text:
Scientists levitate particles with sound to find out how they cluster together
Scientists from the University of Chicago and the University of Bath used sound waves to levitate particles, revealing new insights about how materials cluster together in the absence of gravity—principles which underlie everything from how molecules assemble to the very early stages of planet formation from space dust.
"Much of the universe is made up of particles assembling," said Heinrich Jaeger, the Sewell Avery Distinguished Service Professor of Physics, who co-authored a new study that appears in Nature Physics. "With acoustic levitation, we have a beautiful model system to study assembly at scales visible to the human eye, where we can track each particle with precision, and then relate the results to a wide range of often much more microscopic phenomena."
Jaeger's lab conducts innovative studies of the laws governing the interactions of particles—which they've used to create a robotic gripper to pick up almost any object and to explain a long-standing physics mystery that lets you run across the surface of a pool filled with water and corn starch.
In this case, the team was interested in the shape of prototypical clusters that form when, starting from a single particle, more are added one by one. They used sound waves to levitate plastic particles in midair—each about one millimeter in diameter, about the thickness of a penny—and studied how these particles interact with each other as they formed clusters, broke up and then reassembling into different configurations.
Groups of six particles form three distinct compact shapes: parallelogram, chevron and triangle. (Courtesy of Melody Lim)
When there are five particles or fewer, they found, the particles cluster densely in only one configuration. However, when there are at least six particles, there are a number of different shapes they could assemble into when brought together tightly.
By using high-speed cameras to track the levitated particles, the researchers were able to capture these various configurations. They found that groups of six particles can form three distinct compact shapes: parallelogram, chevron and triangle. Adding one more particle to make seven meant that particles clustered together in one of four shapes, which scientists termed a flower, a turtle, a tree or a boat.
"Six particles is the minimum needed to change between different shapes, which is where things get interesting," said co-first author Anton Souslov, then a UChicago postdoctoral researcher and now on the faculty at the University of Bath. "For us scientists, defying gravity to levitate dust also has this more fundamental interest of developing Earth-based experiments to understand how bodies in space like planets start to form." This would be the very earliest stages, the scientists added, when the future planet is just a clump of space dust perhaps a centimeter across—before gravity starts to become a factor.
One unique aspect of the experiments is that the sound not only levitates the particles, but can also be used to affect how they interact as they float.
"A surprise was that by changing the sound wave frequency, we could manipulate the clusters and influence the shape that emerged," said graduate student Melody Lim, the first author on the paper. Modeling the physics behind such acoustic forces, which was done by Souslov and professor of physics Vincenzo Vitelli, gives scientists a new means to control the assembly process.
They found that rearranging the shapes often depends on one particle acting as a "hinge" and swinging around the others to reconfigure, which could be very useful in a range of potential applications.
The research team now intends to look at how acoustic levitation can bring together larger numbers of particles to assemble more complex structures.
Citation: "Cluster formation by acoustic forces and active fluctuations in levitated granular matter." Lim et al, Nature Physics, March 4, 2019. Doi: 10.1038/s41567-019-0440-9
Funding: National Science Foundation.
—Adapted from a press release by the University of Bath.
New method uses heat flow to levitate variety of objects
Lab experiment mimics early-stage planetary formation process
Levitation , Heinrich Jaeger , Particle physics , Postdoctoral researchers , Graduate students , Research


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Canaletto's Ristorante
Dining In Venice!
Well, sort of...
Dining at an Outside Café...
Well sort of...
Canelleto's
Canelleto's is actually a restaurant at The Venetian Hotel in Las Vegas. Which means, when you dine at one of the hotel's "outdoor" cafes, you actually have a roof over your head. And what a roof!
The clouds on the ceiling made it feel like dusk, 24 hours a day. The street lamps felt like they were just lit. The sounds of singing gondoliers and sloshing water could be heard in the nearby Grand Canal. And the musicians playing flute, violin and cello created an atmosphere that felt like a summer evening in an real Italian piazza.
When Don and I dined last May, we chose to sit "outside" so we could take in the view. But when I ventured inside in search of the restroom I was amazed at the festive interior. And there was a pretty spectacular view from the upper floors!
Italian Dining
My enthusiasm sounds like someone who has never dined in Venice, Italy. In fact, I have such good memories of the "real thing" that I really expected not to be impressed. But I do love playing pretend. And I do love a restaurant with a gimmicky theme. I'd say Canaletto's pulled it off. And I must say, I love the idea of sidewalk cafes with white tablecloths, minus the issues that come with Italian pigeons.
I took some time to study the menu artwork which showed a bustling harbor scene and Palazzo Ducale. Then I got very hungry absorbing the mouthwatering details inside the menu. It was nice enjoying a little Chianti and some warm Italian bread as we made up our minds!
Our waiter had an accent but I didn't dare ask. I'd like to just assume he was Italian, although chances are he was not. We were given just the right amount of attention and the food didn't come out too quickly. I hate feeling rushed when you're trying to enjoy your wine.
Pasta, Soup & Salad
Don's pasta with prosciutto and cream sauce was deliziososissma. Picture me giving my fingertips a quick kiss, so you know what that means. My Insalata Cesarina, was surprisingly yummy with egg slices and a large sheet of parmesan! I ordered the Minestrone with crossed fingers.
When I was 11 my family moved to Italy for a half year and I remember soothing my homesickness with minestrone. I've been searching since 1969 for the amazing combination of vegetables, cheese and spices, that I remember adoring. Once in a blue moon have I tasted a soup that comes close. The minestrone didn't quite make it. But that's okay. The search is part of the fun.
Playing Tourists
When in Rome, (or in Venice) I say, "Act like a tourist and pose on the bridge!" It was a good way to end our meal, before hiking back to our hotel room. We worked off a few calories as we got a bit lost, kind of like you do in the real Venezia!
Tiki Time Out West
Tiki Stops in Nevada & California
This past spring Don and I had a chance to make 3 retro Tiki Stops on our road trip from Texas to California and back.
There wasn't much dining to be had at the first and no time for dining at the other 2, but they were all quite worthy of a write up!
1- Frankie's in Las Vegas!
Being in Vegas puts you in the retro mood. We took a 10-minute cab from our hotel to this 24-hour lounge, far from the touristy Strip.
Our driver chuckled with us and took our photo before entering. (More or less wishing us luck) When we stepped back out later that evening, we got to see the bright pink neon.
When we entered through the red door, we thought our daylight eyes would adjust.
They didn't. It was so dark we couldn't see the bamboo walls or mermaid on the ceiling, until viewing these "flashy" photos.
It took nerve to use the camera flash, since we seemed to be the only tourists. But we wanted to see (and remember) this awesome setting that was designed by Bamboo Ben.
He and owner P. Moss, with the help of a number of tiki artists created an atmosphere of southseas exotica and modern primitivism! Frankie's Tiki Room has been hopping since it opened less than 10 years ago. I admire Moss' mission to revive the tiki glory days while preserving the name and stucco structure of an actual 1950's Vegas cocktail lounge.
Bar & Drinks
The bar was an exciting clutter of Polynesian delights. The black and white TV played beach-y film clips while retro island music played.
We used our cell phones to light up the tropical menu, all priced at $9. It wasn't an easy choice since there were 77 cocktails offered at Frankie's. I chose a tasty, coconut Malakula. The menu gave it 3 skulls for "strength" instead of 5.
Bartender, Mike
A space opened at the bar, so we moved to chat with Mike, the most energetic, upbeat bartender you could hope for.
Being tourists, we bought some quite amazing tiki mugs designed by a local artist and Mike called our cab. There's no food to be had at Frankie's, so some of us can only linger so long. But it was well worth the cab fare to come enjoy for a while!
2- Bali Hai in San Diego Area
We discovered this tiki lounge/restaurant on Shelter Island after seeing it pictured, along with a recipe in a 1959 Ford Motor Co. Travel Cookbook.
We were mighty excited to find it open and still being operated by the same family since 1955!
Not Sure...
These Polynesian figures are shown in the cookbook illustration. No one seems to know the full history of the character nicknamed "The Goof" on the roof top.
The other greeter was by the door. "Mr. Mai Tai" was less cheery, but equally odd. I'm not sure about political correctness at tiki bars, but there were many more carved tiki figures to wonder about once we stepped inside.
Grand Round Room
When we stepped inside, we were greeted by live acoustic Hawaiian music and about 100 tiki artifacts.
The shiny, massive support logs were impressive, as was the wall of glass with its spectacular view of San Diego Bay. But from 4 to 6, the action was centered around the dramatic bar under a narrow cone-shaped ceiling.
Mai Tais
We squeezed in at the corner of bar, with light illuminating the thick stone surface. The timbers holding the cone roof held dangling lanterns and glowing puffer fish, as well as a sign with changing numbers.
A man drinking a Mai Tai beside us, warned us about the strength of Bali Hai's Mai Tais. "No juice. You have to be careful." Just then, the sign changed to 2,285,362. That's a lot of Mai Tai's served at Bali Hai!
Two Mai Tais
We each ordered one. I ordered mine in the special Mr. Mai Tai mug.
Once again, I'm not sure about these tiki images. But I think the half closed eyes are a reminder of what you will look like if you have more than one.
Meal with a View
The dining area was beginning to fill around 6, but we had to take off.
It would have been nice to have dined with that view!
Quick Chat Before Leaving
Big Brian, (as he told us to call him) was the only bartender. He was moving fast, whipping out the cocktails, but I couldn't leave without showing him the cookbook. That odd book had acted like a treasure map, luring us to our little our island paradise.
Big Brian's reaction was pretty fun! He nearly hopped over the bar to get to the book. He was giddy over the "Chicken of the Gods" recipe and raced back to the kitchen (abandoning the bar) to show the chef. It was a perfect ending to our second Tiki Adventure. (I look like I had numerous Mai Tais in this photo)
3- Don the Beachcomber in Huntington Beach, California
It was a bright Sunday afternoon when we found Don's on the Pacific Coast Highway.
Once again we aimed early for a tiki visit, but the place was throbbing by 5.
The wonderful swooping roof and swordfish sign lured us right off the Highway. It was tricky getting into the parking area, which was bustling with very efficient traffic directors, who must double as security guards or bouncers.
They were having their weekly Reggae Event and we made the mistake of trying to go in the VIP door. We eventually found the bamboo door in front, with sign. "Host to Diplomat and Beachcomber, Prince and Pirate."
"Don" or Ernest Gantt from Texas
This is the guy who started the real Polynesian craze in 1930's Hollywood.
Inspired by his own island travels, he ended up with a chain of Tiki Lounges all over the country and a list of over 80 patented drinks. None of the original restaurant/lounges remain, but the nostalgic chain has been revived in 3 US locations. The other 2 are in Hawaii.
The Other Don
I had my Don pose with the sign before heading in. A man snickered nearby, when I snapped the photo. "He must be important!" the man teased. I agreed, "Oh he is! This is Don."
I felt bad when I had to explain to the man that "my" Don wasn't "The" Don. That Don died in 1989 at 82. I guess the teasing man was a tourist or he would have known that.
Once again, I wish we had been able too stay for a meal. It would have been a slice of tropical heaven to sit beside a waterfall or Hawaiian mural and sample the Polynesian foods that became especially popular after WWII.
The real tiki craze began in the '40's after soldiers returned home, craving the exotic foods they had sampled in the Pacific. I'm sure there wasn't really anything that unusual about the dishes served up then or now, with all their decorative pineapples and flowers, but I wouldn't mind trying!
We passed up the Reggae event, and headed for the cozy Dagger Bar.
Karaoke was in full swing, at 4:30 in the afternoon.
Enjoying the Show
Once again we found ourselves relaxing with more locals than tourists. There seemed to be some karaoke regulars and a few were pretty decent. A couple made us wince, but that's all part of it. The fine fellow with gray beard, knit Rasta hat, braids and croqueted eye patch (with crocheted eye) was quite the performer.
The lai-adorned woman pictured dancing along, was actually our delightful server. I had a chance to tell the "pirate" he did a nice job before we left. He said "Thanks!" instead of "Aye!" So I guess we didn't get to meet a pirate, prince or diplomat after all.
The Hut... Next Time!
We only had 3 Tiki Adventures on our trip. But on our way home we did spot this fine image not far from our hotel in Tucson.
We'll have to try The Hut on our next Western Road Trip! I have a feeling there could be many more to choose from. Tiki is making a comeback!
Bob's Ranch House in Las Vegas
A Ranch in Vegas?
This past April, Don and I stopped in Las Vegas on a road trip. Why on earth would we decide to leave the festive neon city to track down this 1950's ranch, hidden within the sprawling suburbs?
A Cookbook of course!
Some people use a travel book or YELP for dining suggestions while on the road. But, Don and I took a couple cookbooks on our trip, instead.
This book was put out by Ford Motor Company in 1963 to promote road travel across the States. The book is a hoot! It's filled with recipes and illustrations, from some of the best roadside and city dining establishments back in the day. Browsing through the pages makes you want to go back in time and visit these iconic places and sample their featured dishes. But the majority of these old cafes, clubs and inns, no longer exist. So Don and I gave ourselves something new to add to our list of adventure goals for our 4 week road trip from Texas to California. We would try to track down a few of these curious places that still exist... and then give them a try! Our lunch at Bob's Ranch House was our first "dining with the cookbook" adventure!
Hidden in the Suburbs
This ranch used to be about 7 miles outside of Las Vegas. Now the 10 acre ranch is surrounded by neighborhoods, interstate and shopping centers. But once you drive underneath the wood sign, it feels just like it might have 50 years ago. Just head down the road towards the old windmill... well maybe not. That's a cell phone tower!
Bob's House
I was excited to know the ranch was still serving since it opened in 1955. Bob passed away a few years ago, but back in the 1950's it is said that Bob loved cooking for his friends so much, that he finally took their advice. He turned his ranch house into a restaurant.
Where's the Entrance?
It was pretty quiet around noon on a weekday when we arrived. (Except for the roaring of the nearby freeway) We followed the path, past a fountain and a few flower beds, searching for the entrance.
If we hadn't seen the sign, I would have been hesitant to go further. It really seemed like we were invading someone's private home.
Should we knock?
The door had a nice little square opening, kind of like the one the Wizard looks through, when Dorothy and her friends knock on the door at the entrance to the Emerald City.
We weren't as polite as Dorothy, we just walked on in.
This is Vegas after all, so it wasn't surprising to first be greeted by a big old cocktail lounge when we stepped inside. There were a few saddles tucked here and there, creating a unique Ranch-Vegas decor.
The view in the front dining room matched the illustration in the book! We grabbed a couple of captain's chairs at a table with a view out the window. Note the cowboy, etched in the glass.
This is the illustration in the cookbook. You can see the glass windows looking out over a pond and trees.
Liz, our server, handed us each a hefty brown and gold menu. I'm pretty sure the design, (With the words "Supper Club") had not changed since 1955. The inside of the menu had been updated, however. No signs of the cheese sauce that was featured in the Ford Cookbook. Too bad because my mouth was watering for a hot meat pie, slathered with a ladleful of Bob's cheese sauce!
Sharing the Book
After Don and I placed our order, I pulled out the cookbook. I didn't expect Liz to "get it" that we were sort of using this cookbook like a map for a treasure hunt. I didn't expect her to understand our cookbook adventure, but she had the reaction we hoped for. She laughed and shook her head as she stared at the curious book. Then she asked for permission before dashing off to make photo copies of the pages and to share the book with the chef and some regulars dining nearby.
Meat!
This is the kind of place you go to eat meat. I ordered the Duke Burger. (Bob was a John Wayne fan) That's my burger on the grill, before the caremlized onions, mushrooms and Swiss cheese!
We might have felt like outsiders had we not had the cookbook to help break the ice. The Ranch House is not a place tourists just stumble across. The other diners were all regulars who have probably been coming for ages. The knotty pine, western memorabilia and fireplace added to the homey appeal.
My Duke Burger and Don's barbecued pork sandwich were delicious. The steak fries were yummy too and made me almost wish I'd gone for a big old steak, which is probably what the Duke would have ordered.
I couldn't help but wonder what this place must have been like 50 years ago when Bob was cooking and the place was packed.
A Good Visit
We left The Ranch feeling pretty pleased about our first cookbook adventure. Since I'm a big fan of stepping back in time, I was glad that little had been updated in the decor. I guess the windmill-celltower was a big reminder that the ranch is trying to hold onto a little of the past, while moving forward. Gotta appreciate that!
Dining on Nevada's Highway 50
The Lincoln Highway - November 2013
Recently my husband and I drove the nearly 300-mile stretch of the Lincoln Highway, known as the Loneliest Road in America. There aren't many dining options on the loneliest road...but I guess that made it a dining adventure.
Stop 1 - International Café and Bar in Austin, Nevada
Being big fans the Austin in Texas, we liked the name of this tiny town that suddenly appeared. We also liked the idea of a 140 year old (once) hotel, out in the middle of nowhere, serving international food. There was a lot of stuff attracting our attention as we pulled up. I particularly liked the welcoming sign announcing Ice and Free Restrooms and a very intriguing sign on the side saying, Serbian Christmas Jan. 7!
The sign said OPEN, but it was awfully empty when we entered the diner portion of the building. The portrait of W.C. Fields glaring down over the counter seemed to match the look of 60ish woman who entered from the kitchen in a Hawaiian shirt and ponytail. "Hi, do we just sit anywhere?" I asked apologetically, feeling as if we'd rudely interrupted her quiet. She nodded and left the room.
Cozy Wood
There were many tables to choose from. Most were round with Lazy Susans in the center. My photo looks like some kind of comfy pancake house with all the light wood, but there was really nothing cozy about the place. We sat and waited and I was scared to look at Don or I might burst out laughing. We know each other's thoughts too well.
Another woman entered. Her moccasins actually stomped the floor as she headed to our table. She hadn't bothered to pull her pink shirt down over her stomach, or to hide her bra or the tattoos on her bosom. However, our 40ish, frowning server may have been covering something on her neck, since the white hand towel was meticulously wrapped (not slung) around her neck. She slapped 2 sticky menus on the table and I almost jumped. She said nothing, so I greeted first. "Hi, how are you doing?" She answered with. "Do you want something to drink?" She left to get our coffee and Don and I shared nervous grins before searching the menu. There was nothing at all international on the menu! But the menu did mention something about the friendly staff at International Café. Hmm?
Ordering and Eating
When she came with the coffee, Don and I knew better than to stall with ordering. I did make the mistake of changing my order from fried egg to scrambled after she had gone to the trouble of writing it on her pad. She said nothing, but I felt a flood of childlike guilt when she shifted her weight and sighed and closed her eyes very slowly. After a short wait, our plates arrived without a word. The food was steaming hot, but I had no appetite. Don's biscuits and gravy tasted a bit spongy and my hash browns were greasy, I think...but maybe they were good. I'll never know. Our silent pink waitress had me so intimidated I couldn't taste my food.
The Bar
After a while I went in search of the free restroom and discovered the old bar. The morning sun lit up the ornate wood columns and mirror, as well as lots of clutter including a wheelbarrow filled with logs...? Maybe this bar is the reason Pinky and her possible mother were so grumpy. Maybe they had worked into the wee hours and it was all they could do to serve 2 travelers on a Friday morning.
Heading Off
I had so many questions I wanted to ask Pinky, but before we headed to pay at the counter a middle aged couple entered with cheery smiles. I was amused to see they were treated no differently.
I exchanged a few pleasant words with them to practice my social skills before attempting a conversation with Pinky. I was just so curious about the kind of reaction I might get if I asked her about the cafe's history. Or maybe I could be a little braver and find out if she grew up in Austin. Or I could just go all out and torture myself by asking her to pose for a blog photo. But more customers arrived and she was not approachable. I left disappointed that I hadn't had my chat. So disappointed that I actually called a day later. "Do you all serve International food?" I asked innocently. The confused woman's voice answered. "No?" As if no one had ever asked. With a few more questions she did explain that her husband was Serbian and they serve Serbian food for a Christmas celebration once a year. I doubt we'll ever return for the Serbian Christmas, but I bet the ladies in their bright shirts might be a little more lively during the evening.
Stop 2- Ely's Hotel Nevada Café!
A few hours later at the end of the lonely stretch, we stopped for lunch in Ely. I was pretty excited to be in Ely, because Ely happens to my middle name...an old family name. And I was quite thrilled to dine at the Hotel Nevada. This 84 year old casino may not be the oldest building in Nevada, but it was once the tallest! AND, it has a very cool neon sign with the macho miner.
Inviting!
Not only did the neon miner welcome us in, but the donkey mural was very encouraging with the words, Western Hospitality. That's something we were craving by lunchtime!
Nice Floor
As soon as we entered there were things to see...starting with the floor!
Casino Atmosphere
I'm not a big fan of casinos usually, but give me one with neon, buffalo heads and a cowboy and I'm impressed!
Animals and Ranch Stuff
Every nook and cranny was crammed with blinking casino lights or stuffed critters or ranching gear! I love the wall behind this wild cat. In the 1960's, ranchers from the area brought their branding gear right into the casino and branded their mark right onto the wood wall.
I was kind of disappointed that the dining room had been updated with a somewhat corny race car and motorcycle theme. But at least our server arrived with a smile and she took our order and answered an important question of mine. Yes, the locals of Ely pronounce the name as if you're describing something "eel-like". I hated the teasing I got as a child, but defended the name in recent years when people argued about the pronunciation.
It's fun to eat when you're hungry and I was starved since I hardly ate my breakfast. My simple BLT came with a pickle and super-crunchy AND creamy coleslaw which was delicious! Don had a bowl of cream of broccoli soup. (I liked my pick better) We even got a free bumper sticker which did not ride home on our bumper. But the food and atmosphere hit the spot. Clean, fast, yummy and our bill came to less than $10.00!
Yea for Dining Adventures along Nevada's Highway 50!
Breakfasts in Lake Tahoe
Red Hut Waffle Shop
I've added so little to the International list during this crazy travel month of October, but the Regional experiences have been adding up.
Above, we are in South Lake Tahoe, CA at a tiny Waffle Shop at 7 am. Breakfast is an important meal for people who ski or hike, so there are plenty of good spots in the area!
We visited Red Hut a year ago, when Cheryl waited on us. Back then I did more eating than visiting, since I had no blog.
Now I know that Cheryl has worked here for 22 years. This family owned joint started in 1959 and has changed little. Cheryl could have been frazzled since every chair and bar stool was taken, but her calm warmth seemed to relax the place. It felt like she was just serving one big family!
Feast!
If you're planning on hiking the Tahoe area, you have to have a big breakfast! Blueberry Streusel French Toast with a thick, diner-mug of coffee was just about right for a moderate hike.
Since it was our first day and we were going from an altitude of about 65 ft back in Texas to around 7,700...we couldn't take on too much.
Post Breakfast Hike
This is the kind of hike you can handle after French Toast!
We did a little meandering through the Quaking Aspens on what was once part of the Pony Express!
Zephyr Cove Lodge
On another day, we needed a bigger breakfast for a bigger hike, so feasting at Zephyr Cove Lodge in Nevada was the plan.
This has been a busy retreat for over 100 years! We arrived before the restaurant even opened and had the place to ourselves!
The interior has been updated with sort of cheesy furniture, but the fire and lake view made it a perfect way to start the day.
Our server, Vincente has worked at this National Forest Service Lodge for 17 years. In winter and summer the place is packed with tourists, but in October we saw mostly workmen coming in to grab a coffee.
Skillet Meal
A hefty, skillet meal of eggs, potato, spinach, mushroom and cheese was just the fuel I needed for a ten mile hike!
Of course we didn't know we were going to hike that long. In fact when I look at this spread I don't know how we managed to do anything besides nap! Back to cereal breakfasts, soon!
Fueled Up For a Hike
Our Zephyr breakfast lead to a more rugged hike than our Aspen Trail!
But we were also motivated by the amazing views of Emerald Bay as we hiked!
Lighthouse?
Our other hiking motivation was Rubicon's Lighthouse.
We had been tipped off that the lighthouse was unimpressive, but all we could do was laugh when after 5 miles we came upon this weathered little building. This poor outhouse-looking thing was built almost 100 years ago and only worked for 2! Thankfully we packed sandwiches, because our breakfast had been forgotten and we had to head 5 miles back.
POINTS FOR BREAKFASTS IN LAKE TAHOE- Too hard to figure out!

redpajama_set_name: RedPajamaCommonCrawl


text:
Imaging in multiple sclerosis
S A Trip,
D H Miller
NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, London, UK
Correspondence to:
Professor David H Miller
NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK; d.millerion.ucl.ac.uk
http://dx.doi.org/10.1136/jnnp.2005.073213
Multiple sclerosis (MS) is a common central nervous system (CNS) disease characterised pathologically by the development of multifocal inflammatory demyelinating white matter lesions. Magnetic resonance imaging (MRI) is the gold standard imaging technique for the identification of demyelinating lesions which can be used to support a clinical diagnosis of MS, and MS can now be diagnosed in some patients after a clinically isolated syndrome (CIS) using new MRI diagnostic criteria. Clinical trials of disease modifying treatments include MRI outcome measures of disease activity. The use of MR techniques to study the evolution of MS pathology in vivo is an important tool for obtaining better insights into pathophysiological mechanisms underlying the clinical course. This article will concentrate on the practical application of MRI in the management of MS.
MRI CONTRAST HELPS TO IDENTIFY MS PATHOLOGY
MR images are said to have contrast if there are differing areas of signal intensity. The contrast can be controlled to a certain extent by the parameters used and can produce images which contain differing levels of contrast depending on tissue content. For example, fat and water produce different image contrast. Images can be weighted towards particular contrast mechanisms. In T1 weighted images, fat is bright and cerebrospinal fluid (CSF) is dark; with T2 weighting, fat is dark and CSF is bright. Proton density (PD) weighting produces image contrast on the basis of the PD of the tissue. Such weighting of images has been exploited to identify inflammatory demyelinating lesions at different stages in their evolution.1
T2 and PD weighted imaging
T2 weighted imaging identifies MS lesions as high signal foci against the low signal background of white matter. However, periventricular lesions are often indistinguishable from the adjacent CSF which is also of high signal with T2 weighting. Contrast from the lesion can be improved here by using PD weighting because of the lower CSF signal with this sequence. Fortunately, T2 and PD weighted images can be acquired together in a single spin-echo sequence providing complimentary information (fig 1).
Axial magnetic resonance imaging (MRI) of a 30 year old man with relapsing remitting multiple sclerosis (MS) showing multiple periventricular lesions: (A) T2 weighted image; (B) proton density (PD) weighted image; (C) fluid attenuated inversion recovery (FLAIR) image; (D) T1 weighted image following administration of gadolinium (Gd) demonstrating enhancing lesions.
Fluid attenuated inversion recovery (FLAIR) sequence
The problem of identifying lesions in the periventricular region, which is a common site for MS lesions, can also be addressed by suppressing the signal from CSF yet maintaining heavy T2 weighting using a fluid attenuated inversion recovery (FLAIR) sequence (fig 1). This sequence is also superior at detecting cortical/juxtacortical lesions. FLAIR is therefore a commonly used MR sequence on clinical scanners when MS has been raised as a possible clinical diagnosis. The only drawback is inferior quality lesion detection in the posterior fossa and spinal cord where PD and T2 weighting are preferred.
T1 weighted imaging without contrast
Some high signal lesions on T2 weighted imaging will also be visible on T1 weighted images as areas of low signal compared to the normal white matter and are commonly known as "black holes" (fig 2). Such lesions when newly formed will either disappear with time, when it is thought they are caused by reversible oedema or demyelination, or persist as chronic black holes, when it is thought they are caused by permanent axonal loss.
Axial MRI of a 46 year old man with secondary progressive MS showing a large left sided periventricular lesion which is hyperintense with (A) T2 weighted imaging and hypointense with (B) T1 weighted imaging ("black hole").
T1 weighted imaging with gadolinium enhancement
A gadolinium chelate administered intravenously five minutes before T1 weighted imaging detects blood–brain barrier breakdown in association with active inflammation. New lesions appear enhanced (fig 1) and usually persist for a month on average, making them a useful marker for monitoring disease activity. Such lesions play an important role in indicating dissemination in time within the new diagnostic criteria. Triple dose gadolinium or combination with magnetisation transfer imaging (see next section) can both increase active lesion detection further but are not required in clinical practice.
NON-CONVENTIONAL MRI IN MS
The conventional MR techniques already discussed are restricted to the PD, T1, and T2 signal contrast behaviour of MS lesions. While these have transformed the diagnosis of MS and provided information about the significance of lesions, not all the pathological features of lesions can be studied using PD, T2, and T1 weighting, and CNS tissue that appears normal with such images can show pathological changes using quantitative MR techniques that are now discussed.2,3
Magnetisation transfer imaging (MTI)
Tissues contain protons in the liquid phase (mobile pool) and protons which are bound to macromolecules including proteins and lipids (bound pool). The latter have a very broad magnetic resonance frequency that normally decays too quickly for the scanner to detect. Bound pool protons are constantly in a state of exchange with the mobile pool. If a strong radiofrequency pulse is applied far enough away from the resonance of the mobile pool but is still able to excite the bound pool, some of the magnetisation is transferred from the bound to the mobile pool. This produces a magnetisation transfer (MT) weighted image and the magnetisation transfer ratio (MTR) can be calculated from the MT image and an image without MT weighting. Magnetisation transfer imaging (MTI) has been shown to be a sensitive marker of pathological change in many neurological disorders and, as a general rule, MTR decreases with increasing pathological change. Correlative MTI–pathological studies have suggested that the myelin content and the axonal count are the most relevant substrates of MTR changes in patients with MS, especially the former.
MTI in MS has focused on three main areas: (1) using MTI with gadolinium to improve lesion detection (discussed earlier); (2) distinguishing lesions of differing severity; (3) studying MTR in brain tissues that appear normal on conventional MRI. In vivo studies have shown that T1-hypointense lesions ("black holes") have a lower MTR than T1 isointense lesions, supporting the idea that these lesions occur as a result of destructive pathology. MTR values fall considerably when gadolinium enhancement occurs in lesions, with a recovery of MTR over the following months, although not usually back to normal. In some studies, brain MTR declines for several years. The severity of tissue damage has some correlation with the course of MS, as secondary progressive patients display lower lesion MTR than patients with benign MS. Whole brain MTR and segmented normal appearing white matter MTR are lower in patients than in healthy subjects, and independently predict subsequent disability.
MTI can be used to study the time course of lesion development and has shown that some lesions develop in previously normal appearing tissue in which there is declining MTR up to two years before gadolinium enhancement appears. Such lesions are less likely to recover MTR values compared to lesions developing in tissue with a previously normal MTR. Given the sensitivity of MTI to detect pathological change, guidelines for its use in future clinical trials have been developed.
Diffusion is the random motion of molecules in any fluid system including biological tissue. Diffusion weighted imaging (DWI) refers to the process of making MRI sensitive to the molecular motion of water molecules and is potentially a useful technique for studying white matter structure and pathology. Water diffusion can occur in any direction but occurs preferentially along the orientation of axons because their cell membranes act as barriers to diffusion. Such diffusion is said to be anisotropic and is dependent on the structural integrity of white matter tracts. Any disruption to white matter tracts or axonal membrane permeability should lead to an increase in the apparent diffusion coefficient (ADC) and mean diffusivity (MD), a measure of average molecular motion, and also to a decrease in fractional anisotropy (FA), a measure of the directional preponderance of diffusion which can be obtained with diffusion tensor imaging (DTI).
DWI has been applied qualitatively in clinical practice where it can be used to detect ischaemic changes within 30–90 minutes of acute stroke. DWI and DTI have supplemented conventional MRI techniques for the quantitative study of MS pathology in vivo. DTI studies in MS have shown increased ADC and MD with decreased FA in chronic T1 hypointense lesions compared to T1 isointense lesions which is compatible with evidence that T1 hypointense lesions represent more extensive tissue loss. FA is lower in acute, gadolinium enhancing lesions compared to non-enhancing lesions because extracellular oedema alters the anisotropic pattern of diffusion. ADC and MD values are raised, but the extent may depend upon the lesion age.
ADC: apparent diffusion coefficient
ADEM: acute disseminated encephalomyelitis
CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy
CIS: clinically isolated syndrome
CNS: central nervous system
CSF: cerebrospinal fluid
DTI: diffusion tensor imaging
DWI: diffusion weighted imaging
EDSS: expanded disability status scale
FA: fractional anisotropy
FLAIR: fluid attenuated inversion recovery
MD: mean diffusivity
MRI: magnetic resonance imaging
MRS: magnetic resonance spectroscopy
MS: multiple sclerosis
MTI: magnetisation transfer imaging
MTR: magnetisation transfer ratio
SLE: systemic lupus erythematosus
PD: proton density
PML: progressive multifocal leucoencephalopathy
PPMS: primary progressive multiple sclerosis
VEP: visual evoked potential
Changes in normal appearing brain tissue in MS patients have been detected by diffusion measures. As with MTI changes, these can occur early in the clinical course of MS and can precede new lesion formation. Several studies have reported a relation between DWI changes in normal appearing brain tissue and disability in different MS subtypes. DWI has not yet been included in clinical trials but may be useful in future studies of treatments which may prevent axonal loss.
The production of maps by DTI showing the principal direction of diffusion on a voxel by voxel basis allows the path of white matter tracts to be traced through the brain, and this is known as tractography. This novel technique has emerging promise for investigation of white matter pathology in MS and other disorders.
Magnetic resonance spectroscopy (MRS)
Proton magnetic resonance spectroscopy (MRS) enables the in vivo investigation of metabolic alterations associated with brain pathology, and provides a quantitative method for investigating the abnormalities in the normal appearing white matter. At longer MRI echo times, N-acetyl-aspartate (a neuroaxonal marker), creatine and phosphocreatine, and choline containing compounds may be quantified, while at shorter echo times additional metabolite peaks may be seen from myo-inositol (a potential marker of glial cells), glutamate and glutamine, and mobile lipids.
MRS studies in patients with established MS have demonstrated significant abnormalities in the concentration of metabolites in the normal appearing white matter, with notably reduced N-acetyl-aspartate, raised myo-inositol, and raised glutamate. A decrease in N-acetyl-aspartate is thought to indicate axonal dysfunction or loss, while an increase in myo-inositol has been proposed to reflect an increase in glial cell activity or numbers, and raised glutamate may have a role acutely in axonal injury. The stage at which these abnormalities first appear is less clear but two studies of patients with a CIS have shown separately that N-acetyl-aspartate is reduced and myo-inositol is raised. It is relevant to study this early phase of disease in order to search for prognostic markers for the future clinical course and to gain insights into early pathological processes.
DISTRIBUTION OF LESIONS IN MS
Lesions can be seen anywhere in the brain parenchyma, but there are certain areas in which they are typical for MS.1 Characteristic sites are in the periventricular region and juxtacortical white matter. The predilection for these sites may be explained in part by the distribution of venules where blood–brain barrier breakdown takes place. This concept is illustrated by the description of lesions arranged like fingers pointing away from the lateral ventricular walls which is also seen in pathological specimens where they are called "Dawson's fingers". These elliptical or ovoid lesions are believed to develop from demyelination along straight medullary venules arranged perpendicular to the ventricular walls; they are best seen on sagittal images where the common finding of lesions affecting the corpus callosum is also best seen. Juxtacortical lesions are often seen and are more suggestive of MS as they are uncommon with aging. Although current scanners do not commonly pick up grey matter lesions in the cortex, such lesions are seen in a significant number of postmortem brains from MS patients. Below the tentorium, the cerebellar peduncles and white matter, superficial pons, and floor of the fourth ventricle are common sites of lesions.
Optic nerves
The causative lesion of optic neuritis can usually be identified as an area of high signal on T2 or PD weighted imaging when appropriate fat and CSF suppression is applied. In theory, a clinically silent lesion in an optic nerve could provide evidence of dissemination in space, but this is not sought routinely because additional dedicated sequences are required to detect such nerve lesions reliably.
Spinal cord lesions are commonly seen in MS.4 In fact, the presence of cord lesions is more specific for demyelination than in the brain because age related or non-specific ischaemic lesions are rare. T2 weighted imaging typically demonstrates small and circumscribed high signal lesions (fig 3). They tend to be aligned with the long axis of the cord and are usually less than two vertebral segments in length and involve less than half the axial cord area. On axial scans they may display a wedge appearance and reach the outer surface of the cord (fig 3). The lesions are not confined to white matter tracts and may also involve central grey matter. The cervical cord is most frequently affected and most lesions involve the dorsal or lateral cord. "Black holes" on T1 weighted imaging are not usually seen in the spinal cord but gadolinium enhancement of acute cord lesions does occur. Focal cord swelling can occur acutely but this invariably resolves. More diffuse abnormalities can be seen in disabled patients, particularly those with primary progressive disease which has a higher disease burden in the spinal cord.
Cervical spine MRI of a 49 year old woman with a spinal cord clinically isolated syndrome (CIS) demonstrating a lesion at C3/4 on (A) sagittal imaging and (B) axial imaging which shows that the lesion is on the right side of the cord.
Lesion dynamics
T2 hyperintense lesions can alter in size over the course of weeks and a proportion of their volume disappears because of resolution of oedema, although complete resolution is rare. Lesions can also cause local atrophy, a finding best appreciated in the optic nerve or spinal cord. About 50% of acutely T1 hypointense lesions resolve and this may be partly caused by remyelination. Gadolinium enhancement of acute lesions may appear as patchy, homogenous (involving the whole lesions, which is usually small), or ring shaped (often the ring is incomplete).
VARIANTS OF MS
There are more aggressive forms of MS such as so called "tumefactive MS" which presents as a large high signal mass lesion sometimes requiring biopsy. Other terms that have in the past been included within the spectrum of inflammatory demyelination in the CNS include: Marburg's disease, Balo's concentric sclerosis, Schilder's disease, acute disseminated encephalomyelitis (ADEM), and Devic's neuromyelitis optica. Current evidence suggest that Marburg's disease is MS in an unusually aggressive form and that the concentric zones of demyelination and myelination seen in Balo's concentric sclerosis are an occasional finding in otherwise typical MS. Cases previously considered to have Schilder's disease almost certainly had posterior hemispheric white matter demyelination caused by MS or adrenoleucodystrophy. Monophasic ADEM is not uncommon in children, and occasionally occurs in adults although much less frequently than MS. We doubt that recurrent ADEM exists in adults as an entity separate from MS and are concerned that such a diagnostic label may preclude patients receiving MS disease modifying treatments.
In its classical form, patients with Devic's neuromyelitis optica have severe episodes of optic neuritis and transverse myelitis with variable recovery, longitudinally extensive spinal cord MRI lesions, normal brain MRI, and a moderate to pronounced CSF pleocytosis without oligoclonal bands. The suggestion that Devic's syndrome is immunopathogenically distinct from MS comes from the recent observation by Lennon et al5 that 70% of patients with the former condition have a serum autoantibody against CNS vascular and meningeal tissue components.
DIFFERENTIAL RADIOLOGICAL DIAGNOSIS OF WHITE MATTER LESIONS
White matter T2 hyperintensities in the brain are not specific to MS and are seen in a number of other disorders.1 They can even be seen in otherwise normal individuals, particularly with increasing age. The challenge is to recognise the typical lesion morphology and distribution of MS lesions (brain and spinal cord) in conjunction with the characteristic clinical presentations.
Microvascular ischaemic lesions
These lesions are a common form of T2 hyperintense white matter lesions in the general population and are thought to be caused by ischaemic demyelination of the white matter. In addition, small vessel pathology, enlarged perivascular spaces, and sometimes infarcts can all give rise to T2 hypertintense white matter lesions. The frequency of microvascular ischaemic lesions increases with age. Of course, it is not simply the number but also the distribution and clinical context which determines their significance. The increase with age makes it difficult to assess MR imaging in the older patient who presents with a clinical picture suggestive of MS, particularly if lesions are present in sites typical of MS. In the young and the old, it is important to look for a history of risk factors for cerebral microvascular disease such as smoking, hypertension, diabetes, migraine, or potential for cardiovascular embolic disease. The lesions can be punctate or patchy and are more common in the supratentorial white matter where they can be present at any site, though most often are subcortical rather than periventricular. Infratentorial lesions are less frequent but can occur—for example, in the central pons as an area of high signal. Confluent high signal change is more common in the periventricular areas and the subcortical U fibres are typically spared. Microvascular ischaemic lesions are not seen in the spinal cord even with aging or vascular risk factors.
Although not related to ischaemic risk factors, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) can produce confluent subcortical white matter high signal which is usually symmetrical and typically involves temporal poles and external capsules. These appearances are therefore not typical of MS and the clinical picture of strokes, migraine, cognitive impairment, and a dominant family history will also distinguish this condition.
Other inflammatory and vasculitic disorders
There are numerous disorders in this group that have MR appearances that could be mistaken for or even indistinguishable from MS.
Sarcoidosis can affect the CNS producing multiple lesions affecting the cortex, subcortical regions, cranial nerves, and rarely the spinal cord. The key distinguishing feature of this condition from MS is the presence of meningeal enhancement which is due to the granulomatous pathology. This finding highlights the importance of performing any repeat MR imaging with contrast before lumbar puncture as the latter can result in false positive meningeal enhancement on MRI.
Systemic lupus erythematosus (SLE) can present similarly to MS and may also have multiple small T2 signal intensities in the white matter. The MRI appearance is more suggestive of SLE when the lesions are not confined to periventricular white matter but favour the grey–white interface or even involve grey matter itself. The additional systemic clinical features and blood tests will help to distinguish SLE from MS.
Behçet's disease typically affects the diencephalon and brainstem but can also affect supratentorial white matter.
Infectious disorders
Two disorders in particular which are caused by an infectious agent can mimic MRI appearances of MS. Progressive multifocal leucoencephalopathy (PML) is caused by reactivation of latent JC polyomavirus in the immunosuppressed and is a multifocal demyelinating white matter disease. It causes confluent white matter lesions on MRI which do not cause mass effect or enhance. It is relentlessly progressive and usually fatal.
Neurological manifestations of Lyme disease can occur in association with white matter lesions similar to MS, although the usual clinical presentation is with a meningoradiculitis and/or cranial nerve involvement and an inflammatory CSF. The history of tick bite in an endemic area and serological investigation will help to distinguish Lyme disease from MS.
Neoplastic disorders
MS can usually be easily distinguished from the appearances of a tumour, but occasionally large MS lesions can mimic a neoplastic disorder such as primary CNS lymphoma and even metastases or glioma. The clinical course and follow up imaging usually clarify the diagnosis, but biopsy may be required.
The inherited leucodystrophies are a group of rare white matter disorders which result in differing patterns of dysmyelination or demyelination. The MR appearances differ from MS in that the white matter changes are typically confluent and fairly symmetrical without the discrete, disseminated, focal lesions seen in MS. Adult onset disease occurs and can show regional changes on MRI. Adrenomyeloneuropathy often shows changes in the parieto-occipital lobe white matter, and Krabbe's disease (globoid cell leucodystrophy) can selectively affect the corticospinal tracts.
Central pontine myelinolyis results in T2 high signal in the central pontine fibres and occurs following an acute metabolic disturbance, typically rapid correction of hyponatraemia. Extra-pontine myelinolyis can also occur.
ROLE OF MRI IN THE DIAGNOSTIC CRITERIA FOR MS
The clinical diagnosis of MS is based on a history of at least two separate episodes of focal neurological dysfunction supported by evidence of at least two lesions within CNS white matter which have been disseminated in space and time. The first set of criteria formalising the diagnosis of MS by Poser et al6 in 1983 were created before the advent of MRI and the degree of diagnostic certainty was identified by categories ranging from a clinically definite diagnosis to laboratory supported definite MS, clinically probable MS, and laboratory supported probable MS.
During the 1980s and 1990s, MRI became increasingly available and was integrated into the investigation and diagnosis of patients thought to have MS. MRI criteria for the diagnosis of MS were developed by Barkhof et al7 in 1997 and were later modified by Tintoré et al8 in 2000. The Barkhof criteria7 were developed in order to improve the prediction of a CIS converting to clinically definite MS on the basis of one MRI scan. A cumulative chance model with four criteria was used: (1) presence of at least one juxtacortical lesion; (2) at least one gadolinium enhancing lesion; (3) at least one infratentorial lesion; and (4) at least three periventricular lesions. These criteria were found to have a sensitivity of 82%, a specificity of 78%, and an accuracy of 80%. Tintoré et al8 modified these criteria by allowing a substitution of one enhancing lesion by nine T2 lesions which was also predictive of conversion of a CIS to MS.
In 2001, the International Panel on the Diagnosis of MS published new guidelines for the diagnosis of MS which for the first time utilised MRI evidence of lesion dissemination in time and space which could potentially allow the diagnosis of MS at an earlier stage.9 These are commonly known as the McDonald criteria and incorporate the two previous sets of MRI criteria by Barkhof7 and Tintoré.8 The McDonald criteria,9 like the Poser criteria,6 rely on objective evidence of dissemination in space and time but accept that specific MRI abnormalities can provide evidence in patients with a CIS. The modified Barkhof-Tintoré criteria are used to provide evidence of dissemination in space. If these imaging criteria are not fulfilled, two T2 lesions plus the presence of oligoclonal bands can also provide evidence of dissemination in space, but this may lead to a reduction in accuracy of the diagnosis. The MRI criteria for the dissemination in time require the presence of a gadolinium enhanced lesion on an MRI scan done at least three months after the CIS, or a new T2 lesion confirmed on two MRI scans done at least three months after the clinical episode. These criteria have been shown in natural history studies to have a high specificity in predicting at three months and one year whether a patient with a CIS will develop clinically definite MS within three years.10 If a new T2 lesion is allowed as evidence for dissemination in time at three months, specificity is maintained and sensitivity is increased. The McDonald criteria were also applied to the placebo arm of a CIS treatment trial (ETOMS trial) where it was found that the criteria for dissemination in space were associated with an increased likelihood of developing clinically definite MS. Figure 4 provides an approach for diagnosing MS after presentation with a CIS.
Approach to the diagnosis of multiple sclerosis (MS) in a patient with a typical presentation of a clinically isolated syndrome (CIS). CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.
In brainstem CIS, the dissemination in space criteria are less specific than in other types of CIS in predicting conversion to MS because the presence of the symptomatic infratentorial lesion is not used to show dissemination in space.
The potential for spinal cord MRI to aid diagnosis of MS is of interest because, as discussed earlier, the presence of asymptomatic cord lesions is rare in other disorders, and abnormalities in the spinal cord are common in patients with a new diagnosis of MS and thus are useful in providing evidence of dissemination in space. The McDonald criteria allow for the substitution of one brain lesion by one cord lesion.
Diagnostic criteria for primary progressive multiple sclerosis (PPMS)
The clinical presentation of primary progressive multiple sclerosis (PPMS) makes the diagnosis more difficult than relapsing-remitting MS because the defining clinical relapses are absent, making it harder to define dissemination in time and space, and there are often fewer brain lesions with a greater disease burden in the spinal cord. Criteria for the diagnosis for PPMS are included in the McDonald criteria9 and differ in that the presence of isolated oligoclonal bands in the CSF is a requirement. PPMS can be diagnosed when there is additional evidence of dissemination in space, using MRI or visual evoked potentials (VEPs), and in time, using MRI or progression of disability over one year.
Revisions to diagnostic criteria
As this article goes to press, we are aware that the McDonald criteria are being revised; once published, the newly revised criteria will need to be considered in future diagnostic workup algorithms.
MRI ASSESSMENT OF PROGNOSIS
Patients presenting with a CIS will often ask about the likelihood of developing MS in the future and also about the development of disability. The latter question is also relevant in patients who have recently been diagnosed with relapsing–remitting MS who have no significant disability. Several factors have a modest influence on prognosis including type of initial presentation and appearances on MRI scan.
The likelihood of subsequent development of MS has been addressed in natural history studies of CIS.10 Based on data from these studies, approximately 50–60% of all CIS patients will go on to develop MS in the long term. If an MRI scan at presentation is abnormal the likelihood of developing MS is increased to 60–80%, and if the scan is normal the risk is reduced substantially to approximately 20%. Patients with optic neuritis seem to have a lower risk of converting to MS in some studies where they have shown a lower frequency of MRI lesion than other types of CIS.
The prediction of subsequent disability has been assessed by comparing MRI findings at different time points with the expanded disability status scale (EDSS). A normal MRI appearance at presentation with CIS is associated with a lower level of disability many years later. The number of abnormal lesions at baseline has been modestly related to the severity of subsequent disability, and there are also data to suggest that the distribution of lesions may be important, with infratentorial lesions being better predictors of disability. In one CIS cohort, the final level of disability after 14 years was correlated with the total lesion volume after five years and the increase in lesion volume occurring over the first five years. Subsequent changes in lesion volume were less informative. It has been concluded from these data that early lesion accumulation on MRI is related to future disability from MS, although the prognostic information is relatively weak.
MONITORING DISEASE ACTIVITY IN CLINICAL TRIALS USING MRI
As well as being a diagnostic tool, serial MRI scanning can be useful as an objective measure to monitor lesion activity, lesion load, and response to treatment with disease modifying treatments in patients with MS. T2 lesions and "black holes" on T1 weighted imaging are used to measure lesion load, and gadolinium enhancing lesions measure new lesion activity. The number and volume of lesions are the most commonly used measures, but brain and spinal cord atrophy can also be used to monitor disease progression and may be more relevant when considering disability outcome in the longer term.
Exploratory studies of novel therapeutic agents normally have monthly scanning with gadolinium enhancement as the primary end point of treatment efficacy because clinical relapses will be relatively infrequent and disability progression will be minimal during short follow up periods. In larger phase III trials, T2 lesion number, T2 lesion load and atrophy, as well as enhancing lesions, are used as secondary outcome measures. T1 "black hole" lesion load can also be used and may be a better marker for axonal loss secondary to lesions if only persistent "black holes" are measured. Trials of patients with a CIS also employ MRI to select individuals at high risk of conversion to MS for enrolment.
The first trial to show a treatment effect using MRI outcome measures in patients with MS was the interferon beta-1b trial which found significant reductions in both new lesion activity and total T2 lesion load. MRI outcome measures have subsequently been included in all the major clinical trials evaluating the efficacy of disease modifying agents including trials of glatiramer acetate, interferon beta-1a, and mitoxantrone which is used in patients with aggressive disease. The most recent large trial was the AFFIRM study of natalizumab which demonstrated substantial reductions in relapse rate, disability, and MRI outcome measures which were of a higher magnitude than those seen in previous trials of existing disease modifying treatment.
Although conventional MRI outcome measures are used extensively in clinical trials, they must be used in conjunction with clinical and other para-clinical measures as they have been shown to be only modestly correlated with disease progression. It is possible that the relation between MRI changes and clinical status may be confounded by the adaptive capability of unaffected areas of the CNS. Disease progression may only occur when pathology affects functionally important regions—for example, the spinal cord—and when the extent of pathology exceeds a critical threshold. The conventional MRI outcome lesion measures only assess pathology in white matter affected by lesions. The non-conventional MRI techniques discussed earlier have promise in assessing the pathological changes in normal appearing white and grey matter and could be incorporated into future clinical trials. Measures of brain atrophy are also now routinely included in treatment trials monitoring.
An exciting potential area for future study is to use MRI to monitor remyelination in experimental trials. MTR is higher in remyelinated than demyelinated lesions and may be a good tool for use in such trials. Another technique that shows promise in detecting myelin is the short T2 component of multi-exponential T2 relaxation.
We thank Drs Li, Fernando, Swanton, and Lanyon for their assistance with the reproduction of the MR images. The NMR Research Unit is supported by The Multiple Sclerosis Society of Great Britain and Northern Ireland.
Pretorius PM, Quaghebeur G. The role of MRI in the diagnosis of MS. Clin Radiol2003;58:434–8.
▸ A useful pictorial review with 35 MRI images which includes the differential radiological diagnosis of MS.
Symms M, Jager HR, Schmierer K, et al. A review of structural magnetic resonance neuroimaging. J Neurol Neurosurg Psychiatry 2004;75:1235–44.
▸ From the "Neuroscience for Neurologists" series. Reviews non-conventional MRI techniques as applied to neurological diseases including MS.
Miller D, Barkhof F, Montalban X, et al. Clinically isolated syndromes suggestive of multiple sclerosis, part 2: non-conventional MRI, recovery processes, and management. Lancet Neurol 2005;4:341–8.
▸ Part 2 of a comprehensive review of CIS including findings from non-conventional MRI.
Lycklama G, Thompson A, Filippi M, et al. Spinal-cord MRI in multiple sclerosis. Lancet Neurol 2003;2:555–62.
▸ A comprehensive review of all aspects of spinal cord imaging in MS.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106–12.
Poser CM, Paty DM, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–31.
Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120:2059–69.
Tintore M, Rovira A, Martinez MJ, et al. Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis. AJNR Am J Neuroradiol 2000;21:702–6.
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.
▸ The current diagnostic criteria for MS.
Miller D, Barkhof F, Montalban X, et al. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4:281–8.
▸ Part 1 of a comprehensive review of CIS including the role of conventional MRI in diagnosis and predicting prognosis.
Copyright 2005 Journal of Neurology Neurosurgery and Psychiatry


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Q: import environ could not be resolved pylance when using venv I'm new in Python/Django and I'm trying to create a live app.
I did create the django project first, then realized I should do this in a venv. So I created the venv within my project folder. I managed to get my PostgreSQL db connected, and since I'm trying to keep my stuff secure, I'm storing my DB password in a global variable.
import environ

from pathlib import Path

env = environ.Env()
environ.Env.read_env()

My problem is that I keep getting the error:

import environ could not be resolved pylance

in my settings.py file and I've no idea why. I think I've set up my venv correctly and placed it in my project folder.
Is something wrong with my interpreter? I'd really like some help with this please.

This is the error I'm seeing:

I seem to be inside my venv:

I'm able to run my app just fine and update my database no problems. which I'm thinking shouldn't work if there really is an issue with how my venv is setup?
I've tried everything I can think of. Made another venv and played around with it. Only thing I'm stuck on is making sure my interpreter is correct. how can I be sure I'm using the right interpreter? When I try to manually select an interpreter, I don't see any that imply it's in my venv:

A: Solved. I was just using the wrong path when selecting my interpreter manually.
I right clicked on the appropriate Python3.10 interpreter file and copied the Path url. then pasted it right into the command palette to manually set the interpreter. that refreshed vscode and removed the warning.

redpajama_set_name: RedPajamaStackExchange


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Buttons that are used for navigation should be coded as anchor links, and those that submit forms as button elements — each will be styled identically by the framework.
For ease of styling, the framework automatically converts any button element or input with a type of submit, reset, button, or image into a custom styled link-based button — there is no need to add the data-role="button" attribute.
The original form-based button is hidden, but remains in the markup. When a click event fires on a link button, it triggers a click on the original form button.


text:
Q: Dynamically @Autowire bean depending on the @Scope in Spring I have a service which caches the response. I use a simple Map for caching the response.
I also have two scopes: @RequestScope and @GrpcScope. @RequestScope is obviously for requests received from rest controller whereas @GrpcScope is for grpc requests.
My service doesn't know what scope it is currently running in. Both (grpc and rest) controllers uses the same service and there could be only one scope active at runtime.
I want FooService to use RequestScopedFooCache in if the the scope is @RequestScope and to use GrpcScopedFooCache if the scope is @GrpcScope. How can I do that?
// for RequestScope
@RestController
public class FooRestController{
    @Autowired
    FooService fooService;

    @GetMapping
    public BarResponse getFoo(){
        return fooService.fooRequest(...)
    }
}

// for @GrpcScope
@GrpcController
public class FooGrpcController{
    @Autowired
    FooService fooService;

    public BarResponse getFoo(){
        return fooService.fooRequest(...)
    }
}

@Service
public class FooService {

    @Autowired
    FooCache cache;  // doesn't know which bean to autowire however there could be only one of them at runtime

    BarResponse fooRequest(String id) {
        if(cache.get(id))
            ...
    }
}

public interface FooCache {
    ...
}

@Component
@RequestScope
public class RequestScopedFooCache implements FooCache {
    ...
}

@Component
@GrpcScope
public class GrpcScopedFooCache implements FooCache {
    ...
}

Using SpringBoot version 2.4.+

A: Not exactly what you are asking for but I would probably create my own bean methods for FooService and give them qualifying names.
Changed FooService to take FooCache as a constructor:
public class FooService {
    private final FooCache cache;

    public FooService(FooCache cache) {
        this.cache = cache;
    }

    BarResponse fooRequest(String id) {
        if (cache.get(id))
            ...
    }
}

Give the FooCache implementations qualifying names:
public interface FooCache {
    ...
}

@Component("GRPC_CACHE")
@RequestScope
public class RequestScopedFooCache implements FooCache {
    ...
}

@Component("REQUEST_CACHE")
@GrpcScope
public class GrpcScopedFooCache implements FooCache {
    ...
}

A bean manager to setup the FooService beans:
class FooServiceBeanManager {
    @Bean("GRPC_SERVICE")
    public FooService grpcFooService(@Qualifier("GRPC_CACHE") FooCache fooCache) {
        return new FooService(fooCache);
    }

    @Bean("REQUEST_SERVICE")
    public FooService requestFooService(@Qualifier("GRPC_CACHE") FooCache fooCache) {
        return new FooService(fooCache);
    }
}

Specify which bean you want in your controllers using @Qualifer:
// for RequestScope
@RestController
public class FooRestController {

    private final FooService fooService;

    @Autowired
    public FooRestController(@Qualifier("REQUEST_SERVICE") FooService fooService) {
        this.fooService = fooService;
    }

    @GetMapping
    public BarResponse getFoo() {
        return fooService.fooRequest(...)
    }
}

// for @GrpcScope
@GrpcController
public class FooGrpcController {

    private final FooService fooService;

    @Autowired
    public FooGrpcController(@Qualifier("GRPC_SERVICE") FooService fooService) {
        this.fooService = fooService;
    }

    public BarResponse getFoo() {
        return fooService.fooRequest(...)
    }
}

I changed the controller classes to have @Autowired constructors instead of fields. It is the recommended usage (source: Spring @Autowire on Properties vs Constructor)
I also personally prefer to have my own @Bean methods as much as possible because it gives me much more control.


With the accrued use of popups on sites - once you enter, once you leave, while you are location - Popup killers (or stoppers) are all the madness.
Companies use Popup killers as a mercantilism utensil for thwarted webusers - they exterminate the Popup, the webuser uses their service be it as an ISP or Toolbar.
New ISP Disks, Toolbars, and Browsers all now locomote next to whatsoever kind of Popup soul. While we all poorness to come to a close the vexation of having respective popups individual delivered while surfriding in circles the web, to the webmaster a Popup individual can entirely assassinate a site's conventional practicality.
It could be a sign of that once a user clicks on your employ button or affiliate link, it won't work! The someone can sound on it as often as they like. It won't work!
This could be costing you gross sales and applications.
We after switched the utilise buttons and course to a majority HREF relation and transmitted other 1000 visits to it. We have a 10 crease widen in applications.
The lone on-page changes were the Apply control golf links and we animal group the visits via PPC pass.
You can ever changeover them vertebrae if you stipulation to but ponder the future gross opportunity.
It of course has worked for us!


text:
Fabian: Goes to the Dogs
Directed by Dominik Graf
Language: German with English Subtitles
Berlin, 1931. Jakob Fabian works in the advertising department of a cigarette factory by day and drifts through bars, brothels and artist studios with his wealthy and debauched friend Labude by night. When Fabian meets the beautiful and confident Cornelia, he manages to shed his pessimistic attitude for a brief moment and falls in love. Not long after, he falls victim to the great wave of layoffs sweeping the city, plunging him back into a depression, while Cornelia's career as an actress is taking off thanks to her wealthy boss and admirer – an arrangement that Fabian finds difficult to accept. But it's not just his world that is falling apart… Veteran German director Dominik Graf (Beloved Sisters) wowed audiences at the Berlin Film Festival with this dazzling adaptation of Erich Kästner's classic of Weimar literature, set amid the twilight hedonism of pre-Nazi Germany.
"Exhilarating. An unpredictable visual experience... unfolds like avant-garde jazz."
- Ryan Lattanzio, Indiewire
"A sprawling, radical, profoundly thoughtful period drama… puts a timeless spin on the material and makes it feel as urgently relevant as ever."
- Zhuo-Ning Su, Awards Daily
"Enthralling. A vigorous, expansive romance of the times."
- Daniel Kasman, MUBI
"An ambitious remounting of Kastner's text, it's an uneasy calm before a wrathful storm."
- Nicholas Bell, Ion Cinema
"Genuinely haunting… there's no doubt that Fabian will go down as one of the year's best films."
- C.J. Prince, Edge Media Network
"An intimate tale of friendship and tragic romance."
- Jordan Cronk, Sight & Sound
"Fabian could be one of those rare contemporary German films to make a significant mark on a wider stage."
- Jonathan Romney, Screen International
"A love story, an homage to Berlin and also to cinema."
- Carolin Ströbele, Die Zeit
Official Selection – Berlin Film Festival
Winner of Three German Film Awards (Lolas)
Albrecht Schuch
Writers Dominik Graf and Constantin Lieb
Laemmle Theatres Starts March 4!
Metrograph Starts February 11!


text:
Matthew Coleman (born 8 June 1973) is a former Australian racing car driver. He competed in various Australian championships including the Australian Super Touring Championship, the Australian GT Production Car Championship, the Australian Nations Cup Championship, Porsche Cup Australia and the Australian Carrera Cup.

Results

Career results

Complete Bathurst 1000 results

References

External links
Super Touring Register : Matthew Coleman
Driver Database Stats: Matthew Coleman

1973 births
Living people
Supercars Championship drivers
Racing drivers from Victoria (Australia)
Audi Sport drivers
Garry Rogers Motorsport drivers

redpajama_set_name: RedPajamaWikipedia


text:
GLOBE THEATRE.
Everything you need to know about the Globe Theatre at Shakespeare's Globe
We have two performance spaces here at Shakespeare's Globe – the Globe Theatre and the Sam Wanamaker Playhouse. Now 23 years old, the Globe Theatre remains one of the most unique, remarkable and breathtaking theatrical spaces in London.
Use the page below to find out more about the Globe Theatre – explore fun facts, history, construction, photos, virtual tour, seating plan and more.
A 1,570 capacity open-air theatre.
Bankside, London, UK, SE1 9DT.
Opened in 1997, still open today.
Shakespeare called his theatre a 'wooden O' and like his historic playhouse our Globe Theatre is a 360° auditorium. With no roof over the central yard, the theatre is open-air and audiences who attend performances and tours are told to dress for the weather! Events will go ahead in rain, shine and snow.
Seats are arranged in galleries all around the wide, open stage, so spectators and performers can see each other at all times. The Globe Theatre is a space where the audience has always been a vital component of the performance.
The Globe Theatre officially opened in 1997, although workshops and performances had taken place on the stage since 1995.
It also isn't our only performance venue. Shakespeare's Globe is home to the candle-lit Sam Wanamaker Playhouse, and we perform plays and readings in other spaces on site and and even outside by the River Thames. We also tour around the world!
And we don't just stage the works of Shakespeare. We programme a range of Renaissance playwrights, as well as new writing, music concerts, film screenings, family events, educational workshops, community projects, guided tours and more.
Due to the 2020 Coronavirus outbreak, the Globe Theatre hasn't been operating as normal. We are asking for donations to support us at this challenging time.
A 'roofless', open-air theatre (bring your coats!).
Shape is an icosagon, a 20 sided polygon.
Can hold 1,570 people, 700 standing and the rest seated.
Built from oak beams, lime-plaster walls and a water-reed thatched roof.
The twelve signs of the zodiac are painted on this roof over the stage (which we call 'The Heavens').
The only thatched-roof building in London.
We had to fight for special permission to have our thatched roof, as there has been a law against thatched buildings in London since the Great Fire of 1666!
We think that the first Shakespeare play to be performed at the original Globe was Julius Caesar, in 1599. Other playwrights wrote for the Globe too, including Ben Jonson, Thomas Dekker and John Fletcher.
The Globe Theatre you see today in London is the third Globe.
The first opened in 1599 and was built by the Lord Chamberlain's Men, the company that William Shakespeare wrote for and part-owned.
We think that the first play Shakespeare wrote for the original Globe was Julius Caesar in spring 1599. Later that year he also wrote As You Like It and made a start on Hamlet. Over the next fourteen years Shakespeare wrote some of his greatest plays, including Twelfth Night, Othello, King Lear, Macbeth, and Antony and Cleopatra. Other playwrights wrote for the Globe during this time too, including Ben Jonson, Thomas Middleton and John Fletcher.
In 1613, during a performance of Shakespeare's Henry VIII (co-written with Fletcher), a mis-fired prop canon caused the thatch roof to catch fire. The entire theatre burnt down within two hours, according to eyewitness reports (miraculously, no one was killed). The company rebuilt the Globe in a year – with a tiled roof. The second Globe operated until it was closed down by parliamentary decree in 1642.
In 1609 Shakespeare's company started performing in the indoor Blackfriars playhouse as well as the Globe. It was here that Shakespeare conceived his final great plays, including The Tempest.
The current Globe Theatre opened in 1997, after many years of campaigning by the founder of the Shakespeare's Globe Trust, Sam Wanamaker. Find out more about how today's theatre was built below.
UNDERSTANDING THE DIFFERENT 'GLOBE'S
Our company name today and the name for our site in London, which is home to our two theatre venues – the Globe Theatre and the Sam Wanamaker Playhouse.
The name used to refer to the two previous Globes… the originals, as it were!
Our reconstruction. The current venue that you see here today on Bankside.
We aren't the only living 'Globe'. There are many replicas and pop-up venues all across the world that seek to recreate Shakespeare's original performance space.
In 1949 our founder Sam Wanamaker visited London with a mission to find the site of the original Globe, and was surprised to find only a small plaque commemorating the site (which got some details wrong!).
In 1970 Sam set out to build a reconstruction of Shakespeare's original Globe on Bankside. He founded the Shakespeare Globe Trust with a mission to recreate the 1599 amphitheatre as accurately as he possibly could.
Despite many obstacles, Sam persevered with his ambition for two decades.
Sadly, he did not live to see the theatre's completion. He died in 1993, and in 1997 the Globe Theatre was opened by Her Majesty the Queen.
'Sam's vision and his single-minded commitment was undoubtedly the driving force that kept the project on track through the decades.'
– Barry Day, The legacy of Sam Wanamaker
Find out more about the construction of the Globe Theatre.
This video shows a bird's-eye view of the Globe Theatre, and how the shape of the building is the basis of our logo.
This short animation was made to showcase the story of our logo and how it was influenced by the building of the theatre – from acorn, to tree, to wood, to Globe Theatre, to logo.
This film from Superunion shows some examples of the Shakespeare's Globe branding.
Walk around the Globe Theatre with our interactive 360 degree virtual tour, which uses photos, videos and audible wonder to guide you through the space.
Below is an example seating layout for a typical performance in the Globe Theatre.
The entire venue can welcome approximately 1,570 people, 700 of those in the yard standing and the rest seated across three gallery levels. The theatre's shape and the presence of pillars means that your view will be slightly different depending on where you sit (or stand).
YARD & LOWER GALLERY
MIDDLE GALLERY
UPPER GALLERY
In 2018, we had a complete rebrand as a company. Our new logo, a circular symbol, mirrors the Globe Theatre's shape.
Have you ever noticed that our logo has 'cracks' in it? This isn't a computer-designed effect, but an imprint of the oak beam that was used to construct the logo itself. The design was created through an intricate hand-crafted carving and printing process.
Devised by international branding agency The Partners, our new 'circular' logo is in fact, not a circle at all, but has twenty sides – just like the Globe Theatre.
Want to watch a Globe Theatre performance from the comfort of your home?
Our video-on-demand service, Globe Player, allows you to buy or rent a large collection of filmed productions.
Globe Theatre Aug 20
Photos of Shakespeare's Globe in lockdown
Globe Theatre Jul 20
Photographer Helen Murray captures #OurEmptyTheatres
Globe Theatre Mar 20
#WorldTheatreDay
Globe Theatre Jan 20
This wooden O: the history of our unique shape
The old and the new collide: the Globe's new visual identity
Globe Theatre Jun 17
Building Shakespeare's Globe
Find out more about Shakespeare's Globe
Walk around the Globe Theatre
SAM WANAMAKER PLAYHOUSE
HELP SUPPORT OUR BELOVED THEATRE
With so many of our activities still on hold, we need you more than ever to help secure our future. Please donate any amount, small or large.
DONATE ×


This easy nachos recipe is loaded with fresh veggies and spices. It uses pita bread to serve this fabulous Mexican feast.
Spread the pita pieces on a large heatproof serving plate. Top with the kidney bean mix, then sprinkle with the cheese. Bake for 5 minutes or until cheese has melted.
Meanwhile mix the chopped tomatoes with the coriander and set aside.
Serve the nachos topped with tomato and coriander, mashed avocado and sour cream. Serve immediately.


This is one of the 77 letters & documents discovered in a bog in Ireland sometime before 1960. NEWS: Seven boxes of tea has arrived; TJ's wife visited July 7-30th along with their nanny Al MING; reports on TJ's children; picnic at Cavananore which is doing well; mention of Derryvalley auction; TJ's home called "Creggan" - (it was on The Peak in Hong Kong); corn crops looking good, but potato blight has reappeared; new Land Bill has passed & Liscalgot & Legmoylin put in & Urker will be; TJ & children & HSBC returned to good health; David JACKSON expected to return from Yokohama in February or March.
My dear Tom – Once more I am trying to write a line to you, though probably it will not be posted today. The tea arrived yesterday seven double boxes; many thanks to you for it. We have not opened it yet. Minnie's  visit went off happily, the weather was favourable, & all seemed to enjoy themselves. There were only two drawbacks, one was that the visit was not long enough; she & the children came on the 7th of July, & went on the 30th. The other drawback was that Julius  was not with them. I was greatly disappointed but I believe it could not be helped. Dr Barnes  did not think him quite clear from the old complaint, & forbid him to bathe but in a letter received today, Minnie says he is greatly improved since he arrived at [Alalaburgh?]  . Pity that any thing should ail him, he is a dear little fellow.
Every one about this place was highly pleased with our young officer  , he is a fine young fellow, without any upsetting or puppyish ways about him. He has perfectly the measure & appearance of a gentleman; & no one would ever mistake him for anything else. He was as well contented with the "old house at home" as if it had been a royal palace. May God grant him grace. Beatrice  is a very nice girl & Dorothy  is all alive; I believe she does no know what fear is. The two youngest boys are good fine children; Claud  (sic) is my favourite, he is so friendly & [?]. He would seem to help me to go upstairs just as cleverly as if he was able to do it.
I saw the list of your Bank shareholders. All your children's [?] names are on it except Claud's. I hope you will satisfy that omission forthwith, if you have not done it already. There is not a better man among them than Claud, though all are good. He is just as good natured as you were yourself, when you were like him. Both he and Russell  were very sorry young men going away & poor Al Ming  cried herself sick. Minnie insisted on taking Mary Menary  with her; I was unwilling to let her go as sea air never seemed to agree with her; it was nearly finishing her last year; but it appears to be doing well with her now, all the accounts are favourable.
We had a great picnic to Cavananore  , 15 in number, but probably Minnie has told you all about it. You would be delighted to see Cavananore, it never looked better, even in Uncle Bradford's  or Aunt Mary's  time. Ely  nearly killed me walking me so much over it; he was so anxious to show me the improvements. I have grown very feeble and cannot walk much though I am in good health & as merry & stout hearted as ever I was. But you may say that it was a sore crush to see what happened to Derry Valley  the place where I spent many a happy day. I went to bid it farewell that day before the Auction. The news of the sale of it upset poor Sarah Whiteside  greatly & no wonder. I believe there is no great good future for any member of Thomas McCullagh's  family. But one piece of good news I have to tell you. Miss Macready  has come in for a legacy of ₤254 by the death of a sister. She is living in Drummuck  & is very comfortable there.
I was delighted to hear that you were back in Creggan  again & expecting Kathleen  & Amy  so soon. I think that under God Creggan was a great means of preserving your health in an unhealthy climate. I was nearly forgetting to tell you how much I was pleased with Tom's likeness. It is a remarkably good one; when you see it, you see him. I have it set up on top of the What not; so that I can take a look at it any minute.
The weather was very dry for a length of time & water grew very scarce; but God sent rain time enough for every thing except flax. The corn crop is very good, but alas! potato blight has appeared again. The new Land Bill has passed; Jemmy  has put his land into the Land Court & I have put Liscalgot  into it, & will put Urker  as soon as it can be done. It was a great mistake that I did not appeal when it might have been done.
19th Your letter of July 16th has just come in. I congratulate you in hearing your girls back & in such good health; also on the good health of "the old cow"  . I never weary of doing what I can for "the old cow" and for all belonging to her; & I think I am heard. I often observe answers to my petitions, and I feel assured that the blessings which I implore will be alighting after I am mingled with the clouds of the valley; I have made up my mind to live, if I can, till I see you again. Every one is telling me how well I look; & I feel well except for weakness & infirmity.
There is nothing new that I know of among your Irish friends & acquaintances. David  writes that he is to leave Yokohama at the end of the year. I am not sorry on account of the earthquakes  . He expects to be here in February or March. You may remember that I wish him to bear the expense of Urker after I am gone, he has a right to do so.
 Dr. BARNES? Probably a London doctor.
 I have no idea what this might be.
 Beatrice Minnie Shrieve JACKSON, daughter of Amelia Lydia DARE & Sir Thomas JACKSON.
 Claude Stewart JACKSON (1892-1917), youngest son of Amelia Lydia DARE & Sir Thomas JACKSON. He was killed in WWI and died near Ypres, Belgium.
 Al MING was the family nurse to the children of Amelia Lydia DARE & Sir Thomas JACKSON. She travelled with the family and visited Urker whenever they returned from the Far East. A story recounted by a Mary DALY and recorded by Mary CUMISKEY in the Journal of the Creggan Local History Society , 1990, p. 55 describes MING as being about four feet tall with two pigtails down her back and exceedingly small feet (possibly bound?).
 Cavananore, Co. Louth, a family farm.
 Probably Andrew Coulter BRADFORD (1788-1847), uncle to Eliza JACKSON (mother of Sir Thomas JACKSON). He never married and died at Cavananore.
 Derryvalley, Co. Monaghan a farm where McCULLAGHs lived – it was sold to cover debts.
 Sarah (MCCULLAGH) WHITESIDE (1852-1939), daughter of Thomas McCULLAGH & Sarah McCULLAGH.
 Thomas McCULLAGH (1793-1877) of Derryvalley, husband of Sarah McCULLAGH.
 Mary McCREADY governess to the McCULLAGHs of Derryvalley.
 Drummuck, Co. Monaghan was the home of the McCULLAGHs of James McCULLAGH & Eliza WALLACE.
 Creggan was the name of the home that the JACKSONs had on The Peak in Hong Kong.
 James JACKSON, brother of Sir Thomas JACKSON. He has been farming at Legmoylin - land that Sir Thomas had bought for him but that he had managed for some time before for Harriet DONALDSON. He was deemed by other family members to be ineffectual and his wife was credited with the success of the farm.
 Liscalgot is the townland where Eliezer GILMORE & Sarah JACKSON resided. At the time of Griffiths Valuations, Eliezer's father, Samuel, held a lease from Richard ALLEN of 48 acres while David JACKSON held the leasefrom Richard ALLEN for 76 acres and as well had free title to three houses of little value. The leased land that GILMOREs and JACKSON had amounted to about half the townland. Richard ALLEN held the rest.
 Urker townland is where Eliza JACKSON resided and where several generations before her had lived. The JACKSONs at the time of Griffiths Valuiations lease about 55 acres and had farm buildings and a home while Samuel GILMORE leased a couple of acres. The landlord was Thomas P. BALL.
 I don't know if she is referring to specific earthquakes, or the general likelihood.


text:
Massachusetts Woman Pleads Guilty to Bank Fraud
FILE PHOTO: Signage is seen at the United States Department of Justice headquarters in Washington, D.C.
CONCORD – Donna Silva, 44, of Lowell, Massachusetts pleaded guilty in federal court to bank fraud, United States Attorney Jane E. Young announced today.
According to court documents and statements made in court, in February of 2019, Silva was involved in a scheme to defraud several financial institutions. The defendants in the scheme applied for and obtained multiple loans to purchase cars purportedly sold by Allied Imports, a Manchester car wholesaler, and Cap's Auto Sales, a Manchester car retailer. The sales were fraudulent because the defendants never owned or greatly inflated the value of the cars. In total, the defendants defrauded the financial institutions of several hundred thousand dollars.
Silva signed a fraudulent purchase contract and Assignment of Title with Cap's Auto Sales purporting to state that she would buy a car sold by the company. She then used the documents to apply for and obtain a car loan secured by the vehicle, which Cap's Auto Sales did not own or have the title to.
Silva is scheduled to be sentenced on August 15, 2022.
"By submitting false documents to obtain fraudulent loans, the defendant participated in a substantial criminal scheme," said U.S. Attorney Young. "As this case demonstrates, we work closely with our law enforcement partners to identify and prosecute those who commit fraud. By working together, we strive to hold these criminals accountable for their unlawful conduct and seek justice for victims."
This matter was investigated by the United States Secret Service and U.S. Postal Inspection Service. The case is being prosecuted by Assistant U.S. Attorney Charles Rombeau and Special Assistant U.S. Attorney Alexander S. Chen.
pleads


text:
Q: Export to Excel using phpoffice/phpexcel in Laravel 5 I want to export my table in database to Excel. I use the phpoffice/phpexcel library and the Laravel 5 framework. I have read some articles, but I'm still confused.
How to export a table to Excel using phpoffice/phpexcel in Laravel 5?

A: Below are the step to use PHPEXCEL Library with laravel 5
1:- Install "phpoffice" Package in Laravel 5. Below is the link for the packages
2:- Add "phpexcel/phpexcel": "dev-master" to your composer.json.
Ex:- "require": { "phpexcel/phpexcel": "dev-master" }
3:- Then execute "composer update".
4:- Open the file "/vendor/composer/autoload_namespaces.php". Paste the below line in the file.
// Include PHPEXCEL Library with Laravel 5
'PHPExcel' => array($vendorDir . '/phpoffice/phpexcel/Classes'),
5:- Now you can use PHPEXCEL library in your controllers or middleware or library.
use PHPExcel;
use PHPExcel_IOFactory;
For more details you can access "https://github.com/pantlavanya/export-to-excel-using-phpoffice-phpexcel-in-laravel-5" link.


Make time for your Side Effects every Tuesday at Puffers of Pismo. Join Lyne Hamel and Charlotte Marie as they theme up each week, offer set lists to their guests, and let the night unfold. Side-Effected Folk-Pop, Alt-Country & Americana 6:30-9:30ish. Wine Brews Menu Locals! Puffers is the place.
ODonna's do PoP on Sunday!


text:
<< La médecine militaire se réforme... Nouveau concept de stationnement... >>
EADS chief warns jobs cuts coming in defence unit
November 26th, 2013 defencetalk.com (AFP)
A reduction in defence orders will have an impact on jobs in EADS's defence unit, the head of the European aerospace giant said in an interview published Monday.
Tom Enders told vbw-Unternehmenmagazin, the magazine of the Bavarian economic federation, that "if defence orders are cancelled or reduced as has happened in Germany in recent years, an impact on production and employment cannot be avoided."
Enders's comments follow a report by the German news agency DPA last week that EADS is considering cutting the workforce by 20 percent, or 8,000 employees. The group will be renamed Airbus Defence and Space next year as it reorganises.
EADS said no numbers have been decided, but Enders has previously said drastic measures were needed to secure the future of the division.
The restructuring is seen as unavoidable after the failed plan to merge with Britain's defence firm BAE Systems last year.
That was shelved after objections from government stakeholders, notably Germany, which worried it would cause considerable layoffs.
Enders said the outlook is not rosy for defence manufacturers due to the high value of the euro and the eurozone debt crisis pushing countries to cut back on acquisitions of new equipment.
Enders told the Bavarian magazine that EADS had lost over the past few years orders worth several billion euros just in Germany that the company had thought were certain.
He said EADS cannot absorb that without making changes at the affected sites. He did not go into details.
The German newspaper Suedeutsche Zeitung reported Monday that a defence factory of EADS's Cassidian unit located north of Munich would be closed with activities shifted to another facility in Bavaria, where EADS employs some 16,000 people.
An EADS spokesman declined to comment on the report, telling AFP that it would not make detailed announcements on its plans before informing its European works council, which meets in Munich on December 9.
Published by RP Defense - dans Europe EADS Cassidian Defence Aerospace Industry Défense Aéronautique Enders Industrie


Posted 11 June 2015 by Sarah & filed under Uncategorized.
Check out The Journal's article about Stella's upcoming appearances in Newcastle in honour of Refugee Week.
Visit http://www.live.org.uk/ to purchase tickets to the concert at Live Theatre.