The latest and greatest of news going on at Ebikes Hawaii! The Ebike industry is very exciting and always advancing. We try our best to keep our customers fully informed, as well as providing updates with the current product lineup of our own.
Awesome video from Electric Bike Report over at the Sea Otter 2019 event! Take a close look at the new Electric Brompton coming to Ebikes Hawaii soon!
Ah yes, the age old question. Should I go down to my local electric bike shop to purchase a bike? Or should I find the seemingly best deal I can online via Amazon or the usual outlets. The prices are so low, how can I resist? We here at Ebikes Hawaii would like to take a moment and address different buying options for all you electric bike seekers out there. More and more we are seeing online outlets push their marketing and discounted prices appealing to all of us budget minded. Although pricing is certainly one aspect of purchasing your future electric bike, there are several other considerations we would like to highlight before making your purchase decision.
Support. Okay, so I've either decided to bite the bullet on shipping or have found some kind of back end loophole online to get the electric bike to Hawaii at a reasonable rate. Although this could be happily ever after for some buyers, we would like to address some real concerns after the initial purchase that may come up during the life of owning the bike. Having good support from the manufacturer, especially living so far away from just about everything in Hawaii is critical. Any failed electrical components can render an electric bike pretty much useless, or in the very best case, a very heavy and hard to pedal regular bicycle. In some cases, the battery or any of the other electric components may fail, and if the manufacturer or online outlet cannot reasonably support their Hawaii based customer (as stated earlier, be Hazmat certified to reasonably ship a replacement battery), you've left with a pretty sweet looking paper weight. A "warranty" without the ability to support customers in Hawaii can often lead to some pretty unsatisfactory results.
Lucky for you, we honor all of our bikes manufacturer's warranty's and are here to support you for the full life of the bike. Need any replacement parts? Easy. We order OEM parts direct from the manufacturer with shipping all handled. Our freight forwarders are well equipped to bring any parts from the mainland needed to keep you on the road. Even if the bike is out of warranty, we are still here to support you and find alternate options to keep you happily on the road. Too many times we have gotten electric bikes that need service that were purchased online /Amazon, leading to a failed repair due to lack of support from the manufacturer. At this point, we have implemented a general service policy of not servicing any electric bikes whose brands do not support dealers. This means full support, which in most cases, is limited to only the brands we sell. Simply put, we only service the bikes & brands that we sell and trust.
And Lastly, numero 3, Try before you buy. If you are already on your journey to owning an electric bike, you may be overwhelmed simply by how many options there are. After outfitting thousands of customers on bikes, we can confidently say that the absolute best way to figure out which electric bike is best for you is to simply try one. Theres so many different factors involved that a simple test ride can reveal which your priorities and needs are. Hub motor, or mid drive? Do I want a city style, cruiser, or off road capable bike? Does a smaller 20" folding ebike make sense, will it have enough power? Speculation while browsing the internet can only do so much, and we truly believe that trying a bike before you buy is very important. Even if your local shop does not have something you want to purchase, you can at least get an idea of what your needs are as you continue your journey for the perfect electric bike.
Yes, the rumors are true. Your friendly neighborhood electric bike shop is now the official Riese & Muller dealer of Hawaii. We first set eyes on R&M several years ago during our first Euro Bike expedition. The sheer size of the Euro Bike convention blew us away, however we could not help but notice Riese & Muller (from Germany) as one brand that stood out from the rest of the pack. Truly a cut above, R&M builds their electric bikes with absolutely no compromises. Quality, quality, quality. From the very first dual Bosch battery systems to their mid-drives paired with internally geared hubs, full suspension comfort bikes, award winning front loading electric cargo bikes (with full suspension), & so much more, we knew at first sight that one day we would have to carry the R&M brand at our humble shop. Well, the day is finally here and our first round of pre-orders are in! Stay tuned for more updates & content with the absolutely to die for electric bike brand that is Riese & Muller.
The Nevo. Low step comfort. Bosch mid-drive combined with the internally geared rear hub.
The Tinker. Compact, elegant, powerful.
The Delite. Dual Bosch batteries. Full suspension, fenders, rear rack, and integrated lights.
Check out our first quick take on the Raleigh Cadent 28mph Speed Pedalec Electric Bike! Highlight features include fenders, integrated lightning, rear rack, and throttle add on capability! This is the follow up to our highly popular iZip Dash model.
Fresh batch of new Raleigh / iZip comfort bikes has arrived! Just in time for the holidays, the Sprite / Vibe models are perfect for your every day cruising needs. For 2019 they have updated the battery design (now centrally located on the downtube) giving the bike overall better balance and ride quality. Swept back adjustable handlebars keep you upright, and the rear rack is built right into the frame for strength and utility. The Sprite / Vibe is powered by a powerful 48 volt TranzX mid-drive system capable of climbing the steepest hills on Oahu! Stop by either our Honolulu or Kapolei stores for a test ride.
We are excited to announce the addition of Bulls Electric Bikes to our lineup! Bulls is an awesome brand from Germany at the forefront of electric bikes, and has carved out a named for itself in the electric mountain bike industry. Offering a wide array of motors systems, our customers will now be able to choose from bikes equipped with the highly rated Brose (Brose S & Brose S MAG) motor systems, as well as the coveted Shimano E8000 series Mtb motors.
In addition to these exciting new drive systems, Bulls also offers bikes with industry leading range. The current lineup pairs the Brose motors with high capacity 630 watt batteries. Keep in mind, batteries currently offered by other manufacturers range anywhere between the 400 watt hour and 500 watt hour range. Further more, motor & battery integration is some of the sleekest we have seen on the market. To the untrained eye, you may not even notice it's an electric bike!
Same tightly integrated Brose system, but with full suspension!
The Brose system is also known for its extremely smooth and quiet activation (due to its internal belt drive). For anybody looking for a truly stealth electric bike, or who wants something with tremendous range on a single charge, the current lineup of Brose powered Bulls bikes is a truly exceptional option.
Just added! The Six 50+ E FS2. Bosch CX powered full suspension (120mm travel) all around ripper!
New Product Announcement! With the growing demand of more compact/portable electric bikes, we have decided to take on our newest brand OYAMA! With roots in Japan and more than 50 years of mechanical and design expertise, OYAMA knows whats up. The CX8D and CX8D Series II add electric boost to an already tried and true platform. Priced at $1499, the CX8D (base model) is an affordable way to ditch the gas guzzler or moped. Great for around town, on campus, getting to beach, etc- this little folder packs a punch with its integrated lithium battery and boost from the rear motor. The CX8D Series II models come with a sleek black/red color way, upgraded components, and of course more power!
The OYAMA CX E8D is a lightweight folding electric bicycle that provides pedal-assisted power up to 20mph with a 250-watt custom-tuned motor ample for daily transportation and commuting needs as well as the thrill of exploring nearby places.
Shimano 8-speed gearing, powerful disc brakes, and wide Kenda tires are supported by a strong and reliable set of double wall alloy rims.
The CNC machined seat post, folding stem, and safety frame latch are all examples of the premium touches OYAMA bicycles are known for.
Electric bicycles give riders an all-important pedal assist for that extra mile, which is especially beneficial if commutes are lengthy or hilly..
First ride on the All Mtn 6.0!
The highly anticipated PW-X powered All Mtn Haibike has hit the shelves! Building off of one of our more popular Haibike models of the previous year, the new all mtn has been updated with slacker geometry, a longer top tube, plus wheels/tires, and of course the all new Yamaha motor.
Re-wind one year and the Bosch Performance Line CX motor was our number 1 pick for performance. And it also came with a price point to match that high end performance. Bosch being one of the biggest names in the game provided an outstanding product for the masses and has been adopted by many manufacturer's as their flagship ebike mid-drive system.
The previous PW system by Yamaha gave us a more affordable alternative while still giving us about 90% (give or take) of the performance of the Bosch system. For casual riders, this performance gap may be a complete non issue as the PW was still plenty capable. A few advantages that the more affordable Yamaha did have over the Bosch however was its increased range / efficiency & no drag from the motor when pedaling (with the power turned off).
Fast-forward to today and we now have the direct competitor to the Bosch CX performance line, the Yamaha PW-X. Power has been increased. The motor/system itself has shaved weight, making it one of the best if not the best weight to power ratio systems in its class. The cranks have been upgraded from square taper to ISIS, and ratcheting of the engagement has been dramatically reduced. The display has been updated as well with its new EXPW (expert) power mode.
Our initial thoughts on this system are very positive. Although the Bosch CX does seem to edge out the PW-X in high cadence power, the difference is now very marginal. However the smooth power application, efficiency (range), and new display are things that we do like more on the Yamaha side. You really can't go wrong with either option, and the All Mtn 6.0 priced at $4400 makes it a very compelling alternative to its Bosch counterparts.
Just uploaded! Our very own Inboard M1 Electric Skateboard Unboxing! Stay tuned for more footage.
Incoming! We are now Acton Global's official dealer of electric skateboards! These boards are an absolute blast to ride and are perfect for getting to class, cruising around town/waikiki, diamond head, etc. The Blink S model is a single motor drive and is truly a must have for students & commuters. The S2 is perfect for those looking to step their game up with a more powerful dual motor. Integrated LED lighting is great for visibility/safety, and a functional kick tail allows riders to make all of those narrow / sharp turns needed to navigate campus & the city.
26x4" tires. Air pressures in the single digits. A silent, efficient & powerful Yamaha mid-drive system. The Fat Six 6.0 lands on Oahu smashing everything in its path. All the benefits of a fat bike without the downside of compromised rolling resistance. In this video we tested this model in various locations including Kauai's north shore. Hawaii + electric fat bike = butter.
The all new Haibike Urban Plus Electric Bike has arrived! A little bit different than what we are used to from Haibike (mostly known for their high performance off road mountain bikes) but they really hit it out of the park on this one. The Urban Plus features an ultra sleek design from head to toe. Integrated down-tube battery, TranzX M25 mid-drive system, integrated fenders & lights and rear rack. The drive system is very powerful and is rated at 500 watts (high wattage rating for a mid-drive). Battery is at 500 watt hours at 48 volts. Speeds can reach up to 28mph making this a "speed pedalec" ebike. Bike components are also decently high end, featuring a crispy Shimano XT derailleur and Tektro Dorado hydraulic disc brakes. Wheels are a friendly 27.5" platform wrapped in very nice Schwalbe Super Moto-X tires. All high quality stuff wrapped up into a very clean package.
The real icing on the cake here is that the Urban Plus comes pre equipped with the fully smartphone integrated COBI system (see youtube video above for more details). This system alone costs around $500, so having it come with the bike out of the box adds tremendous value. The COBI (Connected Bike System) puts you and your smartphone as the center hub of your electric bike. Just download the app from the App Store (compatible with both Android and iPhone) and you're ready to go. There is a built in cradle at the mid point of the handle bars enabling you to insert any smart phone of your choice. Once you power on the bike, it will automatically sync up with your app and you're good to go. The left thumb pad will control the assist level as well as cycling through the menu. Essentially all of the features can be accessed with just the left thumb pad, allowing you to have full control while riding your bike.
GPS & offline maps are built in, allowing you to navigate directly from your hub. Input your destination and COBI will let you know which assist levels will be preferred for your distance. The fitness tab adds your body metrics (KCAL) in addition to heart rate with external sensors. RPM & cadence are built directly into the system. In addition, COBI can remotely control your music allowing you to skip tracks & adjust volume on the fly.
And last but not least, one of our favorite features of the system is its built in alarm. Yes you heard us, a built in anti theft system! Just press the lower left lock icon in your app to lock your bike. If the bike gets tampered with, or moved without unlocking first, an internal alarm will sound off warding off any potential thieves. This features in addition to using a traditional lock should minimize any threats of your new bike getting stolen.
Go ahead and check out our youtube video review (posted above) or come by our store to go for a test ride! We are certain you will be just as blown away as we were with the Urban Plus!
Introducing the Haibike SDURO Hard Four 4.0. Priced at a cool $1499, this is by far the best electric bike we have ever offered at an affordable price. Featuring the same rock solid Yamaha PW mid-drive motor found in all of the full size electric mountain bikes, this little compact bike rips! 24" wheels and low standover height make this bike perfect for anybody up to 5 ft 10. It's small enough to stash away in your house, apartment, condo, work office, car, anywhere! Take it down to the beach, commute to campus- this little guy does it all.
In a land far, far away from the hustle and bustle of Waikiki, lies an untouched landscape of tall green mountains, a pristine turquoise ocean, and a place you can ride your electric mountain bike to your heart's content.
Ka'ena Point Trail is located on the western side of our beautiful island of Oahu. It is an unpaved, yet, ridable path that will lead you on a journey that would seem straight out of the a Jurassic Park movie. This trail is fun to ride on our Haibike rental bikes.
West of Waianae, the trailhead begins at the farthest side of Ka'ena Point State Park where the paved parking lot ends. You can ride ebikes or walk for 2.4 miles to Ka'ena Point Natural Area Reserve.
At the end of your journey on the unpaved path, you will come to a gated area which the state of Hawaii has set up as a Natural Area Reserve. Here lives nesting Laysan Albatross, Hawaiian monk seals, and many other native Hawaiian vegetation and critters.
If you're looking to get off the beaten path, are a semi-experienced ebike rider, and want to experience this trail for yourself, give us a call and we can hook you up with our high-quality Haibikes and some local insider tips for your journey.
Please check the local weather report before heading out to Kaena Point. Riding in the rain is very difficult and conditions can become muddy.
We recommend early morning rides since the sun gets hot on the west side of the island, and bring lots of sun protection and water.
Helmets are highly recommended as the trail can be rocky/ semi-rough terrain.
Our Haibike Rentals start at $80.00 per day and will allow you to ride up to 40 miles on a single battery.
Come on by your friendly neighborhood electric bike shop for some great deals this weekend. Bikes, parts & accessories will be discounted.
The 2017 iZip Dash has arrived! Yes, we are well into 2017 but hey- thats how we do it out here in Hawaii. The Dash is no stranger to our lineup of electric bikes. In fact it has been a staple and one of our most popular speedy commuters to date. Starting back in 2015, the Dash sported a 500watt rear hub drive with mechanical brakes and did not come with any add-ons. Fast forward to 2017 and boy have things changed.
To start, the Dash was reintroduced in 2016 with a 350 watt TranzX mid-drive system. Mid drives have become more and more popular over the years with manufactures. Their benefits include a more balanced platform, standard front & rear wheels (much easier to do maintenance, flat repairs, etc.), mechanical leverage on all of the gears, improved hill climbing ability, better efficiency, & more. The voltage remains at 48, allowing the the bike to still reach speeds of up to 28mph while now having much greater climbing ability. The Dash then came standard with fenders, a sturdy rear rack, and integrated lighting. What a package!
Now in 2017 the Dash has been updated yet again. More subtle this time with improved lighting, a new color scheme, upgraded front fork (now Rock Shox) & updated drivetrain. The bike now sports a new sleek downtime battery that sits snugly inside the downtime (where as previous year models were more "bolted on"). Water bottle mounts have been included and are greatly appreciated. Perhaps the biggest change is the raw aluminum frame color which simply looks badass. Raw finishes are normally priced at a premium. However the 2017 Dash remains a great value priced at $2599.
Is commuting on an Ebike Safer?
Ah yes, the age old question. Is commuting on an electric bicycle actually safer than a regular pedal bike? The answer folks, for many people can actually be yes. Riding an electric bike for commuting purposes can many times be safer than only being propelled by human power alone. How can this be, you may ask? How can a bicycle with an electric motor actually be safer than riding along with my own two legs?
The answer lies within the heavy traffic roads of Oahu and steep elevation that many riders encounter when riding their bikes. As lovely as Oahu is, there is no denying the congested roads. For many of us commuting to work on a bicycle means avoiding dangerous traffic. To make matters worse, when climbing steep hills, the speed of a bicycle and the flow of traffic tends to spread further apart. Cars start whizzing by and making riders feel even more vulnerable.
Lets look at the big picture here. An electric bicycle can be much safer (especially for less experienced riders) for commuting as it allows them to more easily ride at the flow of traffic. No more holding up a huge line of cars when climbing hills, and maintaining 20+ mph over long distances gives riders the confidence they need to actually choose riding a bike over driving their cars. The assist also allows for faster acceleration from a stop. Again allowing riders to more easily go with the flow of traffic instead of holding up angry commuters behind the wheel.
Here at Ebikes Hawaii we believe an electric bicycle to be the ultimate car replacement. We like to think outside the 4 wheel'd box. Think about how many Ebikes could fit into one parking stall, or how much less traffic we would have on our roads if more drivers would consider riding an assist bike to work or run errands. We feel it is our personal duty to educate each and every person on the benefits of an electric bicycle and how it can help shape our future. Mahalo!
2016 Haibike Yamaha SDURO Closeout!
Welcome to the electric mountain bike revolution! Our pedal assisted e-mtb's by Haibike will leave you with an ear to ear smile. Powerful & efficient mid-drive system by Yamaha & Bosch provide incredible performance.
Pedal assist - regardless of your skill level, the pedal assist system will allow you to climb hills and ride without being limited by your physical ability. Skilled riders can enter a new sport where motor assistance introduces new skill sets. Despite some nay sayers, maintaining higher speeds with an electric assisted bike on the trail isn't easy- especially at race pace!
Multi purpose - It's no secret that traffic is horrible on Oahu. Rip your Haibike on the trail then use it as a car replacement to get to work. Forget about gas, traffic, noise, insurance, etc. They are just as capable on the road as they are on the trail allowing you to cover serious distances with minimal effort.
Your health - Riding an electric assisted bike in place of driving can have serious improvements on your health. Studies have shown that the best kind of workout for your long term health is moderate sustained & consistant workouts. The pedal assist system gives you full control between zero assist and turbo model. Choose eco, or sport for a light boost.
Fun factor - An electric mountain bike will make you feel like a kid again. No longer are you restricted by your physical ability. Explore the island in a completely new way.
Ebikes Hawaii is Hawaii's exclusive Haibike dealer, offering the best of the Haibike lineup. We are also a certified Bosch service station and have extensive knowledge of the Yamaha system.
We are reaching the end of our 2016 Haibike SDURO Closeouts! Bullet proof Yamaha PW Drive system paired with Haibike's German engineering design and quality make these bikes a winner.
Some things, like a classic cruiser bicycle, never go out of style. The 7-speed Retroglide iE with step-through frame is everything you've always loved about cruisers — style, simplicity, comfort, value, and fun — now as an electric bike. It's the best of both worlds: the ride you need as an adult (performs perfectly for your daily responsibilities like grocery shopping or heading to work) that makes you feel like a kid again. The 350W Currie Electro-Drive®/TranzX mid-motor system gives you plenty of power to flatten the hills, and turn headwinds into tailwinds, when you want that extra boost. With a long-range battery pack you can pedal to work and still fly around the neighborhood a couple of times afterwards, racing the sun to make it home in time for dinner.
The myth, the legend, the Stromer ST2 is HERE, and NOW available for you to try out!
We are happy to announce a special addition to our electric bike rental fleet here in Honolulu.
The latest and greatest in Electric bike technology has found its way to Oahu! Having won awards at both Eurobike and Taipei Cycle, the ST2 lives up to its Swiss built "tank-like" reputation down to the last detail. For those of you that don't know, this ebike has broken barriers in both design and technology, the first of it's kind to produce 93 miles of range, up to 28 mph of pedal-assisted speed, 750W of engine power and 35 nm of torque, all in an ebike that can cruise down any old bike lane!
We have tested this Swiss workhorse this summer, successfully riding from our Town bike shop all the way to Chinaman's Hat on just one battery. There is nothing like riding 28 mph on a bike that sends it's rider on a high-speed, exhilarating ebike experience that you must try to understand.
Its Schwalbe "BigBen tires", puncture-proof and smooth as butter, help transform this 57.3-pound rocket into a smooth, road conquering vehicle that provides a similar feeling as an amusement park ride would. Don't discount the fact that the ST2 is pedal assist, still giving it's rider some exercise and endorphins, and disavowing any claims that you might be "cheating" by riding an electric bike.
The ST2 is available for rental from our Kapahulu bike shop, check out our "RENT A BIKE!" section to get more information on pricing, availability or call our rental office at (808) 744-4886 for more information. Mahalo!


In the construction of quantum field theory various naive mathematical constructions give rise to ill-defined "divergent" expressions.
Some of these occur in the limit that interaction point are taken close to each other. Since the short distances involved in this limit translates, under Fourier transform, to high frequencies enoded in the wave front set of the distributions; these are called ultraviolet divergences. The correct way to deal with them is called renormalization.
Other divergences occcur in the limit that the spactime support of the interaction (the support of the "adiabatic switching") tends without bounds to all of spacetime, also called the adiabatic limit. Since this large distance involved in this limit translate, under Fourier transform to low frequencies, these are called infrared divergences.
Last revised on November 6, 2017 at 07:20:52. See the history of this page for a list of all contributions to it.


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Insulator Hardware
Sub-Station Hardware
Sub-Station Clamps & Connectors
Lords Vanijya Pvt. Limited is a one of the leading manufacturer of Power Transmission and Distribution Line insulator Hardware fittings, Conductor Accessories, Earthwire Fittings & Accessories,Sub-Station Clamps & Connectors and precision components for Railways.
Our manufacturing facilities are located in Howrah, West Bengal in the eastern part of India. This facility is equipped with modern machinery of reputed Indian and international manufacturers. The facility also has two state of the art forging hammers for ferrous and non-ferrous metal forgings with heat treatment facilities and Aluminium Pressure die casting and Gravity die casting.
Our management team comprises highly qualified technocrats, finance and general management experts with vast and varied experience at the domestic and international level. The team is supported by a reliable pool of staff and labour whose efforts have enabled us to make rapid inroads into our chosen sectors of focus. We are committed to enhance customer satisfaction by supplying consistent high quality products and on-time delivery of products to create value for our customers, our employees and shareholders.
MRS. TRISHNA PATODIA PEREIRA – MANAGING DIRECTOR
Mrs. Trishna Patodia Pereira has a Bachelor of Science degree from Carnegie Mellon University, USA and an MBA from the Indian School of Business, Hyderabad. She is also a Chartered Financial Analyst (CFA).
She comes from a family of entrepreneurs with successful businesses in the manufacture and supply of precision components. Before incorporating Lords Vanijya, Trishna worked professionally in internationally renowned investment banks gaining global experience across London, New York and Singapore.
Trishna is also a member of the Executive Committee of FIEO (The Federation of Indian Export Organisations).
Trishna is supported by a group of highly experienced techno-commercial personnel with functional expertise across engineering, production, finance and sales & marketing as well as industry expertise in railways and power transmission & distribution line hardware fittings and accessories.
OUR FOCUS MARKETS:
POWER : State Utilities, Turnkey Contractors, Export and PGCIL. RAILWAYS: Indian Railways Factories.
Lords Vanijya Pvt. Ltd. All rights reserved
Site designed & developed by Matchstix

redpajama_set_name: RedPajamaCommonCrawl


Imagine that you are a pig farmer. Before you take your pig to market for sale, you want the fattest pig possible. However, weighing the pig everyday will not make the pig fatter. In order for the pig to gain weight, you have to feed the pig a healthy and appropriate diet. The same is true for reading fluency.
Kansas College and Career Readiness Promising Practices state to "Engage the five essential components of reading (phonemic awareness, phonics, fluency, vocabulary, and comprehension) at all grade levels based on individual student needs." The Kansas Standards recognize that all five components are vital for reading achievement; however, fluency seems to be the component of reading that is the most misunderstood. Let's look at some common misconceptions.
Misconception #1: Faster reading is better reading.
Fluency plays a dual role in reading: It is both a measure of decoding proficiency and a bridge to comprehension. If a student has mastered the sub-skills of reading, she will read with automaticity, and this automaticity frees up cognitive desk space, so the mind has time to think about what is being read. According to G. Reid Lyon, "Fluency is the ability to read connected text rapidly, smoothly, effortlessly, and automatically with little conscious attention to the mechanics of reading such as decoding." As such, fluency is not an end in itself. Rather, it provides assessment of foundational skills and gives students the gift of time for constructing meaning from the text. Therefore, a comprehension check allows the teacher to determine if the student is reading fluently enough to comprehend even if she is below benchmark on a timed reading measure.
Misconception #2: All dysfluent readers require the same intervention.
There is always an underlying cause for a reader to lack fluency, so the reading interventionist often needs to put on his detective hat and make use of diagnostic assessments. Rather than merely looking at words read correct per minute, teachers need to pay special attention to accuracy as well. Students who are inaccurate generally need a reading intervention that involves instruction in phonological awareness or phonics. Students who are slow but accurate do not need a sound-based intervention but need assistance in producing automaticity of word recognition. Repeated readings, multiple exposures to words and multi-sensory techniques should be part of the intervention strategy. In addition, using a grid to practice phoneme-grapheme (sound to letter) mapping also increases fluency.
Measures of early childhood literacy also provide insight into the type of intervention needed: problems with identifying the first letter name in a word point to a difficulty in the orthographic processor (the world of symbols) while problems in identifying the first sound in a word point to difficulty in the phonological processor (the world of sound). Furthermore, fluency is also affected by a student's knowledge of vocabulary, sentence structure and text structure.
Misconception #3: Fluency assessment and instruction look the same.
While standard procedures should always be followed when administering an oral reading fluency assessment or a reading curriculum-based measure, instruction is not the same as assessment. First, the student does not need to be timed when reading to practice becoming a more fluent reader, and having the student read an entire passage (rather than just one-minute's worth) helps a student see the relationship between decoding and making meaning from text. Immediate corrective feedback and later mini-lessons that provide an explanation of why the word is pronounced the way it is are both helpful. In addition, repeated reading contributes to forming neural pathways for quicker retrieval; however, four readings are usually sufficient. In addition, teachers can also create speed drills on the sub-skills of reading for practice in fluency. This may involve automatic reading of letters, letter combinations, sight words, words with a particular pattern, or phrases.
When it comes to reading intervention, think like a pig farmer. Design an appropriate "diet" of intervention for your struggling readers that fits their specific needs, and feed them every day with a variety of fluency-building activities.


Malta has great connections, with most major UK airports flying directly into Malta from the UK as well as many more indirect options traveling via mainland Europe. Book yours early to save money!
The main airport is Malta International Airport in Luqa, which is just 30 minutes away from Bugibba. Most major UK airports fly directly into Malta from the UK, as well as many more indirect options traveling via mainland Europe.
Our official travel partners Choice Holidays offer a range of different flight route options from different airlines. Return flights are available from all major UK airports. You can also book tickets, hotels, packages and airport transfers in one go – your one stop travel shop!
Skyscanner updates is also a great place to check the latest flight price updates from your nearest airports, with return flights from main UK airports starting from just £84!


It has been a very sad time for us at Ashiyana. At the beginning of July, we learned of the passing of Vikas, who was one of the Ashiyana family and a senior member of the Nepalese kitchen staff.
Vikas, 24, had been with us for six years, was only ever a pleasure to have around, and an extremely positive force at Ashiyana. Most often smiling, if not actually laughing, Vikas took life effortlessly in his stride. The pressures of working in the kitchen never showed on his face or in his demeanour, and he remained serene amidst all that life presented him with. Even in the aftermath of the earthquake that rocked his country, city and home, he was relaxed and calm.
We were just about to offer Vikas the opportunity of running the kitchen at our new restaurant/cafe, and the management team were excited at this prospect. This was in recognition of his incredible work ethic, his abilities and his beautiful nature.
In May 2015, we set up the Ashiyana Nepal Project to raise money to help our Nepali Kitchen Team rebuild their lives and their homes since the devastating earthquakes struck Nepal. Over a year on, in August 2016, we have so far raised over £12,000 through fundraising events and donations from family members and our wonderful guests. We are now over halfway to our target of £20,000.
On 24th July, we held a Yoga, Sound and Daal Dinner fundraising event at our sister studio, Treehouse Yoga, in south-west London. The event was held in memory of dear Vikas. We had such a lovely afternoon celebrating Vikas's life - Tobie T led a flow yoga class, our friends Peter and Ion the Lion guided us through a wonderful Yoga Nidra, Gong Bath and kirtan, and we finished the evening with a Daal dinner cooked by Ashiyana's Charlotte, Siân and Tobie...and not to forget the famous Ashiyana Chocolate Balls we had for dessert!
We raised a wonderful £376 that day for our Nepali team. Thank you so much to everyone that attended and donated some of your time, energy and money to make the afternoon such a lovely occasion...and a big thank you to Linda d'Antal for providing us with the Treehouse space and kitchen!
We will continue to support Vikas' family with this project. Ashiyana covered the costs of his funeral, which was held in his hometown in Nepal last month.
Whatever your beliefs may be, rest assured that Vikas is still smiling, and touching those that know him with his gentle and inspiring vibration.
We shall miss him deeply.


Craigslist (www.craigslist.org) is a centralized network of online communities featuring free online classified advertisements, with sections devoted to jobs, housing, personals, for sale, services, community, gigs, résumés, and discussion forums. It was launched in the San Francisco Bay Area in 1995 by Craig Newmark.
The early years of Craigslist - before hitting the mainstream consciousness - featured a network of cool, artistic types. Most East Coast DJs were still unaware of CraigsList, and if somebody posted "DJ Wanted," there was a good chance that you could score the job and be compensated at your customary rates. Weddings and corporate events were all possible through CraigsList!
However, the site eventually devolved into a tacky online flea market of bargain-hunters and a horde of discount DJs happy to oblige this new clientele. As an example, a user on CraigsList would post something like "Experienced DJ Needed for Anniversary Party. Must have references and provide demo CD. Compensation - $0. Free drinks and food!" We have not browsed the CraigsList classified in years, but from what we hear, the number of quality jobs posted is few, with competition fierce for these scarce leads.
An alternative CraigsList strategy adopted by some DJs has been to post "DJ For Hire" in the classified section. Particularly if posted repetitively (at no cost), this could result in brand awareness among CraigsList shoppers. The bigger question however is, "Are CraigsList shoppers your target market?" In the case of Ambient DJ Service, the answer is a resounding 'no'.
CraigsList is a great tool for recruiting and networking with fellow DJs. In 2007, our company added its second system, taking the step from single-operator to multi-system operator. That hire, discovered through a CraigsList ad, DJ Iron Mike, has proven to be a smashing success. Through Mike, I was introduced to his friend Christopher Smith (DJ Spinz) who also proved to be highly successful in the Ambient DJ roster. DJ Gary G, another CraigsList contact, became a friend and enlightened us on profitable internet marketing strategies - also becoming a great referral source. Gary introduced us to his mentor DJ Brett Gash, "the Godfather of East Windsor DJs" who has become a great friend and source of referrals.
Fast-forwarding to 2011, we now periodically post in the Jobs Section for entry level disc jockeys. The ads always produce a large and qualified group of respondents who we can weed out in search of our next great DJ! Best of all, there is no charge to place a classified ad.
The moral of the story is that CraigsList, if used properly by a mobile DJ company, can produce extraordinary profits. But it will not be via responding to "DJ Wanted" ads. In the case of Ambient DJ Service, CraigsList helped us to find the right staff, opened doors, and set us on a course of "one thing leads to another." For that, we dedicate this next song to CraigsList and thank you!
Postlude: And as DJ Iron Mike just reminded me, two of our cast members, DJ Extreme and Larry Sargent, also were discovered by the Craigslist relationship ripple effect!


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Intelligent Robotic Autonomy and Perception (IRAP) Lab focuses on robotics problems in civil and environmental engineering applications. Targeting many hardly accessible or dangerous sites in the environment, we solves for robot autonomy dealing with perceptual sensor data. Main research interest and detailed robotics topics include perception based environment mapping, intelligent sensor fusion, decision making and control of the robotic agents, robotic operation and navigation in GPS-denied enthronements (e.g., underwater, indoor).
Giseop Kim and Byungjae Park and Ayoung Kim, 1-Day Learning, 1-Year Localization: Long-term LiDAR Localization using Scan Context Image. IEEE RA Letters, 2019.
Giseop Kim, Ayoung Kim and Youngchul Kim, A new 3D space syntax metric based on 3D isovist capture in urban space using remote sensing technology. Computers, Environment and Urban Systems, 74:74-87, 2019.
Younggun Cho and Ayoung Kim, Channel Invariant Online Visibility Enhancement for Visual SLAM in a Turbid Environment. JFR 2018.
Younggun Cho and Jinyong Jeong and Ayoung Kim, Model Assisted Multi-band Fusion for Single Image Enhancement and Applications to Robot Vision. IEEE RA Letters, 2018.
We introduce our complex urban LiDAR dataset accepted for ICRA 2018.


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The Messy State of Religious Freedom
Despite the challenge of defining and enforcing the right to freedom of religion, it would be wrong for Canada to stop trying, argues Jon Waind.
By: /
By: Jon Waind
Researcher, McGill Initiative in Globalization and the World's Religions
Canada's Office of Religious Freedom (ORF) has launched at a time when the right it seeks to promote and protect is under intense scrutiny. It has been suggested that Ambassador Andrew Bennett, the inaugural head of the office, will need to very carefully measure his words given the diverse interests housed in the Department of Foreign Affairs and International Trade that oversees the ORF. One concern appears to be the possibility that ORF criticism of religious freedom violations abroad might alienate key trading partners for Canada. Even more troubling, though, are fears that trade relations or other matters of diplomacy might cause Ambassador Bennett to temper his voice in a way that could undercut the credibility of the office itself.
The establishment of the ORF has also been decried as unnecessarily and unwisely draining resources from conventional Foreign Service work in an attempt to "pander to domestic faith groups" who pine for a close relationship between religion and the state. Rather than defaulting to such an outmoded position, by seeking to amplify religious freedom, this argument suggests that the promotion and protection of a robust secularism would instead provide a more certain way to ensure that believers of all stripes enjoy maximum liberty.
What these critical perspectives do not question, however, is the significance that religion holds for Canadians in the formulation of laws and policies related to both domestic and foreign affairs. Perhaps leaning on Arnold Toynbee's proclamation that religion "is the serious business of the human race" would be to press this point too far. However, even a cursory glance at the thick history of Supreme Court of Canada cases dealing with religion shows that religious matters hold clear public consequences, even if difficult to navigate as such. The recently proposed Charter of Values in Québec would appear poised to become another significant case in point.
Religion clearly matters to public life in Canada.
Furthermore, practical concerns about the impact of the ORF on Canadian trade interests abroad and theoretical concerns about the application of secularist theory to foreign affairs discourse suggest that religion also matters to the way we think about Canada's role in international politics. José Casanova appears to agree in his essay "Public Religions Revisited" where he contends that the meaningful interactions to be found between world religions "in the global present" simply could not occur if religion itself was a truly private matter. Religion is public, and its significance to human beings reverberates on the international political stage just as it does domestically.
So if religion matters to public life both within Canada and abroad, why should one be sceptical of an office mandated with the promotion and protection of religious freedom?
Elizabeth Shakman Hurdwarns that religious freedom "is not something that can be imposed in a top-down fashion" by governmental authority. It instead needs to be "reimagined as a site of resistance against powerful authorities" by the grassroots campaigns of people attempting to live their everyday lives according to their religious convictions. Furthermore, she maintains that religion is a notoriously difficult term to define and relying on state authority to determine what counts as legitimate religious expression only exacerbates the issue. That is, under circumstances where the state officially engages religious actors as the ORF is mandated to do, the foreseeable outcome is that the state will then set standards that bolster those groups seen to be favorable to it and marginalize those that are not.
This issue is further problematized by Saba Mahmood who, in her essay "Religious Freedom the Minority Question, and Geopolitics in the Middle East," looks at the legal codification of religious liberty as a "technology of modern governance" used to maintain "geopolitical and international legal order" under the unequal power relations that exist between Western and non-Western states. More than simply being afforded "a space of freedom and immunity" through the institutionalization of religious freedom as a principle, Mahmood argues that religious minorities are actually produced by this act of statecraft. As a result, those like minority groups who are "supposed to benefit most from the modern principle of religious freedom… are not merely protected from abuses of state power but are also transformed by virtue of their subjection to the calculus of state and geopolitical power in unique and unpredictable ways." Religious freedom, in this sense, becomes a coercive tool of state power wielded abroad through foreign policies. According to Mahmood, codifying religious freedom in international law actually produces subjugated and marginalized groups by "suture[ing] religious identity to other forms of difference" and thereby destabilizing them through state action.
There are serious concerns, then, about promoting and protecting religious freedom as a human right and institutionalizing it in foreign policy initiatives and international legal instruments. But do these concerns outweigh anything that could be said in favor of institutionalizing religious freedom? Is there really nothing positive to be said about this beleaguered right and its institutionalized promotion and protection?
I want to briefly suggest that there just might be something positive to say, even if it is mostly to say that religious freedom is a positively messy right. Without dismissing the serious concerns raised by Hurd, Mahmood and others, my point here is to nevertheless press against an overly negative view of the institutionalization of religious freedom in both national and international human rights instruments or governmental policies.
To begin with, religion – while admittedly difficult (but not necessarily impossible) to define – provides alternative ways of thinking about freedom to those that dominate contemporary liberalism and the language of rights. The dominant view, it seems fair to say, is that freedom means the raw power to act. Oliver O'Donovan, an Anglican theologian from the United Kingdom, challenges this view in his book The Ways of Judgment by arguing that freedom should not only be conceived of in terms of the power to do what one wants, but also as the capacity to realize a social form (67-69). Contrary to typical Western or liberal notions of freedom, then, this might suggest that the wearing of niqab is in fact a form of freedom because it allows the Muslim women who wear it the freedom to actualize an expression of specifically female piety. To ignore this practice as an expression of freedom is, then, to submit to a monolithic and liberalizing view of freedom as the raw power to act rather than recognizing diverse understandings of this concept that contribute to an intentionally pluralist society. Without the promotion and protection of religious freedom in Canadian society, freedom itself is conceived (inaccurately) in homogenous terms and human society is, unquestionably, less diverse and multicultural than our national policies would suggest.
Second, protecting and promoting religious freedom understood more broadly is actually a way of protecting and promoting the exercise of freedom itself. If religious freedom helps us open up the concept of liberty to include the capacity to fill particular social forms as well as the power to act, then society has a broader basis of freedom than what appears to be a comprehensively liberal perspective that dominates today. This is what at least appears to be a primary concern of John Rawls when in "The Idea of Public Reason Revisited" he seeks to understand how a multiplicity of people with diverse and often conflicting perspectives can get along in a liberal society. To be sure, Rawls's view of religion itself appears to have a deeply and comprehensively liberal perspective. But if his theory of liberalism is truly a political one, then viewing freedom as the raw power to act should be seen as one way of conceiving freedom that is supported by a theory and a community, which exists alongside at least another, if not a plurality, of other conceptions. Interpreting freedom solely as the raw power to act is simply unsustainable as a comprehensive position for a democratic society, even for essentially liberal ones.
This leads, finally, to agreement with the idea that the promotion and protection of religious freedom is itself a messy business, and one that might result in scenarios of unjust discrimination perpetuated by power differentials generated by both religious hierarchies and/or state power. What is less clear after considering various criticisms of the institutionalization of religious freedom, however, is how these scenarios are substantively different from adjudications between most other rights. Sexual freedom, for instance, has proven to be a messy right to promote and protect but there appears to be little traction to the idea that other human rights cover it sufficiently. In fact, the trajectory in Canadian law has been to not merely read sexual freedom into the Charter on analogous grounds, but to actually enshrine sexual freedom into the legal definition of marriage in Canada.
Likewise, if the "serious business" of religious freedom were to be somehow read as a "dead letter" in human rights instruments today, I think it would reflect poorly on Canadian legal culture. Religious freedom surely is as messy of a business as it is a serious one. As such, attempting to set it aside is likely to prove futile as future generations of Canadians will no doubt find a way to read it into the Charter out of sheer necessity.
Perhaps it is here that we find potential value in both Canada's new Office of Religious Freedom and in the institutionalization of religious freedom into international human rights legal instruments. It helps us recognize that the implementation and adjudication of rights are indeed a messy business. Furthermore, this is not only okay, but crucial if we are to have a rich understanding of freedom itself in a world of such diverse peoples, devoted to or at least impacted by a variety of religious traditions. As John Courtney Murray contended in his twentieth-century analysis of American democracy, conflict is not absent from a well-ordered society, but it does have a particular characteristic. Rather than the clashes of the uninformed, a truly civil society is marked by individuals who are "locked together in argument in the full light of a new dialectical day" (24). The ORF is just one way of keeping the often messy dialogue about religious and cultural difference in this full light that Murray mentions; the more important matter is to keep that dialogue open and full of light. Hopefully the ORF, and Canadian society as a whole, is up to that task.
Office of Religious Freedom
Also in the series
Religion and Foreign Policy
Religion: Friend or Foe?
Peter Denton
We need to ask a different question if we hope to truly understand the role of religion in international relations, argues Peter Denton.
Russia's Political Orthodoxy
Alicja Curanović
Alicja Curanović on how the Kremlin and the Russian Orthodox Church became political bedmates.
Nation-building and Religion: A Q&A with Dr. Charles Keyes
Charles Keyes
Dr. Charles Keyes on how religion and religious differences can strengthen rather than undermine political order.
Religion & Diplomacy
Ian Linden
Ian Linden reflects on critical responses to championing religious freedom.
Let's Talk about Religion
OpenCanada Staff
Dr. Chris Seiple on why religion needs to be treated as a real factor for analysis by foreign policymakers.
Religious Freedom: The Diplomatic Dimension
Anne Leahy, Canada's representative to the Vatican, on how Canadian foreign policy can help protect religious freedom abroad.
Bringing Religion into Foreign Policy
Robert Joustra
To promote religious freedom internationally, Canadian policymakers must first debate this principle at home, argues Robert Joustra
What's Wrong With Promoting Religious Freedom?
Elizabeth Shakman Hurd
The U.S. State Department's new office of religious engagement begs the question: What forms of religion should be protected? Elizabeth Shakman Hurd considers the consequences.
Freedom, Faith, and Foreign Policy
Daniel Cere on the state of the debate over the role of foreign policy in advancing religious freedom.
I fled Zimbabwe for a new life in Canada. Why does everyone here think I'm from the Caribbean?
By: Ray Mwareya
Book Excerpt: China Unbound
By: Joanna Chiu
Send Omar al-Bashir to The Hague
By: Nicholas Coghlan
Book Review: The Bridge in the Parks
By: Tyler Wentzell
Empty words
By: Amy Melvin


It's been an active week with the House and Senate releasing budget and revenue proposals and their fiscal committees cranking through bills to meet the April 9 deadline for passing bills on to the floor. And. . . good news about the Working Families Tax Credit.
Senate Democrats have proposed a capital gains tax designed to affect the wealthiest 8,000 Washington residents. The $780 million proceeds from this tax would pay for cutting small business taxes, reducing low-income senior citizen property taxes, eliminating the sales tax on certain items such as diapers and returning $220 million in taxes back to 400,000 of the state's most underprivileged families – phase-outs begin when income is greater than $19,000 per year. The vehicle for this proposal will likely be a striking amendment for SB 5961 - a bill in Senate Ways and Means.
Last week, the House approved an operating budget for 2019-21 (HB 1109) by a vote of 56 to 38. This budget includes an additional $1 million to boost statewide delivery of Washington's 211 information service. The budget also includes an additional $13 million for the Housing and Essential Needs Program and $21 million focused on permanent supportive housing and youth homelessness. The Senate Committee on Ways and Means held a public hearing on the bill Tuesday. Last week, the Senate Democrats indicated how they would amend the House proposal by releasing its budget proposal.
The House Capital Budget (HB 1102), which includes $150 million for the Housing Trust Fund, has been put on the House Floor Second Reading calendar. The Senate Capital Budget (SB 5134) puts $175 million in the Housing Trust Fund and was voted on by the Senate Ways & Means Committee on Monday. While advocates were seeking $200 million, the Senate proposal is the largest appropriate ever proposed for the Housing Trust Fund in a biennial budget.
During this active time, we'll be updating our tracking list almost daily. But even if we do get a bit behind (note the update time at the top of the list), you'll find all the links you need to get the latest amendments, roll call votes and bill reports.
You can sign up for these updates here.


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Q: Is there an AOP solution for Silverlight? I see that there is PostSharp AOP support for Silverlight, but is there a product that works like the Castle DynamicProxy library, but in Silverlight?

A: For runtime AOP you can use Castle DynamicProxy. Yep, it works.
I just grabbed the binaries for Castle Silverlight DynamicProxy for the Silverlight RhinoMocks package @ http://www.ayende.com/20/section.aspx/download/230
For compile time AOP, consider Mono.Cecil which I've used successfully on Silverlight assemblies. Presumably, other frameworks that enable compile time AOP should work as well.

A: Castle Dynamic Proxy itself? or LinFu?

redpajama_set_name: RedPajamaStackExchange


So sorry I haven't been blogging here. So many good things are happening at the Reiki clinic I haven't had time to even be on line much.
Also I have uploaded more meditations!
One is Free (for a Limited time so download it fast) and the other is $2.99. I am working on uploading more soon. I have also announced the dates for the Reiki I class in Barcelona, Spain (Click here for more info) and included a Reiki Booster attunement if you already are a reiki person and just want an attunement.
We have a Belly Dancing Workshop coming up and lots more in the works, so please keep checking back on the website.


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Genetic Analysis of CLCN7 in an Old Female Patient with Type II Autosomal Dominant Osteopetrosis
Endocrinol Metab. 2018;33(3):380-386
Endocrinol MetabJournal ArchiveEndocrinol Metab. 2018;33(3)
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Publication date (electronic) : 2018 September 18
doi : https://doi.org/10.3803/EnM.2018.33.3.380
Seon Young Kim1, Younghak Lee2, Yea Eun Kang2,3, Ji Min Kim2,3, Kyong Hye Joung2,3, Ju Hee Lee2,3, Koon Soon Kim2,3, Hyun Jin Kim2,3, Bon Jeong Ku2,3, Minho Shong2,3, Hyon-Seung Yi2,3
1Department of Laboratory Medicine, Chungnam National University College of Medicine, Daejeon, Korea.
2Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.
3Research Center for Endocrine and Metabolic Diseases, Chungnam National University College of Medicine, Daejeon, Korea.
Corresponding author: Hyon-Seung Yi. Research Center for Endocrine and Metabolic Diseases, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea. Tel: +82-42-280-6994, Fax: +82-42-280-7995, jmpbooks@cnuh.co.kr
Received 2018 May 25; Revised 2018 July 18; Accepted 2018 August 09.
Type II autosomal dominant osteopetrosis (ADO II) is a rare genetically heterogeneous disorder characterized by osteosclerosis and increased bone mass, predominantly involving spine, pelvis, and skull. It is closely related to functional defect of osteoclasts caused by chloride voltage-gated channel 7 (CLCN7) gene mutations. In this study, we aimed to identify the pathogenic mutation in a Korean patient with ADO II using whole exome sequencing.
We evaluated the clinical, biochemical, and radiographic analysis of a 68-year-old woman with ADO II. We also performed whole exome sequencing to identify pathogenic mutation of a rare genetic disorder of the skeleton. Moreover, a polymorphism phenotyping program, Polymorphism Phenotyping v2 (PolyPhen-2), was used to assess the effect of the identified mutation on protein function.
Whole exome sequencing using peripheral leukocytes revealed a heterozygous c.296A>G missense mutation in the CLCN7 gene. The mutation was also confirmed using Sanger sequencing. The mutation c.296A>G was regarded to have a pathogenic effect by PolyPhen-2 software.
We detect a heterozygous mutation in CLCN7 gene of a patient with ADO II, which is the first report in Korea. Our present findings suggest that symptoms and signs of ADO II patient having a c.296A>G mutation in CLCN7 may appear at a very late age. The present study would also enrich the database of CLCN7 mutations and improve our understanding of ADO II.
Keywords: Type 2 autosomal dominant osteopetrosis; CLCN7 gene; Osteosclerosis; Whole exome sequencing
Osteopetrosis is rare, heterogeneous, and inherited disorders of the skeleton characterized by increased bone mass and universal osteosclerosis. The disease was first described by the German radiologist Heinlich Albers-Schönberg in 1904 [1]. Osteopetrosis is related to congenital defect in the development or function of the osteoclast, thereby leading to generalized sclerosis of bone and reduction of bone marrow. Moreover, previous investigations reveal that osteoclast fail to produce the sufficient lysosomal enzymes for bone resorption in to extracellular space [2].
Several types are known with different models of inheritance and severity in osteopetrosis. Autosomal recessive osteopetrosis is known to be caused by loss-of-function mutation in genes including T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 (TCIRG1), chloride voltage-gated channel 7 (CLCN7), osteoclastogenesis associated transmembrane protein 1 (OSTM1), pleckstrin homology and RUN domain containing M1 (PLEKHM1), sorting nexin 10 (SNX10), TNF superfamily member 11 (TNFSF11), TNF receptor superfamily member 11a (TNFRSF11A), etc. Intermediate recessive osteopetrosis induced by type II carbonic anhydrase deficiency is usually found during childhood and the severity of the disease is variable [3]. The most aggressive forms tend to have autosomal recessive inheritance, whereas the benign types are observed in adults and inherited in an autosomal dominant manner [3]. Comparing to different types of osteopetrosis with life-threatening complications in the first decade of life, type II autosomal dominant osteopetrosis (ADO II also known as Albers-Schönberg disease) is more benign condition principally affecting adolescents and adults. Life span in the adult onset form is also usually normal [2]. However, it causes commonly diffuse osteosclerosis predominating in spine and pelvis, thus promoting to development of the classic sandwich vertebra appearance in patients with ADO II [4].
ADO II is the relatively common form of osteopetrosis and has an incidence of 1 in 20,000 births. To date, mutations in at least 10 genes have been identified to induce failure of osteoclast differentiation or function in humans [2]. Above 70% of patients harbors heterozygous dominant negative mutations of the CLCN7 gene [5]. Mutations in CLCN7 gene lead to dysfunction of chloride channel in osteoclast, resulting in ADO II. CLCN7 plays a key role in lysosomal acidification which is crucial in dissolving bone mineral and organic bone matrix by osteoclast [6].
Herein, we report a case of a 68-year-old woman with ADO II who presented with pain in hip joint. We also detect a heterozygous mutation in CLCN7, the first report in Korea, through whole exome sequencing using genomic DNA of the patient. The mutation of the patient was also regarded to have a pathogenic effect, which was predicted by in silico analysis of the effect of amino acid substitution.
This study was reviewed and approved by the Institutional Review Board of Chungnam National University Hospital (CNUH 2015-09-042). Written informed consent was obtained from the subject before participating in the study. Current research was also conducted in accordance with the precepts of the Declaration of Helsinki.
DNA preparation
A 10 mL of peripheral blood sample was obtained from the patients. Genomic DNA was extracted in the whole blood samples of the patient with QiaAmp DNA blood mini kit (Qiagene, Valencia, CA, USA).
Whole exome sequencing
After informed consent was acquired, whole exome sequencing was conducted using genomic DNA of the patient through the service from Macrogen (Daejeon, Korea). The human exome capture by the SureSelect V6-Post kit (Agilent, Santa Clara, CA, USA) was used. Paired-end sequencing was performed using Illumina Hiseq 2500 platform (Illumina, San Diego, CA, USA). Data analysis was conducted by the Macrogen exome sequencing pipeline. Briefly, the raw data were mapped to the reference genome (hg19) with the BWA v0.7.12, and variants were called using GATK v3.4.0. Variants were annotated with ANNOVAR. The population frequencies of single nucleotide variants (SNVs) and small insertions and deletions (indels) were annotated with dbSNP, ESP6500, and 1000 genome database. The mean depth of the target regions was 83.1 reads. The 96.7% of target sequences were covered with >20 independent reads. The throughput of the exome sequence is available upon request.
Polymerase chain reaction and Sanger sequencing
Genomic DNA was subjected for polymerase chain reaction (PCR) and Sanger sequencing on CLCN7 exon 4 using following primers: forward, 5′-TTG CCT TTT TCT GCC ACA G-3′; reverse, 5′-GAG GAG GAG GGA GGA GGT G-3′. The PCR reaction was performed using the following protocols: denaturation was conducted for 1 minute at 94℃, followed by 35 cycles of 94℃ for 30 seconds, 61℃ for 30 seconds, and 72℃ for 1 minute, with a final 7-minute extension at 72℃. The amplified 400-bp PCR products were purified using ExoSAP reagent, and forward and reverse sequencing were performed using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems Inc., Foster City, CA, USA) and an ABI 3730 XL automatic sequencer (Applied Biosystems) using the same primers.
Prediction of functional effects of human single nucleotide polymorphism
Polymorphism Phenotyping v2 (PolyPhen-2) as a tool for annotating coding nonsynonymous single nucleotide polymorphisms was used to predict the functional effects of amino acid substitution on the structure and function of a human protein [7]. PolyPhen-2 helps us to hypothesize the clinical significance of the mutations in humans. This program evaluates the mutations as benign, possibly damaging, or probably damaging based on pairs of false positive rate thresholds (http://genetics.bwh.harvard.edu/pph2/index.shtml).
Clinical report
A 68-year-old female patient visited department of orthopedics due to pain in hip joint. She complained of continuous both hip pain for 3 years prior to hospital visit and was unable to walk independently 3 months ago. She underwent total knee arthroplasty due to osteoarthritis 2 years ago, and then has been in a wheelchair since 3 months ago. She was scheduled to have a total hip replacement operation. There was no family history of known symptoms and diseases of the skeletal system. Her height was 150 cm, and body weight was 45 kg. Physical examination revealed that blood pressure 120/70 mm Hg, pulse 70 beats per minute, respiratory rate 18 breaths per minute, body temperature 36.8℃. Intraoral examination revealed no gingival inflammation or recession and abnormalities in teeth of the patient.
Laboratory findings of the patient showed hemoglobin of 13.4 g/dL, white blood cells 5.24 k/µL, and platelet count 225 k/µL. Renal function and serum chemistry were within normal limit: blood urea nitrogen 15.0 mg/dL, creatinine 0.42 mg/dL, Na/K 139.9/4.0 mEq/L, total protein 6.4 g/dL, albumin 4.0 g/dL, calcium/phosphorus 8.6/4.7 mg/dL, alkaline phosphatase 59 IU/L, and C-telopeptide 0.349 ng/mL. Liver function test were normal: serum bilirubin 0.82 mg/dL, and aspartate transaminase/alanine transaminase 38/15 IU/L. Serum parathyroid hormone was 29.37 mIU/mL (reference range, 10 to 65) and 25-hydroxy vitamin D was 16.3 ng/mL. Thyroid function test showed normal: free thyroxine 0.99 ng/dL, triiodothyronine 1.32 ng/mL, and thyroid stimulating hormone 2.54 µIU/mL. Serum protein electrophoresis was normal and immunofixation electrophoresis also revealed no evidence of monoclonality in serum protein. Twenty-four-hour urinalysis results were all within normal limits: creatinine 0.73 g/day, phosphorus 628.25 mg/day, calcium 288.75 mg/day, and sodium 112.7 mEq/day. All laboratory findings were summarized in Table 1.
Laboratory Findings of the Patient with ADO II
Simple X-ray for skull, spine and pelvis, bone scan, and dual-energy X-ray absorptiometry were included in radiologic investigations. Lateral skull view on radiograph revealed thickening of the inner and outer cortical tables (Fig. 1A). The base of the skull appeared relatively higher radiodensity with loss of trabecular pattern (Fig. 1A). Lateral view of lumbar spine also showed sandwich vertebra appearance as well as increased radiodensity. Moreover, simple radiography of pelvis shows generalized increased bone density and "bone-in-bone" appearance in her right femur head (Fig. 1B). The bone mineral density of the patient was shown to be remarkably increased using dual-energy X-ray absorptiometry (Fig. 2). Whole-body bone scintigraphy revealed abnormal uptake in proximal epiphysis of both humeri, tibias, and fibulas. High uptake was also found in tight femoral head and acetabulum, but kidneys and bladder were not visible, suggesting bone superscan (Fig. 3).
Radiographic signatures of the patient with type II autosomal dominant osteopetrosis. (A) Mile sclerosis of skull base and cortical thickening (arrowhead). (B) Cortical thickening (arrowheads) in femurs. LAT-LT, lateral-left.
Bone mineral density (BMD), T and Z score in the patient with type II autosomal dominant osteopetrosis. (A) BMD at lumbar spine. (B) BMD at left femur. The reference data for the Z score was calculated from healthy Asian people of the same age and sex. BMC, bone mineral content.
Whole-body bone scintigraphy with technetium 99m-methyl diphosphonate. Tracer uptake in proximal epiphysis of both the humeri, tibias and fibulas, head and acetabulum of the femurs was increased. Faint visualization of both kidneys and bladder. RT, right; IV, intravenous; ANT, anterior; POST, posterior.
Genetic analysis with whole exome sequencing and direct DNA sequencing
We obtained 98,367 variants from the patient using whole exome sequencing. Among them, the number of synonymous variant, missense variant, and frameshift variant was 12,074, 11,518, 312, respectively. Three variants were identified in coding regions of CLCN7 gene, including two synonymous variants and a heterozygous missense c.296A>G (Tyr99Cys, rs387907576) SNV at exon 4 of CLCN7. This variant has been reported in ClinVar database as pathogenic/likely pathogenic, and has not been reported in a population databases including 1000 Genome and ESP6500. All genetic data regarding the variants are available upon request. Additionally, direct sequencing of the CLCN7 gene showed a heterozygous mutation at the same position (Fig. 4). This tyrosine residue is also highly conserved across species, for example, human, rhesus, mouse, chicken, zebrafish, frog, and lamprey (Fig. 5). Moreover, PolyPhen-2 prediction result of probable damaging was reported based on in silico analysis of the effect of amino acid substitution (Fig. 6). The in silico prediction by SIFT was damaging (score, 0.000) and MutationTaster predicted it as disease causing variant.
Genetic analysis of chloride voltage-gated channel 7 (CLCN7) gene in the patient with type II autosomal dominant osteopetrosis (ADO II). Direct DNA sequencing of the patients with ADO II; arrow indicates a heterozygous A-to-G transition at c.296 in exon 4, leading to p.Tyr99Cys.
Alignment of the product of chloride voltage-gated channel 7 (CLCN7) indicating the conservation of mutated residues (Y99C) among different species.
Polymorphism Phenotyping v2 (PolyPhen-2) can predict the possible impact of amino acid substitutions on the stability and function of human proteins using structural and comparative evolutionary considerations. The missense mutations Y99C in chloride voltage-gated channel 7 (CLCN7) were predicted to have a pathogenic effect.
The diagnosis of ADO II was usually based on genetic analysis, typical clinical, hematological parameters, and radiographs of the spine and pelvis. ADO II is the relatively common type of osteopetrosis with an incidence of 1 in 20,000 births [2]. Although our patient was a 68-year-old female, the incidence of ADO II is similar in men and women [5]. ADO II shows highly disease course heterogeneity ranging from asymptomatic early stage patients to severely debilitating phenotypes. The major clinical manifestations of ADO II are long bone fracture, osteoarthritis, osteomyelitis, dental abnormalities, cranial nerve compression, and moderate hematologic failure [8]. However, in the current study, the patient has only hip pain and osteoarthritis without history of other skeletal manifestations. Bone marrow dysfunction is relatively uncommon clinicopathologic finding in ADO II [9], and complete blood counts of our patient was also within normal limits.
For induction of bone resorption, the osteoclast should be differentiated from its precursors, form the ruffled borders with attachment to the bone surface, and remove degraded the organic bone matrix and calcium through secreting acid and proteases [10]. CLCN7 provides the chloride transport required for an efficient proton pumping by the H+-ATPase of the osteoclast ruffled membrane [11]. Therefore, mutations in the chloride channel 7 gene lead to acidification failure of extracellular lysosome between osteoclast and bone, resulting in a defect in bone resorption [12]. Subsequently, these studies on patients with ADO II have provided the potential value of the development of CLCN7 inhibitor for treatment of osteoporosis and metabolic bone diseases. Treatment with CLCN7 inhibitors prevents bone resorption without changes in bone formation in ovariectomized rat model [13], but further studies using CLCN7 inhibitors have not been performed. However, cathepsin K, acid-activated protease mediating type I collagen cleavage in the resorption lacunae, has been an attractive target for the drug development of osteoporosis. Odanacatib as a cathepsin K inhibitor was recently developed and showed reduction in fractures in postmenopausal women, but significantly higher risk for stroke in the odanacatib group was detected in a large phase III clinical trial, leading to early termination of clinical trial [14].
CLCN7 has 12 transmembrane hydrophobic domains and two cytosolic domains, which are comprised of 25 exons spanning over 30 kb in the human genome [1215]. CLCN7 forms a homodimer having two homologous subunits, consisting of eighteen intramembrane α helices, four chloride ion binding sites, and two cystathionine beta synthase domains [16]. In ADO II, pathogenic variants of CLCN7 comprise nonsense variants, frameshifts, insertions, deletions, and missense variants. Approximately 70% of patients with ADO II harbors autosomal dominant mutations of the CLCN7 gene [3]. The mutation c.296A>G of our patient is located in exon 4 of the intramembrane α helices in CLCN7. We found that the result of probable damaging was reported based on in silico analysis of the effect of amino acid change (Fig. 6). Because this variant was reported as pathogenic/likely pathogenic in ClinVar database, absent in population databases, and multiple lines of computational evidences support a deleterious effect, we regarded this variant as a pathogenic variant [17]. Previous investigations demonstrated the variation in age at diagnosis of ADO II. In a Chinese osteopetrosis family, ages of patients with ADO II ranged from 3 to 29 years [1819]. In contrast, the age at diagnosis of ADO II was 68 years in our patient. Moreover, Chinese and Korean patients with mutation c.296A>G in CLCN7 showed a substantial difference in bone phenotype. This suggests that no straightforward genotype-phenotype correlation could be established between CLCN7 variants and disease characteristics.
In conclusion, we report on a germline CLCN7 mutation in adult female patient with ADO II. This is the first description genetically confirmed with the heterozygous missense c.296A>G (Tyr99Cys) mutation in a Korean patient with ADO II.
This study was supported by the research fund of the Daejeon and Chungcheong Branch of Korean Endocrine Society (2018). Hyon-Seung Yi was supported by the Basic Science Research Program, through the NRF, funded by the Ministry of Science, ICT, and Future Planning, Korea (NRF-2018R1C1B6004439). Seon Young Kim was supported by the research fund of Chungnam National University.
CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS: Conception or design: H.S.Y., S.Y.K. Acquisition, analysis, or interpretation of data: H.S.Y., S.Y.K., Y.L., Y.E.K, J.M.K., K.H.J., J.H.L., K.S.K., H.J.K., B.J.K., M.S. Drafting the work or revising: H.S.Y., S.Y.K. Final approval of the manuscript: H.S.Y.
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Korean Endocrine Society
(open-access, http://creativecommons.org/licenses/by-nc/4.0/) :
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Funded by : Daejeon and Chungcheong Branch of Korean Endocrine Society
Funded by : National Research Foundation of Koreahttps://doi.org/10.13039/501100003725
Award ID : NRF-2018R1C1B6004439
Funded by : Chungnam National Universityhttps://doi.org/10.13039/501100002462
Laboratory findings
Hemoglobin, g/dL 13.4
White blood cells, k/μL 5.24
Platelet, k/μL 225
Blood urea nitrogen, mg/dL 15.0
Creatinine, mg/dL 0.42
Na/K, mEq/L 139.9/4.0
Total protein, g/dL 6.4
Albumin, g/dL 4.0
Calcium/phosphorus, mg/dL 8.6/4.7
Alkaline phosphatase, IU/L 59
C-telopeptide, ng/mL 0.349
Bilirubin, mg/dL 0.82
Aspartate transaminase/alanine transaminase, IU/L 38/15
Parathyroid hormone, mIU/mL 29.37
25-Hydroxy vitamin D, ng/mL 16.3
Free T4, ng/dL 0.99
T3, ng/mL 1.32
Thyroid stimulating hormone, μIU/mL 2.54
24-Hour urine creatinine, g/day 0.73
24-Hour urine phosphorus, mg/day 628.25
24-Hour urine calcium, mg/day 288.75
24-Hour urine sodium, mEq/day 112.7
ADO II, type II autosomal dominant osteopetrosis; T4, thyroxine; T3, triiodothyronine.


Kate Southorn graduated in 2001 from the University of Liverpool with commendation and a Distinction in Equine studies. After graduation, Kate joined the team at Springwood Veterinary Centre then joined the equine team at Markeaton in 2002.
Kate subsequently spent 4 years in equine practice in Lancashire with a bias to stud work/AI and dental care and the re-joined the equine team at Scarsdale Vets in October 2008.
Kate is one of the BEVA approved AI vets, is an Inspector of Riding Establishments. She has completed all three dental modules as part of the RCVS Cert AVP in Equine Dentistry (2012) and plans to complete the remaining equine practice module in the next year.
Kate enjoys many aspects of equine practice, but has particular interest in performance and advanced dentistry, surgery, reproduction and artificial insemination and wound management. She also enjoys internal medicine and dermatological cases.
Outside of work, Kate has 2 lively little boys, 6 chickens, 3 ducks, 4 lambs, an elderly spaniel, two ponies and a very tolerant husband. She enjoys making American pancakes on a Sunday morning for her family; and drawing and painting when she gets some time to herself.
Kate occasionally breeds her own ponies, but mainly takes them showing. Her 128cm show pony Highbent Tiffany qualified for the RIHS and multiple other championships last year. Kate and her family recently moved to a smallholding and seem to spend all their time fencing and mending things but is hoping to get her home-bred welsh section B, Stanrose Nimrod (Nemo to his friends) into the ring under saddle as a lead rein show hunter pony this winter.