Coaching Centers for Class K-12 in Madhya Pradesh, India. Find list of Best coaching centers for Class K-12 in Madhya Pradesh for all subjects and all boards like State boards like UP boards, Maharashtra Board, Bihar Board or CBSE board, ICSE board etc. Get complete reviews, Contact details, Address etc of coaching centers for Class K-12 in in Madhya Pradesh. Students can also book class with coaching centers offering education for class K to 12. Coaching centers for Class 1 to 5, Coaching for Class 6, Coaching for Class 7, Coaching for Class 8, Coaching for Class 9, Coaching for Class 10, Coaching for Class 11, Coaching for Class 12.
Over the years, the name of "Yours Reliable Institute" has become synonymous with success in 6th, 7th, 8th, 9th, 10th, 11th, 12th class coaching in Bhopal. Yours Reliable has over the years designed, delivered, perfected and innovated the art and science of teaching and guiding students for entrance exam of IIT and main exam of 6th, 7th, 8th, 9th, 10th, 11th, 12th, which are recognized as the Premier Technology Institutions across the world.
Green Valley Coaching Institute was established in 25 March 2011, by Jitendra Birla Sir with the aim to educate students who wants to make their career in agritech. In starting strenght was less but our students perfom well with the hardword of our faculties as a result our students get higher rank in competative exam. We provide quality education for the Agritech competative exams (PAT/CPAT/PVT/ JET/BHU PAT/SHIATS PAT/ICAR/ BUPAT/CGPAT). Practice, persistence and performance when inculdated in the meticulous guidance of GVCI are sure to produce the output of excellence in terms of career and development of holistic personality, and this is the objective of Green Valley Coaching Institute. Green Valley Coaching Institute Started in year 2011 With only 10 Students in a small classroom , Since then it went on growing every year. It is ambition & vision of Jitendra Birla Sir, to run a class. It has been providing.' The Complete Guidance For Bright Success' to All Agriculture Entrance Examination Students.The hard work & Sincere efforts of this one man resulted in a huge increase in Students Strength. Soon the need arose to expand.The main purpose of GVCI built up a bright academic career to poor & needy Student for their bright Success. The main objective of the top and best known PAT Coaching Class – Green Valley Coaching Institute in Indore, is to provide an edge to Students and Sharpen their Skills, give them a clear picture of what to expect at Agriculture Entrance examinations and assist them in their preprations.
Overseas education consultant in Bhopal.


text:
Saved from Reckless Youth by Art
October 29, 2009 by Marion Maneker
The Wall Street Journal interviews Kim Chang-Il, South Korea's retail magnate turned art collector and painter. Kim made a fortune at a young age, to hear him tell it, he was saved by art:
Mr. Kim coped badly at first with the sudden wealth and he says he spent a reckless amount at bars. But in 1977, when he was 26 years old, he had an epiphany as he walked around Insadong, a culture and art district in downtown Seoul near his old high school.
"The art made me feel safe. Like it would save me from my recklessness." He was taken, he says, with what he likes to call a "dream virus" that pushed him into the realm of art, and he started to collect with a passion.
Today, Mr. Kim displays many of the works he's accumulated in Cheonan, an hour's drive from Seoul. There, outside his Arario Gallery, sculptures by great contemporary artists such as Keith Haring, Damien Hirst and Armand Fernandez are free for the public to enjoy anytime. He also owns galleries in Seoul, Beijing and New York.
The Collector: Kim Chang-Il (Wall Street Journal)
Classic Car Sales Down Slightly at Pebble Beach 2017
Christie's Exits Financial Services
Cleveland Museum's David Franklin Resigns
Clapton Tries a Richter Refrain
VIP Art Fair Gets More than Dealers
Real Connoisseurs Buy Privately
Filed Under: Collectors

redpajama_set_name: RedPajamaCommonCrawl


text:
News / Yemen / Editor's Choice
Yemen's Houthis gain more ground against Saudi-led militants in Ma'rib
Saturday, 08 February 2020 11:31 AM [ Last Update: Sunday, 09 February 2020 3:58 AM ]
Fighters from the Houthi Ansarullah movement stand guard as people gather for a pro-Palestinian rally in Sana'a on January 31, 2020. (Photo by AFP)
Fighters from Yemen's popular Houthi Ansarullah movement have gained more ground against Saudi-led militants in the oil-rich Ma'rib Province.
Yemen's al-Masirah TV channel reported on Friday that the Houthis, which have been defending war-wracked Yemen against the Saudi aggression, advanced west of the city of Ma'rib, retaking several sites from the Saudi-led militants loyal to former Riyadh-backed President Abd Rabbuh Mansur Hadi.
The Yemeni fighters, it added, are currently on the western outskirts of Ma'rib, their first presence in the area since the start of the Saudi war in 2015.
مشاهد جديدة لعملية تحرير جبل صلب الاستراتيجي والمواقع المجاورة له غربي مدينة مأرب ضمن مسارات عملية "البنيان المرصوص"#المسيرة #المسيرة_نتhttps://t.co/301ejpv1c8
— قناة المسيرة (@almasirah) February 7, 2020
The Houthis' latest advance comes at a time that pro-Hadi militants attempt to capture areas they had lost in Ma'rib's neighboring al-Jawf Province.
The Yemeni forces launched an operation, dubbed al-Bunyan al-Marsoos, late last month in a bid to liberate the militant-held areas in Ma'rib and adjacent regions. The operation came after the Houthis managed to fend off an attack by the Hadi loyalists in the Nehm district of Sana'a province.
Houthi fighters gain ground in Sana'a, pro-Saudi militants claim tactical withdrawal
Fighters from Yemen
Saudi Arabia and a coalition of its vassal states launched the war on Yemen in March 2015 in an attempt to reinstall the Hadi regime and eliminate the Houthis.
The military aggression, coupled with a naval blockade, has killed and injured hundreds of thousands of people, and plunged Yemen into what the UN says the world's worst humanitarian crisis.
'Houthis still stand strong'
On Friday, Turkey's TRT World TV channel provided a general analysis of the situation in Yemen, saying Saudi Crown Prince Mohammed bin Salman waged the war with the assumption that the Houthis were a "ragtag force."
However, it noted, five years into the war, the Houthis "stand as strong as the first day of fight."
"At first, the plan looked perfect on paper. With the support of a mix of powerful Western and Persian Gulf monarchies, Saudi Arabia's de-facto leader, the young, ambitious but politically inexperienced Mohammad bin Salman (MBS), would bulldoze everything in his way to prove himself worthy for the title of crown prince," the report said.
"The moment came in 2015, when MBS, then-Saudi defense minister, decided to flex his muscle in the country's "backyard" Yemen... Fast forward to 2020, everything Saudi Arabia had planned in Yemen went wrong," it added.
The report further emphasized that bin Salman has now become "a victim of his own assumptions, considering the Houthis a mere ragtag force and hoping the Saudi intervention would be a walk in the park."
Yemen Houthis Abd Rabbuh Mansur Hadi Ma'rib Jawf
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Situated on a large, sloping coastal property formed by undulating sand dunes, this pool was inspired by the lifestyle and long-term vision of the owners who use the pool and spa for relaxation and entertaining.
The spa seating is designed for relaxing with friends and family while enjoying the coastal view over the pool, tennis court and township beyond. The Aqualink in-house controller with its iPad and iPhone controls enable the owners to turn on the spa from the golf course.
What a wonderful way to ease those post-exercise aches and pains.
Aquarius Pools is dedicated to producing pools that will provide a lifetime of satisfaction for every customer. The company builds approximately 30 high-quality architectural concrete swimming pools each year in Victoria's eastern and Bayside suburbs and on the Mornington Peninsula. The company is a member of SPASA Victoria and has been recognised for its innovative designs and quality workmanship with many awards over the years. Most notably, in 2016, Aquarius Pools won the most prestigious awards: gold for Pool of the Year in both the SPASA Australia and SPASA Victoria awards.


Q1:As a Native American, and as a former Philippines school teacher, what do you think of effectiveness of Philippines English schools?
By now most people in the world are very familiar with studying English in the Philippines. When I first found the schools here and saw how they were doing things I was very amazed. I quickly understood why so many students were choosing to study in the Philippines rather than more traditional choices like Singapore, Canada, America, and Australia. There are very big differences and there's no doubt in my mind that you can improve and get much more value for your investment by studying in the Philippines.
Q2:What are positive points of Philippines study in comparison to study in English language schools in Western countries such as US and U.K.
Many students choose to study in schools based in English speaking countries but are extremely disappointed with their expectations and results afterwards. The most obvious problems is that many of these schools don't offer 1:1 classes. Instead, they offer larger group classes that really don't give students enough time to practice and improve their fluency and confidence in the language. At the same time, these schools are often at least twice as expensive and the majority of these students just end up spending time with students who speak their native tongue. This is not the way to improve spoken English. The Philippines offers 1:1 classes supported by small group classes and this is truly the way to get more experience with the language and learn at a much faster pace.
Q3:What do you think of the unique man-to-man-class system in Philippines?
This is the biggest difference. This is what makes students who study in the Philippines improve at much faster rates than those in other Native English-speaking countries. In the end, if you are working one on one with a teacher and they are giving you all of their attention you have no place to go but up. It means that this is YOUR time and not divided into just a few minutes between a large group class.
Q5: Do you have any comments on so-called "peculiar accent" or "dialect" noticed by some Philippines English teachers.
Filipino teachers are not native teachers. With that said, the Philippines has a strong American culture historically. They grow up watching American movies and tv shows and this is the English that they have the most influence from. Also, the schools in the Philippines have very strict hiring standards when it comes to their Filipino teachers. In my experience, I never saw this as a big problem. I always tell my students, you will never sound exactly like me and that's ok. For example, in America there are many different people who come from different places with different accents. The goal is to speak clear, understandable English and there's no problem with that when learning from Filipino teachers.
Q6: Is there any English proficiency gap between them?
The native language in the Philippines is not English. They are not native speakers. That is not a bad thing. Filipinos are excellent with grammar and other subjects. Not just speaking. Some Filipinos speak English exactly like Americans. What I've noticed about the schools in the Philippines Is that they are very good at recognizing the strengths of their teachers. If you are learning speaking from a Filipino teacher you are definitely learning from a well-qualified teacher in that area.
Q7: How long does it take for English beginners to be able to speak a basic English conversation in Philippines language schools?
This is a very broad question but there is an easy answer. Beginners will always see the most improvement in the quickest amount of time. I was always so proud of my students who were almost 0 English-speakers and then after just a few weeks we were already able to have basic conversation. Each person is different but with the one on one attention you will see incredibly improvements in a short amount of time.
Q8: Is there any suggestion for better English educating and guiding system of Philippines English schools?


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Can I get updates on monthly specials, deals, etc.?
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text:
The News Agency of the International Society for Krishna Consciousness
When Death Comes Calling, So Does Oscar the Cat
By: for CNN on Sept. 2, 2007
Oscar the cat doesn't like to be put out in the hall when a patient is dying.
PROVIDENCE, Rhode Island (AP) -- Oscar the cat seems to have an uncanny knack for predicting when nursing home patients are going to die, by curling up next to them during their final hours.
His accuracy, observed in 25 cases, has led the staff to call family members once he has chosen someone. It usually means the patient has less than four hours to live.
"He doesn't make too many mistakes. He seems to understand when patients are about to die," Dr. David Dosa said in an interview. He describes the phenomenon in a poignant essay in Thursday's issue of the New England Journal of Medicine.
"Many family members take some solace from it. They appreciate the companionship that the cat provides for their dying loved one," said Dosa, a geriatrician and assistant professor of medicine at Brown University.
The 2-year-old feline was adopted as a kitten and grew up in a third-floor dementia unit at the Steere House Nursing and Rehabilitation Center. The facility treats people with Alzheimer's, Parkinson's disease and other illnesses.
After about six months, the staff noticed Oscar would make his own rounds, just like the doctors and nurses. He'd sniff and observe patients, then sit beside people who would wind up dying in a few hours.
Dosa said Oscar seems to take his work seriously and is generally aloof. "This is not a cat that's friendly to people," he said.
Oscar is better at predicting death than the people who work there, said Dr. Joan Teno of Brown University, who treats patients at the nursing home and is an expert on care for the terminally ill
She was convinced of Oscar's talent when he made his 13th correct call. While observing one patient, Teno said she noticed the woman wasn't eating, was breathing with difficulty and that her legs had a bluish tinge, signs that often mean death is near.
Oscar wouldn't stay inside the room, though, so Teno thought his streak was broken. Instead, it turned out the doctor's prediction was roughly 10 hours too early. Sure enough, during the patient's final two hours, nurses told Teno that Oscar joined the woman at her bedside.
Doctors say most of the people who get a visit from the sweet-faced, gray-and-white cat are so ill they probably don't know he's there, so patients aren't aware he's a harbinger of death. Most families are grateful for the advance warning, although one wanted Oscar out of the room while a family member died. When Oscar is put outside, he paces and meows his displeasure.
No one's certain if Oscar's behavior is scientifically significant or points to a cause. Teno wonders if the cat notices telltale scents or reads something into the behavior of the nurses who raised him.
Nicholas Dodman, who directs an animal behavioral clinic at the Tufts University Cummings School of Veterinary Medicine and has read Dosa's article, said the only way to know is to carefully document how Oscar divides his time between the living and dying.
If Oscar really is a furry grim reaper, it's also possible his behavior could be driven by self-centered pleasures like a heated blanket placed on a dying person, Dodman said.
Nursing home staffers aren't concerned with explaining Oscar, so long as he gives families a better chance at saying goodbye to the dying.
Oscar recently received a wall plaque publicly commending his "compassionate hospice care."
[ death ] [ pets ]
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Sisters Face Death With Dignity and Reverence
Lessons From a Stop Light
ISKCON Theater Star Rasajna Dasi Passes Away
Mahavishnu Goswami Passes on Peacefully at 91
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Come and enjoy your Saturday morning with Chayah as she performs at the Burlingame SDA Church for their worship service! Come early to get your seat and to be inspired by God's Word and music. All are welcome!


text:
Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004
A. R. Larsen, S. Böcher, M. Stegger, R. Goering, L. V. Pallesen, R. Skov
Department of Medical Microbiology and Immunology
In Europe, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have been caused predominantly by isolates belonging to the "European CA-MRSA" clone (sequence type 80, staphylococcal cassette chromosome mec type IV). In this study, the epidemiology of European CA-MRSA was investigated on a nationwide scale, covering the period from 1993 to 2004. Denmark has been a low-prevalence country regarding MRSA since the mid-1970s but has experienced an increase in the number of new MRSA cases in recent years. Our results show that European CA-MRSA contributed to this increase. The isolates primarily caused skin and soft tissue infections (SSTIs) in patients outside hospitals, and transmission between household members was the predominant mode of spread. Although some of the isolates were found in hospitalized patients, nosocomial transmission seemed likely in only one instance, pointing to endogenous infections as an important factor. Compared to the CA-MRSA clone most common in the United States (USA300), the European CA-MRSA clone seems less well adapted to persist in hospital environments. Patients with a recent history of travel or family relation to the Mediterranean or Middle East were highly overrepresented. The epidemiological data indicated that the European CA-MRSA isolates were introduced into Denmark on multiple occasions, paralleled by an increasing level of genetic diversity of the isolates found during the study period. European CA-MRSA has previously been described as a rather uniform clone. However, we found pronounced, diverse pulsed-field gel electrophoresis subtypes, staphylococcal protein A gene (spa) types, and susceptibility patterns.
https://doi.org/10.1128/JCM.01381-07
10.1128/JCM.01381-07
Dive into the research topics of 'Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004'. Together they form a unique fingerprint.
European Union Medicine & Life Sciences 100%
Denmark Medicine & Life Sciences 93%
Methicillin-Resistant Staphylococcus aureus Medicine & Life Sciences 89%
Epidemiology Medicine & Life Sciences 69%
Clone Cells Medicine & Life Sciences 27%
Family Relations Medicine & Life Sciences 11%
Middle East Medicine & Life Sciences 10%
Soft Tissue Infections Medicine & Life Sciences 10%
Larsen, A. R., Böcher, S., Stegger, M., Goering, R., Pallesen, L. V., & Skov, R. (2008). Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004. Journal of clinical microbiology, 46(1), 62-68. https://doi.org/10.1128/JCM.01381-07
Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004. / Larsen, A. R.; Böcher, S.; Stegger, M. et al.
In: Journal of clinical microbiology, Vol. 46, No. 1, 01.2008, p. 62-68.
Larsen, AR, Böcher, S, Stegger, M, Goering, R, Pallesen, LV & Skov, R 2008, 'Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004', Journal of clinical microbiology, vol. 46, no. 1, pp. 62-68. https://doi.org/10.1128/JCM.01381-07
Larsen AR, Böcher S, Stegger M, Goering R, Pallesen LV, Skov R. Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004. Journal of clinical microbiology. 2008 Jan;46(1):62-68. doi: 10.1128/JCM.01381-07
Larsen, A. R. ; Böcher, S. ; Stegger, M. et al. / Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004. In: Journal of clinical microbiology. 2008 ; Vol. 46, No. 1. pp. 62-68.
@article{264fc1febf354731ac3409880779b98f,
title = "Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004",
abstract = "In Europe, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have been caused predominantly by isolates belonging to the {"}European CA-MRSA{"} clone (sequence type 80, staphylococcal cassette chromosome mec type IV). In this study, the epidemiology of European CA-MRSA was investigated on a nationwide scale, covering the period from 1993 to 2004. Denmark has been a low-prevalence country regarding MRSA since the mid-1970s but has experienced an increase in the number of new MRSA cases in recent years. Our results show that European CA-MRSA contributed to this increase. The isolates primarily caused skin and soft tissue infections (SSTIs) in patients outside hospitals, and transmission between household members was the predominant mode of spread. Although some of the isolates were found in hospitalized patients, nosocomial transmission seemed likely in only one instance, pointing to endogenous infections as an important factor. Compared to the CA-MRSA clone most common in the United States (USA300), the European CA-MRSA clone seems less well adapted to persist in hospital environments. Patients with a recent history of travel or family relation to the Mediterranean or Middle East were highly overrepresented. The epidemiological data indicated that the European CA-MRSA isolates were introduced into Denmark on multiple occasions, paralleled by an increasing level of genetic diversity of the isolates found during the study period. European CA-MRSA has previously been described as a rather uniform clone. However, we found pronounced, diverse pulsed-field gel electrophoresis subtypes, staphylococcal protein A gene (spa) types, and susceptibility patterns.",
author = "Larsen, {A. R.} and S. B{\"o}cher and M. Stegger and R. Goering and Pallesen, {L. V.} and R. Skov",
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journal = "Journal of Clinical Microbiology",
T1 - Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004
AU - Larsen, A. R.
AU - Böcher, S.
AU - Stegger, M.
AU - Goering, R.
AU - Pallesen, L. V.
AU - Skov, R.
N2 - In Europe, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have been caused predominantly by isolates belonging to the "European CA-MRSA" clone (sequence type 80, staphylococcal cassette chromosome mec type IV). In this study, the epidemiology of European CA-MRSA was investigated on a nationwide scale, covering the period from 1993 to 2004. Denmark has been a low-prevalence country regarding MRSA since the mid-1970s but has experienced an increase in the number of new MRSA cases in recent years. Our results show that European CA-MRSA contributed to this increase. The isolates primarily caused skin and soft tissue infections (SSTIs) in patients outside hospitals, and transmission between household members was the predominant mode of spread. Although some of the isolates were found in hospitalized patients, nosocomial transmission seemed likely in only one instance, pointing to endogenous infections as an important factor. Compared to the CA-MRSA clone most common in the United States (USA300), the European CA-MRSA clone seems less well adapted to persist in hospital environments. Patients with a recent history of travel or family relation to the Mediterranean or Middle East were highly overrepresented. The epidemiological data indicated that the European CA-MRSA isolates were introduced into Denmark on multiple occasions, paralleled by an increasing level of genetic diversity of the isolates found during the study period. European CA-MRSA has previously been described as a rather uniform clone. However, we found pronounced, diverse pulsed-field gel electrophoresis subtypes, staphylococcal protein A gene (spa) types, and susceptibility patterns.
AB - In Europe, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have been caused predominantly by isolates belonging to the "European CA-MRSA" clone (sequence type 80, staphylococcal cassette chromosome mec type IV). In this study, the epidemiology of European CA-MRSA was investigated on a nationwide scale, covering the period from 1993 to 2004. Denmark has been a low-prevalence country regarding MRSA since the mid-1970s but has experienced an increase in the number of new MRSA cases in recent years. Our results show that European CA-MRSA contributed to this increase. The isolates primarily caused skin and soft tissue infections (SSTIs) in patients outside hospitals, and transmission between household members was the predominant mode of spread. Although some of the isolates were found in hospitalized patients, nosocomial transmission seemed likely in only one instance, pointing to endogenous infections as an important factor. Compared to the CA-MRSA clone most common in the United States (USA300), the European CA-MRSA clone seems less well adapted to persist in hospital environments. Patients with a recent history of travel or family relation to the Mediterranean or Middle East were highly overrepresented. The epidemiological data indicated that the European CA-MRSA isolates were introduced into Denmark on multiple occasions, paralleled by an increasing level of genetic diversity of the isolates found during the study period. European CA-MRSA has previously been described as a rather uniform clone. However, we found pronounced, diverse pulsed-field gel electrophoresis subtypes, staphylococcal protein A gene (spa) types, and susceptibility patterns.
U2 - 10.1128/JCM.01381-07
DO - 10.1128/JCM.01381-07
JO - Journal of Clinical Microbiology
JF - Journal of Clinical Microbiology


text:
Some Rambling Thoughts on Lust and Love as Sources of Desire
I am quite ignorant about Buddhism, but if I'm not mistaken the religion places special emphasis on the proper handling of desire. Some believe the point of Buddhism is negating desire entirely in order to attain bliss and, eventually, Nirvana, yet even an ignoramus like me recognizes this as a misleading assumption. As far as I know, Buddhism does not advocate nullifying desire outright – which would be both impossible and counterproductive – but instead instructs its followers to understand and handle desire properly. Of course, desire and its proper handling play a crucial role in Christianity as well. Now, I am neither theologian nor a philosopher, merely an obscure novelist, but even as such I have been fascinated by desire and its inherent negative and positive implications, so much so that I rather unintentionally made it the central theme of my one, and thus far, only novel.
Conflict is the lifeblood of most narratives, and the seeds of conflict are usually found in the choices characters make. These choices are inevitably fueled by their desires, and the source from which desires spring determines both the course of the narrative as a whole and, more specifically, the consequences the characters must face. While I was writing the book, I depicted the proper/improper handling of desire as a matter of lust versus love. Characters driven primarily by lust misunderstood and mishandled desire while characters inspired by love displayed a deeper understanding and handling of desire. In my novel, I present lust as base and crude; love as refined and transcendent. The former springs from the material, while the latter, from the spiritual. The excerpt below presents the only direct reference I make to desire in the novel. It is taken from a scene where Reinhardt, a father, makes a rather feeble attempt to describe the difference between lust and love to his son Béla during a visit to an art gallery.
"Desire can come from two very different sources: love and lust," Reinhardt explained. He found the expression on his son's face disquieting, yet plowed ahead regardless. "Love appeals to the higher elements within us. It is elegant and refined. Love appreciates beauty. Admires it. Nurtures it. Preserves it. Lust, on the other hand, appeals to the lower elements within us. It is grotesque and coarse. Lust misjudges beauty. Scorns it. Deprives it. Destroys it."
Nothing I have written in this post thus far is terribly original, but I find it interesting that desire and its motivations are rarely discussed explicitly in our contemporary world. Perhaps the topic is too obvious to be worthy of discussion or too threadbare to warrant extensive consideration because it seems nearly everyone understands the difference between lust-fueled desire and love-fueled desire. People are also aware of the negative consequences lust-fulfilled desires bring and the benefits of desires fulfilled through love, yet most seem incapable of resisting desires motivated mainly by lust. This is somewhat understandable in our contemporary world. I imagine few civilizations in history actively encouraged the misunderstanding and mishandling of desire with as much tenacity as ours does today.
The end goal of desire is gratification, which in our spiritually impoverished world exists almost exclusively in the material; hence, most desires today are aimed solely at gratifying physical cravings for material goods, sex, status, and power. Harnessing lust is the most effective way of satisfying these material aims because lust views the object of desire as exactly that – an object. When eyes possessed by lust look out into the world, they see only things – things whose sole purpose for existence is pleasure/desire gratification. Oblivious to the existence of anything beyond the realm of the material, lust manipulates desire and makes it into a ruthless predatory force that tears mercilessly into the objects it covets in a misguided attempt to satiate wants it regards as needs.
As I wrote my novel, I began to detect this pattern in some of my characters. Driven by the desire for riches, or fame, or hedonism, these characters viewed and treated those around them as means to their ends and used them as objects to gratify their desires. Some were corrupted beyond redemption, yet others became plagued with guilt or struggled to comprehend why the satisfaction they managed to wring from their satiated desires was so short-lived and fleeting.
Unwilling to see the world as it really is, desire fueled by lust cannot perceive metaphysical reality. When lust is unleashed upon the world, it may, albeit vulgarly, satisfy physical desires, but its scorn for the metaphysical ultimately leaves behind a gaping hole that can never be satisfied through the physical alone. This ignorance, willful or otherwise, eventually brings suffering to the lust-possessed as well because they remain securely locked in the world of things themselves. Unable to recognize Beings, they fail to see themselves as Beings and regard themselves as merely things. Yet, they are Beings nonetheless – but their indulgence in lust has cost them the price of spirit, as Shakepeare's Sonnet 129 makes clear:
Th' expense of spirit in a waste of shame
Is lust in action; and till action, lust
Is perjured, murd'rous, bloody, full of blame,
Savage, extreme, rude, cruel, not to trust,
Enjoy'd no sooner but despisèd straight;
Past reason hunted, and, no sooner had,
Past reason hated, as a swallowed bait,
On purpose laid to make the taker mad -
Mad in pursuit, and in possession so;
Had, having, and in quest to have, extreme;
A bliss in proof, and prov'd, a very woe;
Before, a joy proposed; behind, a dream.
All this the world well knows; yet none knows well
To shun the heaven that leads men to this hell.
Desire itself is neutral. What seems to make it negative or positive is how it is understood and how it is handled. Desire ruled by lust is inherently negative, but desire ruled by love is not only positive, but essential. Love understands the true source of desire and works toward that end. By refusing to allow baser instincts to overpower our desires, we are offered the chance to see the true source of our desires. We can then work toward harmonizing our desires with the spiritual and, hopefully, gratify these desires in the material world in a manner that simultaneously aligns with the spiritual.
The characters in my novel that recognized this truth push beyond mere base physical cravings and pleasure-seeking, and elevate their desires in a manner that, at the very least, attempts to be in harmony with love. This does not imply that love-fueled desire is limp-wristed, passive, or weak. On the contrary, since their desires were inspired by love these characters can perceive the world as it really is and act accordingly. If strength and harshness are required, they are more than capable of supplying it, but even then it is done in love – in the understanding that they are Beings in a world of Beings, not a thing in the world of things.
None of the characters in my novel are pure representatives of desire motivated purely by lust or love. In other words, it is not a story populated by demons and saints. Some characters are more aligned with love than others, but even those in greater harmony with love occasionally misunderstand or make missteps.
I believe the same holds true in our world. Desire is an enormous part of our experience in this material realm, and I doubt any of us is capable of completely adhering to love when confronted by desire. Even our most noble and successful efforts to gratify our desires in harmony with love undoubtedly contain elements of lust, but the more we position our desires in love, the more we resist the urge to gratify our desires primarily through the lust, the more we shun the heaven that leads men to this hell, the closer we will get to understanding the world as it really is and ourselves as we truly are or, at the very least, are meant to be. That, in essence, is what I attempted to convey in my novel and this post.
Epimetheus
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Wednesday, 17 October 2018.
Intensified bilateral cooperation between Serbia and Japan
State Secretary of the Ministry of Foreign Affairs Nemanja Stevanovic has received today Parliamentary Deputy Minister of Foreign Affairs of Japan Kenji Yamada.
In the cordial talks, the two collocutors concluded that the relations between the two countries were intensified, substantive and multifaceted. The two sides asserted the readiness to further strengthen mutual dialogue, exchange visits on all levels and further connect the economies of the two countries.
Mutual satisfaction was expressed at the achieved results and the level of cooperation with an assessment that 2018 was a very important year for the relations between the Republic of Serbia and Japan. The year started in the best possible way in January with the historic visit of Japanese Prime Minister Shinzo Abe to the Republic of Serbia which gave a strong impetus to further promotion of cooperation.
State Secretary Stevanovic reiterated his gratitude for the high level of solidarity that the Japanese people showed towards Serbia in the form of past donations and grant aid. He also underlined that support and solidarity were mutual and they constituted permanent asset in the further development of friendly relations between Serbia and Japan.
Following the meeting in the Ministry of Foreign Affairs, the signing ceremony for the Agreement on Japanese grant to demine the municipality of Bujanovac, with ITF Enhancing Human Security, was held.
The Agreement was signed by Ambassador of Japan in the Republic of Serbia Junichi Maruyama and Director of ITF Ambassador Tomaž Lovrenčič, in the presence of State Secretary Stevanovic and Parliamentary Deputy Minister of Foreign Affairs of Japan Yamada.
Tags: Japan Nemanja Stevanovic State Secretary Ministry of Foreign Affairs


We board the boat from the small harbour surrounded by high mountains covered in glistening ice and snow; as we travel out the stillness and light on the ice mountain evokes a very magical atmosphere. During the six day tour we will take five trips in to the Fjords (3 hour duration). Here orca can be found feeding on herring in large numbers and we usually find them within 20 minutes of leaving the harbour. You will be given a protective thermal suit to keep warm in the icy wind and cold (and be served hot chocolate and cakes onboard). The boat offers a great vantage point from which to take photographs, especially when the orca are hunting. There is a lot of lively surface activity and interactions when they are hunting which everyone enthusiastically tries to capture on camera. This, together with the stunning scenery in the background, provides an opportunity to capture some truly amazing photos.


Europe endured incessant political discord throughout the twentieth century, and some historians refer to the period's conflicts as the Long War. During the Balkan Wars of 1912–13, regional fighting in southeastern Europe ignited conflict across the continent which continued through both world wars and the Cold War. This book illuminates the complex diplomatic and military struggles of a region whose instability, rooted in nineteenth-century nationalistic fervor, provided a catalyst for the political events that ensued. From the assassination of Archduke Franz Ferdinand in 1914 to the incarceration of Radovan Karadzic in 2008, this narrative history offers a fresh interpretation of a complicated and brutal era.


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Talgaun village in Manang has been inundated due to floods caused by incessant rains.
२०७८ साल असार १ गते, मंगलवार ११:२३ AM
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Talgaun in the Himalayan district of Manang has been inundated due to floods caused by incessant rains.
Talgaun in Naso Village Municipality-1 has been inundated due to continuous rains on Sunday, Monday and Tuesday. According to local Minrashi Gurung, 10 houses near the Marshyangdi River have been inundated. According to him, about half of the houses have been submerged. Other homes are also at risk. The locals have left their homes and moved out. They are struggling to find a safe place.
Locals have demanded rescue as other houses in the slum are also at risk. Though the locals said that they could not contact the police and the administration, Manang Chief District Officer Bishnu Lamichhane said that the police had been deployed in the area. He said that the team of the police post in the lake and the locals were involved in the rescue operation. He said that work was underway to move goods from the flooded houses and keep them in a safe place. Citizens are requested to stay in a safe place.
According to him, the school and ward office along with the village have also been inundated. Due to the rains, Ghopte khola near Nayabazar of Chame has overflowed and flooded the settlement. According to Lamichhane, one house in Nayabazar was flooded and two others were damaged. The road is damaged. There is a problem with ventilation. Earlier, the flood in Ghopte khola had entered the settlement on May 30. The floods damaged some tents, electricity poles and roads. He added that Tuesday's floods also damaged the Belly Bridge in Timang.
सम्बन्धित शिर्षक
अवैध जडीबुटी सहित तीन जना पक्राउ
तनहुँमा ट्रक दुर्घटना हुँदा एकको मृत्यु
लमजुङमा मोटरसाइकल दुर्घटना हुँदा एकको मृत्यु एक घाइते
मनाङको पिडा
दुई महिनादेखि मनाङ प्रमुख प्रशासकीय अधिकृत अधिकारी विहीन
दुई महिना देखि विधुत उत्पादन बन्द


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Corrigendum (January 2010)
Research ArticleNeuroscience Free access | 10.1172/JCI25437
TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury
Koichi Obata,1 Hirokazu Katsura,1 Toshiyuki Mizushima,1 Hiroki Yamanaka,1 Kimiko Kobayashi,1 Yi Dai,1 Tetsuo Fukuoka,1 Atsushi Tokunaga,1 Makoto Tominaga,2 and Koichi Noguchi1
1Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Japan. 2Section of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan.
Address correspondence to: Koichi Noguchi, Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Phone: 81-798-45-6415; Fax: 81-798-45-6417; E-mail: noguchi@hyo-med.ac.jp.
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First published September 1, 2005 - More info
Published in Volume 115, Issue 9 on September 1, 2005
J Clin Invest. 2005;115(9):2393–2401. https://doi.org/10.1172/JCI25437.
© 2005 The American Society for Clinical Investigation
First published September 1, 2005 - Version history
Received: April 22, 2005; Accepted: June 7, 2005
Cold hyperalgesia is a well-documented symptom of inflammatory and neuropathic pain; however, the underlying mechanisms of this enhanced sensitivity to cold are poorly understood. A subset of transient receptor potential (TRP) channels mediates thermosensation and is expressed in sensory tissues, such as nociceptors and skin. Here we report that the pharmacological blockade of TRPA1 in primary sensory neurons reversed cold hyperalgesia caused by inflammation and nerve injury. Inflammation and nerve injury increased TRPA1, but not TRPM8, expression in tyrosine kinase A–expressing dorsal root ganglion (DRG) neurons. Intrathecal administration of anti–nerve growth factor (anti-NGF), p38 MAPK inhibitor, or TRPA1 antisense oligodeoxynucleotide decreased the induction of TRPA1 and suppressed inflammation- and nerve injury–induced cold hyperalgesia. Conversely, intrathecal injection of NGF, but not glial cell line–derived neurotrophic factor, increased TRPA1 in DRG neurons through the p38 MAPK pathway. Together, these results demonstrate that an NGF-induced TRPA1 increase in sensory neurons via p38 activation is necessary for cold hyperalgesia. Thus, blocking TRPA1 in sensory neurons might provide a fruitful strategy for treating cold hyperalgesia caused by inflammation and nerve damage.
Hyperalgesia to cold stimulation is a well-documented symptom of inflammatory and neuropathic pain both in the clinical setting and in experimental animal models. Cold hyperalgesia appears to be mediated by the activation of unmyelinated or thinly myelinated fibers (1, 2). Indeed, the behavioral signs of cold, but not mechanical, allodynia in rats with nerve injury were mediated by capsaicin-sensitive afferents (3, 4). However, the molecular mechanisms underlying this abnormal sensitivity to cold remain unknown. Temperature is sensed by a subpopulation of peripheral primary afferents known as thermoreceptors. Recently, the existence of 6 thermosensitive ion channels has been reported, all of which belong to the transient receptor potential (TRP) superfamily, including TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 (also known as CMR1), and TRPA1 (previously known as ANKTM1) (5–8). Among them, TRPA1 and TRPM8 have been identified as cold-sensitive ion channels. TRPM8 is activated by menthol and cooling, with an activation temperature of approximately 25–28°C (9, 10) whereas TRPA1 is activated at approximately 17°C, a temperature that is reported as painfully cold by humans (11, 12).
Neurotrophic factors, which support neuronal survival and growth during the development of the nervous system, have attracted attention because of their important roles in pathological pain (13, 14). They include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived NGF (GDNF). Among them, NGF is known to be a major contributor to inflammatory pain (15, 16). Levels of NGF increase dramatically in inflamed tissue, and the enhanced retrograde transport of NGF increases the expression of substance P (SP), calcitonin gene-related peptide (CGRP), BDNF, and TRPV1 in tyrosine kinase A–expressing (trkA-expressing) dorsal root ganglion (DRG) neurons (13–16). All of the neuropathic pain models are created by partial nerve injury in which some primary afferents are axotomized and others are spared. There is compelling evidence indicating that not only injured primary afferents, but also their uninjured neighbors, show an alteration of excitability and gene expression and that these changes have functional roles in neuropathic pain (17, 18). For example, SP, CGRP, BDNF, and TRPV1 also increase in spared DRG neurons after partial nerve injury (19, 20).
The activation of p38 MAPK in nociceptive neurons participates in generating pain hypersensitivity through transcription-dependent and transcription-independent means (21, 22). We now show that NGF-induced p38 activation in primary afferent neurons regulates TRPA1 expression after inflammation and nerve injury, and this induction of TRPA1 in sensory neurons contributes to the development of cold hyperalgesia. Our findings point to the potential blockade of TRPA1 in sensory neurons as a new therapeutic strategy for inflammatory and neuropathic pain.
TRPA1, but not TRPM8, expression increases in trkA-expressing DRG neurons following peripheral inflammation. We first investigated the role of TRPA1 and TRPM8 in cold hyperalgesia after inflammation induced by CFA. The CFA injection clearly increased the number of paw lifts on a cold plate at 5°C for the 5-minute testing period (Figure 1A). The number of paw lifts increased from 1.8 ± 0.5 before CFA injection to 10.6 ± 2.7 at day 1 and 10.3 ± 2.2 at day 3; cold hyperalgesia gradually resolved by day 7. In contrast, contralateral paw lifts were remarkably few (data not shown).
Time course of the exaggerated response to cold after peripheral inflammation and nerve injury. (A and B) The number of paw lifts on a cold plate at 5°C for the 5-minute testing period was examined at days 1, 3, 5, and 7 after CFA injection (A) and L5 SNL (B). Data represent mean ± SEM; n = 8 per group. BL, baseline. *P < 0.05 compared with the naive control.
In situ hybridization histochemistry (ISHH) revealed that most of the TRPA1 and TRPM8 mRNA-labeled neurons in the DRG were small or medium in size (Figure 2A), consistent with previous studies (9–11). Using a computerized image analysis, we found that 32.4% ± 1.8% and 29.1% ± 2.7% of DRG neurons were positively labeled for TRPA1 and TRPM8 mRNA in naive control rats, respectively (Figure 2B). There was no change in the percentage of TRPA1 mRNA–positive neurons on the contralateral side (data not shown); however, inflammation induced a significant increase in the percentage of TRPA1 mRNA–positive neurons in the ipsilateral DRG at days 1 and 3 (44.1% ± 2.9% and 42.0% ± 2.2%, respectively); the levels gradually declined, returning to normal by day 7 (Figure 2C). This upregulation corresponded well with the development and maintenance of CFA-induced cold hyperalgesia. In contrast, there was no significant difference in the percentages of TRPM8 mRNA–positive neurons over 7 days (Figure 2D). These changes in TRPA1 and TRPM8 mRNA were also confirmed by RT-PCR (Figure 2E). In the spinal cord, neither TRPA1 nor TRPM8 mRNA were detected (data not shown).
Marked upregulation of TRPA1, but not TRPM8, mRNA in DRG neurons after peripheral inflammation induced by CFA. (A) Bright- and dark-field photomicrographs of ISHH showing expression of TRPA1 and TRPM8 mRNA in the naive DRG and the ipsilateral DRG at day 1 after inflammation. Scale bars: 100 μm. (B) Scatterplot diagrams made by plotting the individual cell profiles at day 1 after CFA injection. The gray lines represent the borderlines between the negatively and positively labeled neurons (signal/noise [S/N] ratio = 10). (C and D) Time course of the mean percentages of TRPA1 (C) and TRPM8 (D) mRNA–positive neurons after CFA injection. (E) mRNA expression of TRPA1 and TRPM8 in the DRG after inflammation, as detected by RT-PCR. Quantification of RT-PCR data is shown at right. Data represent mean ± SD; n = 4 per group. *P < 0.05 compared with the naive control.
Several studies have demonstrated an increase in levels of TRPV1 protein, but not in levels of mRNA, after peripheral inflammation (23, 24). Therefore, we examined the changes of TRPM8 expression in the DRG at the protein level using immunohistochemistry (Figure 3A). Consistent with the data obtained from ISHH, there was no difference in the percentages of TRPM8-immunoreactive neurons at day 3 after inflammation (Figure 3B). We found that inflammation increased TRPA1 expression in small- and medium-size neurons (Figure 2, A and B). Cutaneous nociceptors can be divided into 2 broad groups: NGF-responsive/trkA-expressing neurons and GDNF-responsive/c-ret–expressing neurons (25). Double labeling showed that both TRPA1 and TRPM8 heavily colocalized with trkA after inflammation (Figure 3C). However, only TRPA1-expressing neurons coexpressed SP, CGRP, and TRPV1 (Table 1). Furthermore, approximately 10% of TRPA1-labeled neurons were also labeled for TRPM8, indicating that inflammation increased TRPA1 in TRPM8-negative peptidergic neurons.
No change of TRPM8 protein in the DRG and no overlap between TRPM8- and TRPA1-expressing neurons after inflammation. (A) Protein expression of TRPM8 in the naive DRG and the ipsilateral DRG at day 3 after inflammation, as detected by immunohistochemistry. TRPM8-immunoreactive (TRPM8-IR) neurons were invariably small or medium in size (arrows). (B) Quantification of the percentage of TRPM8-IR neurons at day 3 after CFA injection. (C) Double labeling by a combined method of ISHH and immunohistochemistry for TRPA1 or TRPM8 mRNA and trkA-IR, SP-IR, CGRP-IR, and TRPV1-IR in the DRG at day 3 after CFA injection. Double labeling for TRPA1 and TRPM8 mRNA by dual ISHH is shown at right. TRPA1- and TRPM8-expressing neurons were clearly distinguishable. Open arrows indicate double-labeled neurons. Scale bars: 50 μm.
Percentages of trkA-IR, SP-IR, CGRP-IR, or TRPV1-IR neurons in TRPA1 or TRPM8 mRNA–positive neurons in the DRG
Anti-NGF and a p38 MAPK inhibitor alleviate inflammation-induced cold hyperalgesia and TRPA1 upregulation. NGF injection in a peripheral target induces p38 MAPK activation in trkA-expressing DRG neurons; activation of p38 MAPK in DRG neurons contributes to persistent inflammatory pain via the transcriptional regulation of key gene products (23). To determine whether alterations of the endogenous NGF and p38 MAPK pathway might be involved in inflammation-induced cold hyperalgesia, anti-NGF or a p38 MAPK inhibitor, SB203580, was delivered intrathecally before CFA injection and maintained for 3 days via a catheter whose tip was positioned close to the L4/5 DRG. Intrathecal administration of anti-NGF or SB203580 into naive rats produced no significant changes in basal pain sensitivity (data not shown). We found that both anti-NGF (1 μg/μl–1/h–1) and SB203580 (0.5 μg/μl–1/h–1) infusion significantly inhibited inflammation-induced cold hyperalgesia at days 1 and 3 (Figure 4A). Furthermore, anti-NGF reduced inflammation-induced heat hyperalgesia and mechanical allodynia whereas SB203580 attenuated heat hyperalgesia but not mechanical allodynia at days 1 and 3, consistent with previous reports (23).
Anti-NGF and a p38 MAPK inhibitor reverse cold hyperalgesia and TRPA1 upregulation induced by inflammation. (A) Cold and heat hyperalgesia were tested using the cold plate test and the plantar test, respectively, at days 1 and 3 after CFA injection. Mechanical allodynia was determined with a Dynamic Plantar Aesthesiometer. Data represent mean ± SEM; n = 8 per group. (B and C) Quantification of the percentages of TRPA1 (B) and TRPM8 (C) mRNA–positive neurons at day 3 after CFA injection. Data represent mean ± SD; n = 4 per group. (D) Double labeling for TRPA1 or TRPM8 mRNA and p-p38–IR at day 3 after CFA injection. Open arrows indicate double-labeled neurons. SB, SB203580. *P < 0.05 compared with the naive control; #P < 0.05 compared with the vehicle group. Scale bar: 50 μm.
We then assessed the effects of anti-NGF and SB203580 on inflammation-induced TRPA1 upregulation in the DRG. CFA induced a substantial increase in the percentage of TRPA1-positive neurons in the vehicle group at day 3, but pretreatment with either anti-NGF or SB203580 prevented this increase (Figure 4B). However, there was no apparent change in the expression of TRPM8 (Figure 4C). Furthermore, double labeling showed that phosphorylated p38 (p-p38) was predominantly expressed in TRPA1- but not TRPM8-positive neurons at day 3 after inflammation (Figure 4D).
NGF, but not GDNF, increases TRPA1 expression in DRG neurons through the p38 MAPK pathway. To further investigate the effects of NGF and the p38 MAPK pathway on TRPA1 expression in the DRG neurons, we injected NGF (1 μg or 10 μg in 10 μl saline) intrathecally into naive rats. Three days after the 10-μg NGF injections, 46.8% ± 5.7% of the neurons were TRPA1 positive; this percentage was higher than that of TRPA1-positive neurons in the saline group (32.6% ± 1.5%). This increase, however, was significantly reversed by cotreatment with SB203580 (Figure 5A). Additionally, TRPA1 levels did not change after the 10-μg GDNF injection, and neither NGF nor GDNF significantly altered TRPM8 expression (Figure 5B).
NGF, but not GDNF, induces an increase of TRPA1 expression in DRG neurons via p38 MAPK activation. Quantification of the percentage of TRPA1 (A) and TRPM8 (B) mRNA–positive neurons at day 3 after the injection. Data represent mean ± SD; n = 4 per group. *P < 0.05 compared with the naive control. #P < 0.05 compared with the NGF 10-μg group.
TRPA1 induced in spared DRG neurons contributes to cold hyperalgesia following nerve injury. The L5 spinal nerve ligation (SNL) model (26), which is one of the most popular models of neuropathic pain, is unique because the L4 DRG neurons are clearly separated from the axotomized L5 neurons (20). Recent studies have shown increased expressions of SP, CGRP, BDNF, and TRPV1 in the spared L4 DRG following L5 SNL, which indicates that the molecular phenotypic changes in the spared L4 DRG are just like those produced by peripheral inflammation (18–20). Therefore, we investigated the role of TRPA1 and TRPM8 in nerve injury–induced cold hyperalgesia using the L5 SNL model. The L5 SNL clearly increased the number of paw lifts on a cold plate, and cold hyperalgesia lasted for more than 7 days after surgery (Figure 1B). The contralateral side of nerve-ligated rats and both sides of sham-operated rats did not show cold hyperalgesia (data not shown). We then examined the changes of TRPA1 and TRPM8 expression in the L4 and L5 DRG after L5 SNL. Seven days after surgery, the L5 SNL decreased both TRPA1 and TRPM8 mRNA expression in the L5 DRG (Figure 6A). In contrast, the percentage of TRPA1 mRNA–positive neurons significantly increased in the L4 DRG at day 7 after L5 SNL (43.1% ± 5.9%), mainly in small- to medium-diameter neurons. However, there was no change in the expression of TRPM8 in the L4 DRG.
Anti-NGF and a p38 MAPK inhibitor suppress cold hyperalgesia and TRPA1 upregulation in the spared L4 DRG neurons caused by injury to the L5 spinal nerve. (A) Dark-field photomicrograph of ISHH showing the expression of TRPA1 and TRPM8 mRNA in the naive DRG, the injured L5 DRG, and the intact L4 DRG at day 7 after L5 SNL. (B) Cold hyperalgesia was determined using the cold plate test at days 3 and 7 after L5 SNL. Data represent mean ± SEM; n = 8 per group. (C and D) Quantification of the percentage of TRPA1 (C) and TRPM8 (D) mRNA–positive neurons at day 7 after surgery. Data represent mean ± SD; n = 4 per group. *P < 0.05 compared with the naive control; #P < 0.05 compared with the vehicle group. Scale bar: 100 μm.
To ascertain whether NGF-induced p38 activation in the uninjured L4 DRG regulates TRPA1 expression and contributes to cold hyperalgesia after L5 SNL, we administered anti-NGF or SB203580 into the intrathecal space. The treatment of anti-NGF and SB203580 diminished L5 SNL-induced cold hyperalgesia at days 3 and 7 (Figure 6B). Furthermore, we found that both anti-NGF and SB203580 application blocked the L5 SNL–induced increase in TRPA1 but not TRPM8 expression in the spared L4 DRG at day 7 (Figure 6, C and D).
Knockdown of the TRPA1 gene prevents and reverses inflammation- and nerve injury–induced cold hyperalgesia. Our results suggest that cold hyperalgesia after inflammation and nerve injury is critically dependent on functional TRPA1 in DRG neurons. We therefore predicted that a selective knockdown of TRPA1 expression should prevent inflammation- and nerve injury–induced cold hyperalgesia. To test this, rats with peripheral inflammation or nerve injury were intrathecally treated with either an antisense oligodeoxynucleotide (AS-ODN) targeting TRPA1 or a mismatch ODN (MM-ODN) beginning 12 hours before CFA injection or L5 SNL. We found that the CFA- and SNL-induced increase in the number of paw lifts on a cold plate was significantly less in the TRPA1 AS-ODN group (0.5 nmol/μl–1/h–1) than in the MM-ODN group (0.5 nmol/μl–1/h–1) (Figure 7, A and B). The number of paw lifts in the MM-ODN and AS-ODN groups (0.05 nmol/μl–1/h–1) groups was not different from that of the vehicle control rats. However, AS-ODN had no effect on CFA- and SNL-induced mechanical allodynia and heat hyperalgesia.
Reversal of hyperalgesia to cold by a selective blockade of TRPA1 expression. (A and B) Pretreatment with TRPA1 AS-ODN (0.5 nmol/μl–1/h–1) (AS 0.50) prevents cold hyperalgesia, but not heat hyperalgesia or mechanical allodynia, induced by peripheral inflammation (A) and injury to the L5 spinal nerve (B). Cold and heat hyperalgesia were tested using the cold plate test and the plantar test, respectively, at days 1 and 3 after CFA injection or at days 3 and 7 after L5 SNL. Mechanical allodynia was examined using a Dynamic Plantar Aesthesiometer. Data represent mean ± SEM; n = 8 per group. #P < 0.05 compared with the MM-ODN (0.5 nmol/μl–1/h–1) (MM 0.50) group.
We then confirmed that the level of TRPA1 mRNA in the DRG neurons of the AS-ODN–treated rats was significantly lower than that in the MM-ODN–treated rats (Figure 8A) whereas there was no difference in TRPM8 expression between TRPA1 AS-ODN–treated rats and control rats both in the CFA model and in the L5 SNL model (Figure 8B). The distribution of FITC-labeled ODN showed the progressive increase in the fluorescence associated with DRG cell bodies, indicating that the uptake of the ODN occurred in a time-dependent manner (Figure 8C). Furthermore, the treatment with AS-ODN, beginning 12 hours after CFA injection, reversed the inflammation-induced cold hyperalgesia at day 3 but not at day 1 (Figure 8D).
Confirmation of a selective blockade of TRPA1 expression in a time-dependent manner. (A and B) TRPA1 AS-ODN (0.5 nmol/μl–1/h–1) attenuates the induction of TRPA1, but not TRPM8, mRNA induced by peripheral inflammation and injury to the L5 spinal nerve. Quantification of the percentage of TRPA1 (A) and TRPM8 (B) mRNA–positive neurons at day 3 after CFA injection or in the L4 DRG at day 7 after L5 SNL. Data represent mean ± SD; n = 4 per group. (C) Fluorescence in the naive DRG and the DRG at 6 and 24 hours after intrathecal injection of FITC-labeled ODN. Scale bar: 50 μm. (D) Effect of treatment with TRPA1 AS-ODN (0.5 nmol/μl–1/h–1) following CFA injection on CFA-induced cold hyperalgesia at days 1 and 3. Data represent mean ± SEM; n = 8 per group. *P < 0.05 compared with naive control. #P < 0.05 compared with MM-ODN (0.5 nmol/μl–1/h–1) group.
Noxious cold stimulation induces very rapid phosphorylation of p38 MAPK through the TRPA1 channel. Recent work has failed to reproduce cold responsiveness in TRPA1 in vitro (27). To investigate how TRPA1 can be activated by noxious cold stimulation in vivo, we examined the phosphorylation of p38 MAPK in the DRG 2 minutes after noxious cold stimulation. We did this because activation of p38 in primary afferents is involved in acute nociceptive processing by a nontranscriptional mechanism and examination of p-p38 is very useful as an indicator of the activated DRG neurons after noxious stimulation in vivo (28). We applied thermal stimulation by immersion of the hind paw of naive rats into cool to cold water (28°C, 16°C, and 4°C) and found that at 28°C, there was no increase in p38 phosphorylation in the DRG (Figure 9, A and B). However, noxious cold stimulation at lower temperatures (16°C and 4°C) increased the phosphorylation of p38 in the DRG, mainly in small-size neurons 2 minutes after stimulation. Double labeling showed that at 4°C, the majority of the p-p38–labeled neurons also expressed TRPA1 (Figure 9C). Furthermore, we found that pretreatment with AS-ODN but not MM-ODN inhibited noxious cold stimulation–induced p38 activation (Figure 9D), which suggests that the TRPA1 channel is required for p38 activation after noxious cold stimulation.
Activation of p38 MAPK in TRPA1-containing neurons by noxious cold stimulation. (A) p-p38 labeling in naive DRG and ipsilateral DRG 2 minutes after cold stimulation at 4°C. (B) Quantification of the percentage of p-p38–IR neurons after innocuous and noxious cold stimulation. (C) Double labeling for TRPA1 mRNA and p-p38–IR in naive DRG and ipsilateral DRG 2 minutes after cold stimulation at 4°C. Open arrows indicate double-labeled neurons. (D) Effect of pretreatment with TRPA1 AS-ODN (0.5 nmol/μl–1/h–1) on the percentage of p-p38–IR neurons after cold stimulation at 4°C. Data represent mean ± SD; n = 4 per group. *P < 0.05 compared with naive control. #P < 0.05 compared with MM-ODN (0.5 nmol/μl–1/h–1) group. Scale bars: 100 μm.
The present study demonstrates the following new findings: (a) CFA and SNL increased TRPA1, but not TRPM8, expression in trkA-expressing DRG neurons; (b) anti-NGF and SB203580 decreased the induction of TRPA1 and alleviated cold hyperalgesia after injection of CFA and SNL; (c) TRPA1 AS-ODN prevented and reversed only cold hyperalgesia after injection of CFA and SNL; (d) NGF, but not GDNF, increased TRPA1 expression in DRG neurons via p38 MAPK activation; (e) noxious cold stimulation induced p38 activation in TRPA1-containing neurons, but p38 activation was prevented by administration of TRPA1 AS-ODN.
Because of beneficial effects of cooling on pain, there have been few studies examining the underlying mechanisms of cold hyperalgesia after peripheral inflammation. However, cold hyperalgesia is often observed in patients suffering from rheumatoid arthritis (29), and noxious, but not innocuous, cold (< 10°C) induces an exaggerated response after CFA induces inflammation in rats (30, 31). We found that TRPA1, but not TRPM8, expression increased in trkA-expressing DRG neurons after inflammation and that the time course of the change in TRPA1 level in the DRG matched the emergence of enhanced sensitivity to cold (5°C). Furthermore, anti-NGF and SB203580 diminished this inflammation-induced cold hyperalgesia and TRPA1 upregulation. Because TRPA1 is activated by cold-range temperatures with a threshold of approximately 17°C, which is close to the reported noxious cold threshold (11, 12), these findings suggest that inflammation increases TRPA1 expression in DRG neurons via an NGF-induced p38 activation and that this induction of TRPA1 contributes to hyperalgesia to noxious, but not innocuous, cold stimulation.
We found that after inflammation, TRPA1-expressing neurons expressed SP and CGRP whereas TRPM8 did not colocalize with these nociceptive markers. Further, there was no overlap between TRPM8- and TRPA1-expressing neurons. Because our histological characterization does not address whether the number of active receptors changed, we cannot deny the possibility that TRPM8 may participate in inflammation-induced cold hyperalgesia. However, it seems likely that TRPA1 and TRPM8 are expressed in sensory neurons in 2 clearly distinct populations and might have different functional roles in pathological pain conditions. An unexpected finding in the present study was that neither inflammation nor NGF injection increased TRPM8 expression, although TRPM8 heavily colocalizes with trkA. Furthermore, TRPM8-expressing neurons did not coexpress TRPV1 after inflammation. In primary cultures, approximately 50% of the menthol-sensitive neurons also respond to capsaicin in the presence of NGF (11), and sensitivity to cold and capsaicin in these neurons was increased by NGF (32, 33). This discrepancy may be due to the high levels of NGF, which sensitize and upregulate TRPV1 levels, that are present in these cultures (6, 11). On the other hand, the percentages of TRPA1 and TRPM8 mRNA–positive neurons in the present study are much larger than those previously obtained in mouse DRG (3.6% for TRPA1 and 5–10% for TRPM8) (9–11). This discrepancy may be due to the species difference in ion channel expression between rat and mouse DRGs. Alternatively, another explanation is that there were differences in the criterion used to distinguish between positively and negatively labeled neurons (34).
Cold hyperalgesia is also a common feature of neuropathic pain, for which there is currently no effective therapy. In previous studies, much attention was focused on the directly damaged primary afferents and their influence on the activity of the dorsal horn neurons (35, 36). However, it is evident that the spared L4 DRG neurons and their fibers are also functionally important in the maintenance of neuropathic pain in the L5 SNL model (17, 18). For example, L4, but not L5, dorsal rhizotomy can reverse mechanical allodynia (37), and spontaneous activity in C fibers from the L4 spinal nerve has been recorded (38). A recent report of an in vitro study showed that after L5 SNL, the percentage of cold-responsive neurons increased in the uninjured neighbors of injured neurons, with no significant changes in the response properties (39). These observations are consistent with our data showing that L5 SNL increased TRPA1 expression in the uninjured L4 DRG.
We also found that both anti-NGF and SB203580 prevented L5 SNL–induced cold hyperalgesia. Wallerian degeneration following nerve lesion leads to an increase in cytokines and growth factors (40, 41). NGF content increases as early as 1 day after L5 SNL in the sciatic nerve, which contains both axotomized L5 nerves and spared L4 nerves (19).The MAPK family includes ERK, p38 MAPK, and JNK, and we recently demonstrated that L5 SNL induces activation of p38, but not ERK or JNK, in the L4 DRG through alterations in the target-derived NGF (20). Some reports have shown that deprivation of NGF does not attenuate cold hyperalgesia in other neuropathic pain models (42, 43). Nevertheless, our observations suggest that after L5 SNL, NGF is synthesized and released in the degenerative nerve fibers and acts upon nearby sensory fibers, inducing TRPA1 upregulation in the intact L4 DRG through the p38 MAPK pathway and thus increasing cold hyperalgesia.
The role of TRPA1 in cold transduction is still controversial; a recent report showed that TRPA1 was not activated by cooling to 4°C in vitro (27). Indeed, TRPA1 can be activated by stimulation other than temperature, such as mustard oils and a cannabinoid compound by bath application (12, 27). However, we found that TRPA1 AS-ODN reversed only cold hyperalgesia induced by inflammation and nerve injury. In addition, noxious cold stimulation induced a stimulus intensity–dependent p38 MAPK activation, predominantly in TRPA1-expressing neurons, which was prevented by administration of TRPA1 AS-ODN. Although it is possible that the phosphorylation of MAPK may not be an accurate reflection of activity (28, 44), our findings indicate that noxious cold stimulation is one of the most likely physiological activators of TRPA1 in vivo. Alternatively, other membrane proteins, such as K+ channels, Na+/K+ ATPases, and degenerin/epithelial sodium channels, may also be involved in transduction of signals mediating cold sensing (45).
We also cannot exclude the possibility that the results of the cold plate test may reflect a number of pathophysiological alternations in the spinal cord and the higher central nervous system, especially in the neuropathic pain model (46). For example, the effects of the p38 MAPK inhibitor on pathological pain can be mediated by the inhibition of p38 activation in the spinal cord (47, 48). However, several reports showed that p38 inhibition in the DRG occurred after intrathecal administration of SB203580, using the same dosage in the present study (20, 23). Furthermore, TRPA1 is specifically expressed in primary sensory neurons but not in the spinal cord or brain (6, 11). In fact, we demonstrated that pharmacologically preventing the induction of TRPA1 in DRG neurons attenuated cold hyperalgesia. Taken together, these results indicate that increased TRPA1 in primary afferent neurons probably has a crucial role in the pathogenesis of cold hyperalgesia after inflammation and nerve injury. Considering that TRPV1 upregulation in sensory neurons contributes to inflammation and nerve injury–induced heat hyperalgesia (8, 20), blocking TRPA1 and TRPV1 simultaneously may represent a new approach to effectively treating clinical inflammatory and neuropathic pain.
Animals. Male Sprague-Dawley rats weighing 200–250 g were used. All procedures were approved by the Hyogo College of Medicine Committee on Animal Research and were performed in accordance with National Institutes of Health guidelines on animal care. Rats that did not receive surgery (n = 8) were used as naive controls for immunohistochemistry, ISHH, and RT-PCR.
Surgical procedures. All procedures were performed with the rats under pentobarbital anesthesia (50 mg/kg, i.p.). For peripheral inflammation, the rats received a subcutaneous injection of 100 μl of CFA diluted 1:1 with saline into the plantar surface of the left hind paw. For partial nerve injury, we used the SNL model (26) with the following modification: the left L5 spinal nerve was tightly ligated and cut just distal to the ligature. In sham-operated rats, the nerve was exposed without ligation. Intrathecal delivery of 10 μl of NGF (1 μg or 10 μg; R & D Systems), GDNF (10 μg; R & D Systems), and the p38 inhibitor SB203580 (10 μg; Calbiochem) was performed as previously described (19). To obtain a sustained drug infusion, an ALZET osmotic pump (7 day pump, 1 μl/hr; DURECT) was filled with SB203580 (0.5 μg/μl) in 50% DMSO or anti-NGF antibody (1 μg/μl; Chemicon International) in saline, and the associated catheter was implanted intrathecally 12 hours before CFA injection or L5 SNL. The lack of effects of DMSO was determined in preliminary experiments, consistent with previous reports (49, 50). AS-ODN (5′-TCTATGCGGTTATGTTGG-3′), MM-ODN (5′-ACTACTACACTAGACTAC-3′), and FITC-labeled ODN directed to TRPA1 were designed and manufactured by BIOGNOSTIK. Although it has frequently been questioned whether ODN can reach DRG with sufficient concentration by intrathecal delivery, several reports have demonstrated that intrathecal ODN accumulates in DRG cells (51, 52). Therefore, AS-ODN (0.05 or 0.5 nmol/μl–1/h–1) and MM-ODN (0.5 nmol/μl–1/h–1) were delivered intrathecally by an osmotic pump either 12 hours before CFA injection or L5 SNL or 12 hours after CFA injection.
Stimulation. Cold (28°C, 16°C, and 4°C) stimulation was produced by immersion of the hind paw into a water bath (6 times in 10 seconds, interval 10 seconds, total 2 minutes). The survival time after stimulation in all experiments was 2 minutes. In an additional group of rats, either AS-ODN (0.05 or 0.5 nmol/μl–1/h–1) or MM-ODN (0.5 nmol/μl–1/h–1) was delivered intrathecally by an osmotic pump 24 hours before stimulation.
Behavioral analysis. Rats were habituated and basal pain hypersensitivity was tested before drug administration or surgery. Room temperature and humidity remained stable for all experiments. To estimate cold sensitivity of the paw, the cold plate test was performed as previously described (31, 46). Briefly, each rat was placed in a plastic cage with a Peltier plate (Neuroscience) kept at a cold temperature (5 ± 0.5°C). After 5 minutes of adaptation, the number of paw lifts in the next 5 minutes was recorded. Paw withdrawal latency to a noxious heat stimulus was measured using the Hargreaves radiant heat apparatus. Mechanical withdrawal thresholds on the plantar surface of the hind paw were measured with a Dynamic Plantar Aesthesiometer (Ugo Basile), which is an automated von Frey–type system. The threshold was taken as the force applied to elicit a reflex removal of the hind paw. Both latencies and threshold were determined as the mean of 3 measurements per paw (20).
Immunohistochemistry. The left L4/5 DRGs (16 μm) were cut and processed for trkA, SP, CGRP, TRPV1, TRPM8, and p-p38 immunohistochemistry according to previously described methods (53). The polyclonal primary antibodies were used in the following dilutions: trkA, 1:400 (Chemicon International); SP, 1:400 (DiaSorin); CGRP, 1:400 (Amersham Biosciences); TRPV1, 1:400 (Oncogene Science); TRPM8, 1:100 (developed by M. Tominaga, Okazaki Institute for Integrative Bioscience); and p-p38, 1:400 (Cell Signaling Technology).
ISHH. The procedure for ISHH was performed according to previously described methods (54). The rat TRPA1 and TRPM8 cRNA probes corresponding to nucleotides 302–788 and 264–837, respectively, were prepared. For the double labeling of TRPA1 or TRPM8 mRNA and trkA, SP, CGRP, TRPV1, or p-p38 protein, immunohistochemical staining of trkA, SP, CGRP, TRPV1 or p-p38 was performed using an avidinbiotinylated peroxidase complex (ABC) kit (Vector). Afterwards, TRPA1 and TRPM8 mRNA were detected using ISHH with a radioisotope-labeled probe as previously described (55). For the double labeling of TRPA1 and TRPM8 mRNA, we used dual ISHH with digoxigenin-labeled and 35S-labeled probes in the same sections as previously described (55). At least 1200 neurons from 4 rats were quantified for each AS probe in the single ISHH and the combined immunohistochemistry/ISHH study according to previously described methods (55).
RT-PCR. RT-PCR analyses were carried out according to previously described methods (20). PCR amplification was performed using Taq DNA polymerase (PerkinElmer) and primers specific for the following: Trpa1, 5′-CCCCACTACATTGGGCTGCA-3′ and 5′-CCGCTGTCCAGGCACATCTT-3′; Trpm8, 5′-GCCCAGAGCCAGCATATCGA-3′ and 5′-CCACAAGCAGCAGGTGGGTA-3′; and Gapd (GAPDH), 5′-TGCTGGTGCTGAGTATGTCG-3′ and 5′-GCATGTCAGATCCACAACGG-3′. The ratio of TRPA1 or TRPM8 to GAPDH mRNAs was considered to indicate the level of each transcript. The mRNA level was expressed as a percentage of the mRNA level in the normal control ganglia.
Statistical analyses. Differences of values between treatment groups were tested using 1-way ANOVA followed by individual post hoc comparisons (Fisher exact test) or pairwise comparisons (2-tailed Student's t test). P < 0.05 was accepted as significant.
This work was supported in part by Grants-in-Aid for Scientific Research and the Open Research Center grant, Hyogo College of Medicine, both from the Japanese Ministry of Education, Science, and Culture. This work was also supported by Grants-in-Aid for Researchers in Hyogo College of Medicine. We thank Yuki Obata and Nobumasa Ushio for technical assistance. We thank D.A. Thomas for correcting the English usage.
Nonstandard abbreviations used: AS, antisense; BDNF, brain-derived neurotrophic factor; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglion; GDNF, glial-derived NGF; ISHH, in situ hybridization histochemistry; MM, mismatch; NGF, nerve growth factor; ODN, oligodeoxynucleotide; p-p38, phosphorylated p38; SNL, spinal nerve ligation; SP, substance P; trkA, tyrosine kinase A; TRP, transient receptor potential.
Conflict of interest: The authors have declared that no conflict of interest exists.
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Elixir of Youth or just another hyped molecule?
If you have ever looked upon the internet for anti-aging serums and creams or read a dermatologist's interview, chances are high of you being familiar with the word "retinol". I am yet to meet a dermatologist who wouldn't swear by the anti-aging benefits of retinoid, (i.e. a common term for all Vitamin A derivatives including Retinol).
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Retinoids range from Retinyl Palmitate, Retinol, Retinaldehyde, Retinoic Acid (Tretinoin), in order of increasing strength, anti-aging potency and incidence of side effects.
Retinoids or retinol work on epidermal level by increasing the cell turnover. By exfoliating the surface layer of the skin it ends up smoothening the texture and decreasing pigmentation. The main action is however on the dermal level where it amplifies the collagen production (increasing the thickness of dermis) and induces the hyaluronic acid & glycosaminoglycan (moisture holding molecules) synthesis, hence leading to effacement of existing fine wrinkles and preventing formation of deep wrinkles. The diagram below entails the structure of the skin after and before usage of Retinol.
The drugstore or cosmoceutical creams contain retinyl palmitate (weakest & most tolerable), retinol (most common one) or retinaldehyde, while the retinoic acid (tretinoin) is available on dermatologist's prescription only.
Which one is the best, you would ask now?
Well the one that you are able to tolerate.
Its best to start with weaker formulations i.e. retinyl palmitate (dry, sensitive skin) or retinol (normal skin) and gradually build up the skin's tolerance to stronger formulas over next 6-9 months or may be a year for sensitive skins.
Some degree of redness, irritation and peeling is inevitable with retinoids but there are tricks to help you with that too. Start with twice weekly application and gradually amplify frequency to thrice weekly & then daily. Moisturizing beforehand or using a retinol product with hyaluronic acid is a good strategy as well. You might need a richer moisturizer than your regular one to deal with dry spots that might appear especially in more sensitive areas of face (corners of nose & mouth, around eyes & chin). Also make it a point not to skip the sunscreen when using retinol.
Which is the best age to start using retinol?
Though aging is thought to set in late 20's or early 30's, its never too early to start retinol, given today's hectic lifestyles and over-polluted atmosphere. Probably, bringing in your preventive aging regime in your mid 20's is a good thought. Start experimenting with retinol and find the ones that your skin loves.
My skin may not tolerate retinol, are there any alternatives?
Yes, some natural formulations with rose hip oil, sea fennel, lycopene, liquorice extract and bakuchiol (pronounced as buh-koo-chee-all) are claimed to have retinol like action which are gentler but as per studies none is as effective as retinol which is the best bet to boost collagen, fade dark spots, minimize large pores and smoother younger looking skin.


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search filter All ContentJournal of Palestine Studies
Book Review| May 01 2020
Review: Incarcerated Childhood and the Politics of Unchilding, by Nadera Shalhoub-Kevorkian
Incarcerated Childhood and the Politics of Unchilding
, by Nadera Shalhoub-Kevorkian.
. 174 pages. $110.00 cloth, $88.00 e-book.
Heidi Morrison
Heidi Morrison, associate professor of history at the University of Wisconsin, La Crosse, is the author of Childhood and Colonial Modernity in Egypt (London: Palgrave, 2015) and the volume editor of The Global History of Childhood Reader (New York: Routledge, 2012).
Journal of Palestine Studies (2020) 49 (3): 82–84.
https://doi.org/10.1525/jps.2020.49.3.82
Heidi Morrison; Review: Incarcerated Childhood and the Politics of Unchilding, by Nadera Shalhoub-Kevorkian. Journal of Palestine Studies 1 May 2020; 49 (3): 82–84. doi: https://doi.org/10.1525/jps.2020.49.3.82
There is a symbiotic and self-sustaining relationship between political violence and the abuse of children's rights, be it in India, Mexico, Australia, Europe, the United States, Canada, the Middle East and North Africa region, or elsewhere. Global and state power depend—among other sources—on the domination and exploitation of children. Thanks to groundbreaking work by Hebrew University's Lawrence D. Biele Chair of Law Nadera Shalhoub-Kevorkian, there is now a term to describe the process by which children serve as political capital (that is, expendable currency to affirm regimes of control and achieve government goals). This word is "unchilding." Terminology is crucial for drawing attention to important matters, as well as...
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