song into an unexpected otherworldly direction, quite affecting it is too, a genuine highlight. And the delights kept on coming with 'Mr Sandman' magically turned into 'Mr Santa' (how come no one else thought of that?) and the epic Michael W. Smith composition 'Agnus Dei' which offered an restrained yet ecstatic climax.


Seven decades ago, Weatherby magnums were flipping the industry on its head for their velocity and flat trajectory performance.
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Weatherby Firearms needs no intro. It's the gun you've lusted for. It's an elite brand you respect, even if you've never fired one or even seen one yourself. That kind of brand equity takes sweat equity. And Roy Weatherby had that and more.
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Adam's done a lot of podcasts, but I promise you, if you've heard him before, stick around. He even said at the end of the show, he's never done a show like this.
Also, make sure you check out our sweepstakes with From Field to Plate and SIXSITE! It's an awesome opportunity to hang out with me, Donovan and Jeremiah Doughty in Texas hunting and cooking whitetail deer. The winner will get some sweet SIXSITE gear and an all-expense-paid trip to Texas. Learn more.


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The Left in Disarray
18 October 2017 by Colin Shindler
Review of Sean Matgamna's book The Left in Disarray
Most of the time, the key terms of the anti-capitalist Left have no clear meaning, they express and convey emotion, not reason. They are the tools of demagogy more than of reasoned discourse … our language of politics is decayed, disablingly.
So opens Sean Matgamna's timely book on the moral gangrene of the British Left. In connection with apologia for Mao's murder of 70 million Chinese, he speaks of 'mind-rotting conflation, purging of the real meaning of words, vandal destruction of important concepts, smart-ass apologist's attempts to obscure important distinctions'. And of course, Matgamna focuses in detail on the foggy understanding of Jews, profound ignorance of Zionism – and the raison d'etre for a Hebrew republic in the Land of Israel.
Matgamna and his supporters within the Alliance for Workers' Liberty (AWL) have for decades argued for a rational approach to the vexed question of Israel and have not blown in the wind with other sections of the far Left. The AWL emerged as an opposition to the wholesale support for the Soviet invasion of Afghanistan in 1979 on the revolutionary Left.
An admirer of Trotsky, Matgamna has been labelled a 'Zionist stooge' and a 'turncoat' by the rest of the Trotskyist Left. Neither a Zionist nor a Jew, he has stood apart from the campaign to demonise Israel and, in a sense, defined how socialists should act. Moreover this code of ethics of someone on the far Left would bewilder many official defenders of Israel within British Jewry who are unable to find any blemishes in Netanyahu's policies. Significantly Matgamna quotes the Irish socialist, James Connolly's comment that 'impartiality in the face of injustice is the virtue of a slave'. For those who have moved from the Left to the Right, figures like Matgamna, are particularly perplexing and threatening. They would also argue that such groups are decidedly irrelevant. However as events have demonstrated during the past year, the revolt against elites can come from the most unlikely of ideological origins.
In 1948, the British Left was passionately in support of Zionism. Aneurin Bevan threatened to resign from Atlee's government because of Ernest Bevin's policies in Palestine. Andrei Gromyko, the Soviet representative at the UN, was making quasi-socialist Zionist speeches – indeed Stalin, along with Truman, can ironically be regarded as one of the founding fathers of the Jewish state. British Communists flip-flopped in accordance with Stalin's wishes. Many Trotskyists who had similarly opposed Zionism recognised the need for a state of the Jews after 1945, following the revelations of the Shoah. After all, if socialism was international, then it could also be built in Palestine – and Jews should therefore not be prevented from emigrating there.
In this book, Matgamna traces the path from reasoned discourse in 1948 to 'the most malignant hysteria on the Left' in 2017 and attributes it to a Stalinisation of thought. As newer generations become politically aware, twentieth century history becomes less significant when faced with today's problems. The history of the Jews becomes marginalised and the richness of Zionist ideology is reduced to a malicious soundbite and a meaningless slogan.
CONFUSED ANTI-IMPERIALISM
In part, this is due to a growing identification with the colonised world in the post-war era and a new generation's identification with the struggles for liberation in the 1960s. Even before the post-1967 settlement drive on the West Bank, many on the New Left found it easier to identify with the embryonic Palestinian national movement than with Marxist Zionists in Israel. Yet as Jeremy Corbyn's odyssey demonstrates, this also led to turning a blind eye towards reactionary regimes in the developing world. Matgamna remarks that 'confused anti-imperialism is a central root of the absolute anti-Zionist dominant in the addled Left today'. After all, few drew attention to the fact that at one point in history, Russian nationalism, posing as international Communism, dominated a third of humanity against their wishes. An inability to think outside the received ideological wisdom has led many on the Left up one-way streets such that the elimination of Israel has become a mere detail in the unfolding revolutionary drama.
Perhaps a key question for many Trotskyists was how far to align themselves with the foreign policies of the Soviet Union. During World War II many Trotskyists saw a political equivalence between the Allies and the Nazis. Both, it was argued, had forced workers into uniforms to further the ends of capitalism and imperialism. When the Normandy landings took place in the summer of 1944, the French Trotskyist publication, La Vérité, proclaimed that 'they're all the same… Roosevelt's liberation is the same as Hitler's socialism'.
During the post-war period, Trotskyist groups in different locations supported North Korea during the Korean war, China in annexing Tibet in 1959, the USSR in invading Afghanistan in 1979 and Serbia in the intended ethnic cleansing of Kosovo in 1999. Like many on the Left, they supported Ho Chi Minh and the National Liberation Front during the Vietnam war. What was airbrushed out of the narrative was Ho Chi Minh's killing of hundreds of Vietnamese Trotskyists after the war and the decimation of their sizeable movement. Clearly Ho Chi Minh's imitation of Stalin's murderous practice would not have impressed the student generation of the 1960s.
Matgamna points out today that many on the far Left ignore 'the rise of clerical-fascist terrorism'. Indeed many sided with the ayatollahs during the Iran-Iraq war during the 1980s. But as he incisively points out, when the Comintern under Lenin pledged their support in 1920 for liberation movements in the colonies – it was with the noted exception of pan-Islamic movements. Indeed in 1946, Tony Cliff, later the founder of the Socialist Workers Party, had labelled the Muslim Brotherhood, 'a clerical fascist organisation'. Yet this did not provide any obstacles after his death to his followers enthusiastically cooperating with the Brotherhood to organise the great protest In London against the invasion of Iraq in 2003.
Matgamna does not shy away from anti-Semitism on the Left in Britain – and mentions the racism of such revered founders of British socialist thought, Henry Hyndman and J. A. Hobson. He argues that the attitude towards the Jewish nation is unique. In the universities, he believes that antagonism towards 'Zionist Jews' interfaces with Jews per se and takes on 'a nasty persecuting quality'. He pointedly adds that non-Jews who defend Israel's right to exist are not classified in the same category.
He dismisses comparisons between Israel and apartheid South Africa or Ian Smith's White Rhodesia and suggests that the closest analogy is with the Protestants of Northern Ireland. Yet no one, he points out, has suggested that the Protestant community should leave and return to the mainland.
Matgamna argues that it is Stalinism and its legacy that has created 'the ideological chaos that still engulfs the Left'. Lenin, however, is left untouched. In 1919 the teaching of Hebrew was prohibited in Russia and many Jewish communal institutions were closed down. It can be argued, of course, that this was at the instigation of the Jewish Communists – many of whom were former Zionists. Yet Lenin did not act. Why?
Matgamna also argues that Jeremy Corbyn has reclaimed the Labour party for the working class. Yet Corbyn has been closely associated with the pro-Kremlin section of the Communist Party – the 'Straight Left' faction which opposed perestroika and glasnost – since the 1980s. Some of whom attempted to provide an 'understanding' for Stalin and Stalinism while others even worked for the Soviet Novosti press agency – truly the purveyors of fake news. These associates now form Corbyn's inner circle in the Labour party. While 'Old Labour' policies have been resurrected and indeed there has been a return to Labour's traditional advocacy of a two state solution for the Israel-Palestine conflict, should we not be vigilant as the future unfolds?
TROTSKYISM'S NON-JEWISH JEWS
At the end of his book, Sean Matgamna devotes a chapter to five individuals who shaped the British Left: Tony Cliff, Ernest Mandel, Tony Benn, Gerry Healy and Ted Grant. These vignettes are fascinating but what is left unsaid is their relationship with Jews and Zionism. Three – Cliff, Mandel and Grant – were Jewish.
Tony Cliff (Socialist Workers Party) aka Ygael Gluckstein came from the bosom of the Zionist elite in pre-state Palestine. The South African, Isaac Blank, also embraced anglicisation and proletarianised his name to Ted Grant (Militant Tendency).
Ezra Mandel and Abraham Wajnstok were Jews of Polish origin who had flirted with Marxism Zionism. But as with Cliff and Grant, the aggressive march of Nazism during the 1930s, the Stalinist show trials of old Bolsheviks and the seemingly irrelevance of Zionism pushed them towards Trotskyism. At the war's end, Ezra emerged as Ernest Mandel, having been partly protected by his father's wealth as an Antwerp diamond merchant – although he was incarcerated in Flossenberg concentration camp. Abraham Wajnstok died at Auschwitz but was resurrected by the far Left after 1967 as Abraham Leon, author of The Jewish Question: A Marxist Interpretation. This became de rigueur reading for the anti-Zionists of the New Left.
Tony Benn, of course, was worshipped in old age by the far Left. In the 1950s he was an uber-Zionist and a regular contributor to the Jewish Vanguard, the weekly publication of the Labour Zionists. While Matgamna rightly condemns the demand for the 'Right of Return' of the Palestinians, arguing that in practice it is a means of denying the right of the Jews of Israel to national self-determination, he omits to say that Tony Benn, towards the end of his life, attended the Right of Return movement's rallies at Trafalgar Square. Benn was both unable and unwilling to explain such ideological inconsistencies.
Gerry Healy, of course, was the most sectarian of Trotskyist leaders. Jim Allen, author of the infamous play, Perdition, during the 1980s, the acclaimed filmmaker, Ken Loach and Vanessa Redgrave, the much-admired actress, were attracted by his world outlook. Yet he also accepted funding from Muammar Gaddafi and Saddam Hussein for his Workers Revolutionary Party. He consequently became a devout advocate of the Palestinian cause through his newspaper Newsline and had a remarkably close relationship with Ken Livingstone. He was not averse to crossing the line where anti-Zionism tipped over into anti-Semitism.
Sean Matgamna's book is a fascinating study of the British far Left – through argument and through experience. Clearly not everyone will warm to it, yet it is an important, unusual work for any reader interested in the Left's tortuous relationship with Zionists and Jews in the 21st century.
Fathom 18 October 2017
Categories Book Reviews, Israel and the left
British Jews in the Merchant Navy in WWII
Foreword to the Balfour 100 Essays


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Progreso High School is a public high school of the Progreso Independent School District located in Progreso, TX. It has 560 students in grades 9th through 12th. Progreso High School is the 790th largest public high school in Texas and the 9,884th largest nationally. It has a student teacher ratio of 11.7 to 1.
You can also use the form below to search for alumni info and Progreso High School students.
Progreso High School is ranked 485th out of 2,141 ranked schools in Texas, for total students on lunch assistance.
The percentage of Progreso High School students on free and reduced lunch assistance (98.9%) is significantly higher than the state average of 53.3%. This may indicate that the area has a higher level of poverty than the state average.


Australian small and medium-sized enterprises (SMEs) will have the opportunity to enter the supply chain for the Royal Navy's Type 26 Global Combat Ship program.
BAE Systems, the company in charge of developing the frigate, announced that some 150 Australian companies would pitch their products and services into the project.
The company will be meeting Australian SMEs over the next two days, together with 20 of its major suppliers to the Type 26 Global Combat Ship program, it was further said.
BAE Systems said it was already maturing the detailed design for the ships and that key contracts for long lead items for the first three ships were in place as the company is preparing to start the manufacturing phase.
This is despite of the fact that the British Ministry of Defence said in July this year that the construction start for the Type 26 program was delayed indefinitely. The number of ships to be built was earlier cut from 13 to 8.
BAE Systems Australia is also proposing the Global Combat Ship for the SEA 5000 (Future Frigates) program to replace the ANZAC class frigates.
Posted on September 26, 2016 with tags BAe Systems, Royal Navy, SEA 5000, Type 26.


Here's everything you need to know about Danish brand Storm & Marie!
Everybody is talking about Danish fashion these days, and Storm & Marie will help you understand why (as if you didn't know already). With it's Scandinavian simplicity and cute name, it's hard not to fall in love with this brand. Not up to speed? Don't worry, here's everything you need to know.
STORM & MARIE was established in Copenhagen in 2010 by Signe Elisabeth Vedel and Kim Vedel Hansen, who both have a solid background in the fashion industry. The danish brand is the result of a shared vision of the two, who are a couple both professionally and privately.
The brand is named after the couples twins, STORM & MARIE, and is synonymous with their contrast – The core values of the brand's design being identity and expression. Storm represents the energetic and untamed, while Marie is delicate and elegant, a perfect juxtaposition.
The philosophy behind the brand is that while every collection forms a concept, each piece can still be worn separately, and effortlessly mixed in different ways to create individual style. Clean Scandinavian minimalism is combined with appealing prints and textures, in hight quality fabrics and with the perfect fit.
Signe, who is the designer behind the brand, claims that each collection is a new beginning. It's an exciting project with a story of it's own. It all starts with her love and fascination for fabrics from all over the world, which she gathers and studies, allowing colorrs and prints to take shape. The later, often inspired by natural scenery.
Throughout the history of STORM & MARIE, Signe has designed several classic silhouettes that have become known as the brand's signature shapes. In addition, she works with designs that reflect the zeitgeist so that each collection is new and inspiring for STORM & MARIE's many customers across the world. The spirit and trends of the time are captured through a curiosity of people and their ways of life.
STORM & MARIE is a very precious and personal project for Signe, and it is paramount for her to be able to vouch for every design, fabric and detail.
Do you think Danish fashion is Hygge? Find more of it here!
Miccaela grew up on the west coast of Sweden but because of her love for fashion she spent the last few years living in Oslo and most recently London where she just graduated from London College of Fashion. Traveling, Aperol spritz and art are close to her heart and she is constantly searching for the perfect sunglasses.


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Hamas Reportedly Rejects Proposal for Arab Troops in Gaza
Filed under: Anti-Aircraft Weapons,Anti-Tank Weapons,Egypt,Hamas Weapons Smuggling,Rafah — No To Terror @ 5:46 pm
A new report says that Hamas rejected a joint Egyptian and Jordanian proposal to send Arab troops to Gaza to train Palestinian police forces.
Not surprisingly, Hamas immediately rejected the proposal, according to the Jerusalem Post's Khaled Abu Toameh.
Why? It seems that such a plan would have involved some oversight into of weapons in Gaza, as well as efforts to prevent Hamas' ongoing smuggling of arms, anti-tank weapons, anti-aircraft weapons, missiles, and other contraband from Egypt into Gaza.
Here is a diagram showing how weapons smuggling operations operate from Rafah inside Egypt to Gaza. The diagram depicts how Israel had maintained a security corridor between Egypt and Gaza before ceding control of the Gaza Strip to the Palestinian Authority several years ago.
Diagram: Israel News Agency
Masked Hamas Gunmen Round-Up, Shoot, Kill Opposition
Filed under: Uncategorized — No To Terror @ 10:18 pm
In an all too familiar Gaza episode, masked Hamas gunmen shot and paraded their way through the streets of Gaza to show inhabitants that they are truly street thugs.
The BBC interviewed one Fatah supporter in Gaza, Ahmed Abul Nasser, who described how Hamas sent "maybe 20 gunmen" to take him from his home while his family watched. He says he was released only after signing a boilerplate form promising to not associate himself with Fatah and "respect the Hamas government."
Many other Fatah supporters that Hamas rounded up were beaten, Nasser said.


text:
Current Perspectives in Post-stroke Cognitive Impairment
Published Online: January 23rd 2013 European Neurological Review, 2013;8(2):136–40 DOI: http://doi.org/10.17925/ENR.2013.08.02.136
Authors: Antonio Federico, Alla Guekht, Michael Brainin
Post-stroke cognitive impairment (PSCI) is a particularly serious consequence of cerebral ischaemia and often inhibits or retards patient rehabilitation. Current treatments do not improve long-term outcomes for a significant proportion of patients and remain a substantially unmet medical need. Initiatives to address the challenge of post-stroke rehabilitation have included therapies that modify multiple pathogenetic mechanisms and provide protection to neural networks and facilitate their regeneration. Promising biological agents have been tested, but few have so far yielded clinically conclusive evidence further emphasising the shortage of therapies available to treat this disease. The multimolecular agent Actovegin® has been shown to stimulate capillary flow and neurometabolism after stroke and to provide promising results in the treatment of mixed dementia. Clinical trials are now in progress to fully evaluate this pleiotropic neurometabolic therapy.
Post-stroke cognitive impairment, blood–brain barrier, neurovascular unit, diagnostic variability, lack of consensus, emerging treatment
This article summarises the content of a symposium that took place during the 21st World Congress of Neurology in Vienna, Austria. It aims to describe the vascular and cellular processes that are involved in the maintenance of the blood–brain barrier (BBB), the cells involved in the neurovascular unit (NVU) and its dysfunction in stroke resulting in poststroke cognitive impairment (PSCI) for many patients. There is substantial variability in eported rates of PSCI and this is largely a result of differing assessment methods used to assess the condition and inconsistent treatments and times to treatment initiation in different territories. The lack of agreed guidelines and of consensus among healthcare professionals also contributes to variable levels of diagnosis and treatment outcomes in PSCI. This article will additionally consider these critical matters and discuss the development of a new treatment approach for PSCI that has shown potential and is being evaluated in clinical trials.
The Role of the Blood–Brain Barrier and the Neurovascular Unit in Cerebral Ischaemia
An important concept in the development of stroke and consequent cognitive impairment is the fact that the brain has no reserve of energy or oxygen. It must therefore be constantly perfused through the normal blood supply to supply these factors and to remove metabolic products, particularly carbon dioxide. Any interruption in this continuous process is liable to have a serious effect on the brain region in which it occurs.1The BBB comprises a diverse set of cellular components some of which participate in the NVU. The interaction between these cells is important in the pathophysiology of PSCI and other neurological diseases (see Figure 1).2–4
The tissues of the central nervous system (CNS) make high metabolic demands of the vascular system and the microcirculation of the brain must be responsive to changing requirements.5,6 The NVU is central to this process and maintains a 'metabolic coupling' between brain activity and blood flow. In neurological disease or injury there is a danger of exposure to metabolic products that are toxic to brain tissue and may cause neuronal damage.4,7 ATP-sensitive potassium channels play a major role in sensing metabolic requirements and provide protection of brain tissues against these effects of neurological disease or injury.8 Some functional magnetic resonance imaging (fMRI) studies have suggested that following stroke there is an uncoupling between metabolic requirements, especially for oxygen and vascular supply and this can worsen outcomes.9
Within the NVU, astrocytes provide trophic support to neurons and maintain synaptic functions and dynamic signalling. The end-feet structures of astrocytes have a close contact with cerebral endothelial cells and provide a physical link to the microvasculature. Astrocytes are therefore uniquely positioned to exercise control over local changes in cerebral blood flow as well as regulating tight junction integrity.1,10,11 Pericytes are important in regulating blood flow by contracting or relaxing in response to vasoactive stimuli from surrounding cells.12,13
Microglial cells are cerebral monocytes with a stellate morphology and release a range of pro- and anti-inflammatory mediators but their role in the NVU is as yet, unclear.14–16 In response to changes in neuronal activity, perivascular-released neurotransmitters and other mediators can activate receptors on both smooth muscle cells and astrocytes to alter the tone of brain microvessels.17
Cellular communication within the NVU involves various signalling pathways of neurovascular coupling and interactions among astrocyte, vascular smooth muscle, neuronal and endothelial compartments. These processes comprise numerous factors including cytochrome P450 epoxygenase metabolites, signalling initiated by metabotropic glutamate receptor (mGluR) activation, potassium signalling, 20-hydroxyeicosatetraenoic acid (20-HETE acid) signalling, adenosine signalling, carbon monoxide signalling and calcium (Ca2+) efflux. In addition, the regulation of blood flow by astrocytes may involve both vasodilating and vasoconstricting components.18
Several neurotransmitters are important in vascular coupling in the NVU. Glutamate is the main excitatory neurotransmitter in the brain and may trigger responses via indirect signalling.19 The release of glutamate during neuronal activation may act on astrocytic mGluR receptors to increase Ca2+ in astrocytes and elicit a vasodilatory effect.20 Nitric oxide is released from activated neurons following N-methyl-D-aspartate (NMDA) receptor activation21 and is one of the major vasoactive substances whose role is of prime importance in maintaining endothelial homeostasis. Calcium waves are another form of neurotransmitters and are a type of non-electrical impulse in which increased blood flow results in greater intracellular Ca2+ concentrations in astrocytes and the signal is propagated by release of Ca2+ to surrounding cells or by extracellular ATP signalling.22
Several CNS conditions have overlapping pathogenic processes and molecular mechanisms associated with the NVU. For example, vascular dementia (VAD), Alzheimer's disease (AD) and traumatic brain injury have common pathways, including excitotoxicity factors (glutamate, calpain and CDK-5), neuroinflammation (interleukin [IL]-1, IL-6, tumour necrosis factor-alpha [TNF-a]), oxidative stress (reactive oxygen species), apoptosis (TNF- a, glycogen synthase kinase-3 [GSK-3b]), proteinopathies (b-amyloid) and neurotrophic alterations (brain-derived neurotrophic factor [BDNF], insulin-like growth factor type 1 [IGF-I], vascular endothelial growth factor [VEGF]).11 These processes and secreted factors lead to neurovascular damage and degeneration. In AD, these effects arise from vascular risk factors, elevated cholesterol and ageing on the NVU leading to vascular fibrosis, b-amyloid accumulation,synaptic loss and, ultimately, to progressive cognitive impairment.23
Future therapeutic strategies in the detection and treatment of PSCI are to include the use of biomarkers of NVU integrity.23 An example is asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction and a newly recognised independent risk factor for adverse cerebrovascular events in small vessel disease. A recent study reported significantly increased plasma levels of ADMA in 16 patients with cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy compared with controls (p<0.05).24
The BBB, therefore, is a critical interface in sustaining the brain's need for constant perfusion and consists of a dynamic and functional NVUs that are formed from astrocytes, microglia, capillary endothelium, neurons, pericytes and extracellular matrix all acting in a coordinated manner. Astrocytes, as well as other cellular components of the NVU, appear to play a crucial role in monitoring changes in synaptic activity and signalling between microvascular units. In CNS disease, however, the ordered structure of the NVU breaks down resulting in breaches in the BBB leading to neuronal damage and cognitive impairment.
Post-stroke Cognitive Impairment Critical Concerns
Dementia and cerebrovascular diseases (CVD) account for a substantial proportion of the global burden of disability.25 In terms of prevalence, PSCI is a subset of the VADs and represents a major part of this burden. The estimated total annual cost of dementia, including PSCI, was estimated to be €105 billion in Europe in 2010.26 There are, however, substantial discrepancies of reported incidence and prevalence of post-stroke dementia between hospital- and population-based cohorts of first-ever stroke.27 Initiatives to improve diagnosis and management of PSCI are therefore of great importance but these are complicated by some critical factors, particularly variability in the definition of the condition and a general lack of consensus and comparability between studies and evaluation tools.
PSCI can be identified in patients using two diagnostic criteria: the presence of a cognitive disorder (i.e. dementia or vascular cognitive impairment [VCI]) and a history of clinical stroke or vascular disease by neuroimaging.28 There is a close relationship between stroke and dementia and prevalence data show that one patient in 10 already has dementia when stroke occurs, one in 10 will develop dementia after a first-ever stroke and one in three will develop dementia following a stroke recurrence.29 Factors most strongly associated with pre-stroke dementia include a family history of dementia, media temporal lobe atrophy, leukoaraiosis and previous stroke. Factors most strongly associated with post-stroke dementia include dysphasia, incontinence, early seizure and previous strokes.27
A notable survey of population-attributable prevalence fractions (PAPF) that included 15,020 participants aged 65 years in low- and middleincome countries, ranked stroke second after dementia as contributing to disability.25 A more recent, large study conducted in the US evaluatedthe long-term rate of change in memory functioning before and after stroke onset in 1,574 participants.30 The findings demonstrated that although stroke onset induced large memory decrements, differences in memory were apparent years before the occurrence of stroke.A population-based study conducted over 24 years in France found that among 3,201 patients with first-ever stroke, 20.4 % had poststroke dementia.31 An increasing prevalence of post-stroke dementia was associated with age, vascular risk factors, hemiplegia and prestroke use of antiplatelet agents. These studies show that cognitive impairment is common following stroke and constitutes a substantial world health burden that is likely to increase with ageing populations and emphasise the critical need for effective treatments.
In addition, disease categories of VAD, mild cognitive impairment (MCI), mixed-dementia and prodomal-state of AD are not sufficiently defined or accepted by neurologists. These shortcomings were identified in a review of barriers for patients with dementia in Europe which concluded that multidisciplinary approaches are needed to improve diagnosis and treatments for all patients with cognitive complaints.32 The authors recommended that these approaches should include dementia training for all healthcare professionals, regular updates of treatment guidelines and greater public awareness to destigmatise dementia.
The variability of post-stroke cognition assessment methods is highlighted by the finding that in patients with MCI (without dementia) 3 months after a stroke varies from 17–66 % depending on the criteriaused for testing.33 In addition, the degree of impairment varies with different cognitive domains (see Figure 2). To limit the variability in assessment, training is necessary to standardise scoring and to select the most best-performing test instruments. This was emphasised in a comparison of cognitive tests conducted in Canada on 110 patients after a stroke and 45 age-matched controls with stroke risk factors. The results showed that the Montreal Cognitive Assessment (MoCA) battery of tests was more sensitive in detecting disease than the Mini-MentalState Examination (MMSE).34 In addition, the Trail Making Test A and Band the Digit-Span Forward and Backward Test can be rapidly completed and are helpful in diagnosing and monitoring cognitive decline.35
Following the onset of a stroke there is a delay before cognitive impairment becomes apparent. The dynamic properties and molecular development of this process are not well understood and this creates difficulties for practitioners regarding diagnosis and treatment. The patient-related risk factors that increase the prevalence of dementia after stroke include personal factors such as increasing age, CNS diseases (e.g. pre-stroke cognitive decline without dementia), cardiovascular disease (e.g. atrial fibrillation), other factors (e.g. diabetes) and stroke-related factors (e.g.severity, location and dementia due to vascular lesions).29 It is significant that the rate of dementia is at least twice as high after recurrent stroke27 and it is therefore essential that vascular risk biomarkers such as inflammatory markers are developed to predict the risk of a recurrence.26
The future management of PSCI will require, first, a better understanding of cognitive impairment following stroke and, second, the development of reliable pre-stroke biomarkers. If VCI is to be treated effectively to halt any progression to dementia, therapies to selectively target major pathological processes will be required. Multiple pathways should be targeted to improve neurometabolism and neurorecovery in PSCI.
Current and Future Developments in the Treatment of Post-stroke Cognitive Impairment
The growing health, social and economic burden of PSCI is driving the demand for clinical studies that evaluate the benefits and risks of pharmacological and nonpharmacological therapies. Prevention and treatment of PSCI are, in fact, one of the critical priorities for clinical care and research. Better understanding of the risk factors and estimation of the risk scores for post-stroke dementia are important for selection of patients for preventive clinical trials (on neuroprotective agents, cognitive rehabilitation and other strategies).
Important avenues in VAD treatment are: symptomatic improvement of the core symptoms (cognition, function and behaviour), slowing of progression and treatment of neuropsychiatric symptoms. Controlled clinical trials with donepezil and galantamine demonstrated improvement in cognition, behaviour and activities of daily living; however, a number of adverse events were observed. Trials using memantine showed that it was well tolerated, improved function and reduced care dependency in treated patients compared with placebo. Evidence-based assessment of the efficacy and safety of the number of interventions including cerebrolysin, antidepressants and hyperbaric oxygen therapy have been recently published.36–46
No drug treatment to date, however, has shown convincing clinical evidence of restoring cognitive function or preventing further decline after stroke. There is also uncertainty regarding patient characteristics that might predict response to treatment.
A number of important clinical trials in post-stroke dementia and treatments are ongoing (www.ClinicalTrials.gov) or have recently been completed. The Tel-Aviv Brain Acute Stroke Cohort (TABASCO) trial, with up to 10 years' follow-up after stroke, is focused on the association between predefined demographic, psychological, inflammatory, biochemical, neuroimaging and genetic markers, measured during the acute phase. It is also monitoring long-term outcome including subsequent cognitive deterioration, vascular events (such as recurrent strokes), falls, affective changes, functional everyday difficulties and mortality.47
The DEterminants of DEMentia After Stroke (DEDEMAS) trial is a 5-year observational study in Germany, recruiting 600 patients with acute stroke but without prior dementia. Sophisticated neuroimaging will be utilised in patients developing cognitive impairment (with or without dementia) and in a subgroup of matched individuals without cognitive decline. This trial will focus on interactions between vascular and neurodegenerative mechanisms. Another trial (SMARTease) will use a 16-week telerehabilitation cognitive strategy, during which a trained rehabilitation coach speaks to post-stroke patients regarding their condition by telephone twice weekly.
Motivation and lifestyle intervention are being evaluated in several trials. The Austrian Polyintervention Study to Prevent Cognitive Decline After Ischemic Stroke (ASPIS) is a multicentre, randomised, observer-blind, parallel group clinical trial to evaluate multiple lifestyle interventions following stroke. It will provide essential data about the feasibility and efficacy of lifestyle intervention after stroke in order to develop a new approach to prevent cognitive decline in patients with mild ischaemic stroke.48 In addition, a number of trials are focused on pharmacological treatments. One such trial, for example, is evaluating the efficacy of gliatiline on post-stroke patients with VCI.
Aspirin has been used in the treatment of stroke for many years and there is a large body of evidence to support this.49–51 However, there is little evidence suggesting that non-steroidal anti-inflammatory drugs (NSAIDs) are effective in preventing cognitive decline following stroke. Indeed, most studies indicate little difference between NSAIDs or other treatments or placebo in terms of cognitive impairment.52–54
Neurometabolic agents are potential therapies for PSCI. Actovegin®, for example, contains more than 200 different small molecules, such as oligopeptides, oligosaccharides, eicosanoids and other compounds. It is protein free, its constituent molecules are all less than 5,000 Da and it is derived using a sophisticated calf blood ultrafiltration technology. Actovegin increases aerobic oxidation and has emerged as a promising treatment for VCI based on findings from cellular studies, animal models and some clinical experience within mixed and VAD.55 This treatment has been successfully used to treat stroke, traumatic brain injury and diabetic neuropathy.56 Experience in VCI, however, is much more limited. In early clinical trials in the frequency of adverse events and discontinuation due safety concerns with Actovegin has been low and often comparable with placebo.57
The Efficacy and Safety of Actovegin in Post-stroke Cognitive Impairment (PSCI) (ARTEMIDA) is in progress. This is a phase III, randomised, placebocontrolled trial in which patients commence 6 months of treatment within 7 days of a stroke followed by 6 months of follow-up.57 The endpoints are Alzheimer's Disease Assessment Scale change at 6 months and disease-modifying effects (difference between slopes). The recruitment is completed to this study and the results are expected in 2015. This study is pivotal: the findings are awaited with interest and will establish whether Actovegin is a valid approach for the clinical management of PSCI. The dosage of Actovegin in this trial was driven by levels used in other indications but since the effects are apparently dose dependent, dose-ranging clinical trials are needed to establish optimum treatment regimens in PSCI.
The use of a complex mixture to treat PSCI is an intriguing change of approach to treatment. To develop effective drug treatments for this disease, either a single compound with more than one mode of action or a combination or mixture of therapies with different modes of actions are required, these would target multiple mechanisms of ischaemia and may thus achieve greater efficacy than single-action entities.
The processes involved in neurodegenerative and ischaemic disease have common multifactorial molecular mechanisms related to the NVU. A better understanding of the cellular and molecular processes involved in NVU dysfunction may lead to improved treatments for PSCI and other neurological disease. Future therapeutic strategies may include the use of biomarkers of NVU integrity to assess the extent of neurological damage and may be used as prognostic indicators and guide treatment. The functions of the NVU are complex and effective neuroprotective and neuroregenerative treatments for PSCI need to influence multiple different pathophysiological mechanisms in order to limit neuronal damage and aid recovery.
There is a need to better understand the molecular mechanisms contributing to neuronal damage in VCI and develop better means of assessing it. Pre-stroke epigenetic, imaging and laboratory markers are needed to better determine the risk of cognitive impairment.Interventions with multifactorial effects are needed to improve prognosis of patients with cognitive complaints following stroke.
Among developing treatments for PSCI, evidence from preclinical studies has shown that Actovegin, a multimolecular product manufactured using a calf blood ultrafiltration technology, is a promising neurometabolic therapeutic option. The ongoing phase III clinical trial will determine its efficacy in treatment of PSCI.
Antonio Federico, Alla Guekht and Michael Brainin have received honoraria for lectures and travel support as well as for consultancy for Takeda Pharmaceuticals. The authors have been independent in conceiving and finalising this manuscript and take full responsibility for its contents.
Michael Brainin, Department for Clinical Neurosciences and Preventive Medicine, Faculty of Health and Medicine, Danube-University Krems, Dr-Karl- Dorrek-Str 30, 3500 Krems, Austria. E: michael.brainin@donau-uni.ac.at
The publication of this article was supported by Takeda Pharmaceuticals. The views and opinions expressed are those of the authors and not necessarily those of Takeda Pharmaceuticals.
Editorial assistance was provided by James Gilbart at Touch Medical Media.
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