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|Illustration of an anencephalic fetus|
|Specialty||Medical genetics; pediatrics|
|Symptoms||Blind, deaf, unconscious, unable to feel pain|
|Usual onset||Embryonic development|
|Risk factors||Folate deficiency, antiepileptic medication, diabetes, excessive vitamin A, hyperthermia during pregnancy|
|Diagnostic method||Before birth: Suspected based on high levels of alpha fetoprotein in the mother, confirmed by ultrasound|
After birth: Examination
|Prevention||Folic acid supplementation|
|Frequency||1 in 7,500 births (USA)|
Anencephaly is the absence of most of the brain and skull as a result of issues during early development. Babies with the condition are blind, deaf, unconscious, and unable to feel pain. Reflexes such as breathing and responses to sound or touch may be present.
It is believed to result from a number of factors including folate deficiency, antiepileptic medication, diabetes, excessive vitamin A, and hyperthermia during pregnancy. It is a type of neural tube defect. The underlying mechanism involved failure of closure of the head end of the neural tube. Diagnosis before birth may be suspected based on high levels of alpha fetoprotein in the mother and confirmed by ultrasound.
Prevention is by supplementation of folic acid. The anti epileptic medication, valproate should be avoided during pregnancy, if possible. Treatment involves supportive care. If the baby is born alive, most die within a few hours or days of birth. About 1 in 7,500 births are affected in the United States.
Signs and symptoms
A baby born with anencephaly is usually blind, deaf, unaware of its surroundings and unable to feel pain. Although some individuals with anencephaly may be born with a main brain stem, the lack of a functioning cerebrum permanently rules out the possibility of ever gaining awareness of their surroundings. Reflex actions such as breathing and responses to sound or touch may occur.
Due to the presence of the brainstem, children with anencephaly have almost all the primitive reflexes of a newborn, responding to auditory, vestibular and painful stimuli. This means that the child can move, smile, suckle and breathe without the aid of devices.
The cause of anencephaly is disputed by medical professionals and researchers.
Folic acid has been shown to be important in neural tube formation since at least 1991, and as a subtype of neural tube defect, folic acid may play a role in anencephaly. Studies have shown that the addition of folic acid to the diet of women of child-bearing age may significantly reduce, although not eliminate, the incidence of neural tube defects. Therefore, it is recommended that all women of child-bearing age consume 0.4 mg of folic acid daily, especially those attempting to conceive or who may possibly conceive, as this can reduce the risk to 0.03%. It is not advisable to wait until pregnancy has begun, since, by the time a woman knows she is pregnant, the critical time for the formation of a neural tube defect has usually already passed. A physician may prescribe even higher dosages of folic acid (5 mg/day) for women having had a previous pregnancy with a neural tube defect.
In general, neural tube defects do not follow direct patterns of heredity, though there is some indirect evidence of inheritance, and recent animal models indicate a possible association with deficiencies of the transcription factor TEAD2. Studies show that a woman who has had one child with a neural tube defect such as anencephaly has about a 3% risk of having another child with a neural tube defect, as opposed to the background rate of 0.1% occurrence in the population at large. Genetic counseling is usually offered to women at a higher risk of having a child with a neural tube defect to discuss available testing. It is known that people taking certain anticonvulsants and people with insulin-dependent diabetes have a higher risk of having a child with a neural tube defect.
Relation to genetic ciliopathy
Until recently, medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying set of medical symptoms that are clinically visible in the disorders. Anencephaly is one such disease, part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and, thus, offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome, and some forms of retinal degeneration.
Anencephaly can often be diagnosed before birth through an ultrasound examination. The maternal serum alpha-fetoprotein (AFP screening) and detailed fetal ultrasound can be useful for screening for neural tube defects such as spina bifida or anencephaly.
Meroanencephaly is a rare form of anencephaly characterized by malformed cranial bones, a median cranial defect, and a cranial protrusion called area cerebrovasculosa. Area cerebrovasculosa is a section of abnormal, spongy, vascular tissue admixed with glial tissue ranging from simply a membrane to a large mass of connective tissue, hemorrhagic vascular channels, glial nodules, and disorganized choroid plexuses.
The most common type of anencephaly, where the brain has entirely failed to form, except for the brain stem. Infants rarely survive more than one day after birth with holoanencephaly.
The most severe type of anencephaly where area cerebrovasculosa and area medullovasculosa fill both cranial defects and the spinal column. Craniorachischisis is characterized by anencephaly accompanied by bony defects in the spine and the exposure of neural tissue as the vault of the skull fails to form. Craniorachischisis occurs in about 1 of every 1000 live births, but various physical and chemical tests can detect neural tube closure during early pregnancy.
There is no cure or standard treatment for anencephaly. Prognosis is extremely poor, as many anencephalic fetuses do not survive birth and infants that are not stillborn will usually die within a few hours or days after birth from cardiorespiratory arrest.
In almost all cases, anencephalic infants are not aggressively resuscitated because there is no chance of the infants ever achieving a conscious existence. Instead, the usual clinical practice is to offer hydration, nutrition, and comfort measures and to "let nature take its course". Artificial ventilation, surgery (to fix any co-existing congenital defects), and drug therapy (such as antibiotics) are usually regarded as futile efforts. Some clinicians and medical ethicists view even the provision of nutrition and hydration as medically futile.
In the United States, anencephaly occurs in about 1 out of every 10,000 births. Rates may be higher among Africans with rates in Nigeria estimated at 3 per 10,000 in 1990 while rates in Ghana estimated at 8 per 10,000 in 1992. Rates in China are estimated at 5 per 10,000.
Research has suggested that, overall, female babies are more likely to be affected by the disorder.
One issue concerning anencephalic newborns is organ donation. Initial legal guidance came from the case of Baby Theresa in 1992, in which the boundaries of organ donation were tested for the first time. Infant organs are scarce, and the high demand for pediatric organ transplants poses a major public health issue. In 1999, it was found that among children who die under the age of two, 30–50% do so while awaiting transplant. In order for infant organs to be viable and used for transplant, they must be removed while the infant still has circulation or very soon after circulation has ceased. However, this poses both legal and ethical issues. In the United States, all states have laws that forbid the removal of organs from a donor until after the donor has died, except in the case of altruistic living donations of a kidney or liver segment.
The goal of those in support of organ donation is that it will further contribute to the pool of suitable organs for transplants while the need for lifesaving organ transplants is so great. It has been estimated that 400–500 infant hearts and kidneys and 500–1,000 infant livers are needed in the United States each year. Because anencephalic neonates have partially functioning brain stems, they possess some brain stem reflexes such as spontaneous respirations. For this reason, these patients cannot be declared brain dead.
Within the medical community, the main ethical issues with organ donation are a misdiagnosis of anencephaly, the slippery slope argument, that anencephalic neonates would rarely be a source of organs, and that it would undermine confidence in organ transplantation. Slippery slope concerns are a major issue in personhood debates, across the board. In regards to anencephaly, those who oppose organ donation argue that it could open the door for involuntary organ donors such as an elderly person with severe dementia. Another point of contention is the number of children who would actually benefit. There are discrepancies in statistics; however, it is known that most anencephalic children are stillborn.
Proposals have been made to bypass the legal and ethical issues surrounding organ donation. These include waiting for death to occur before procuring organs, expanding the definition of death, creating a special legal category for anencephalic infants, and defining them as non-persons.
In the United Kingdom, a child born with anencephaly was reported as the country's youngest organ donor. Teddy Houlston was diagnosed as anencephalic at 12 weeks of gestation. His parents, Jess Evans and Mike Houlston, decided against abortion and instead proposed organ donation. Teddy was born on 22 April 2014, in Cardiff, Wales, and lived for 100 minutes, after which his heart and kidneys were removed. His kidneys were later transplanted into an adult in Leeds. Teddy's twin, Noah, was born healthy.
Neocortical death, similar to a persistent vegetative state (PVS), involves loss of cognitive functioning of the brain. A proposal by law professor David Randolph Smith, in an attempt to prove that neocortical death should legally be treated the same as brain death, involved PET scans to determine the similarities. However, this proposal has been criticized on the basis that confirming neocortical death by PET scan may risk indeterminacy.
Anencephaly can be diagnosed before delivery with a high degree of accuracy. Although anencephaly is a fatal condition, the option of abortion is dependent on the abortion laws in the state. According to a 2013 report, 26% of the world's population reside in a country where abortion is generally prohibited.  In 2012, Brazil extended the right of abortion to mothers with anencephalic fetuses. This decision is, however, receiving much disapproval by several religious groups.
The case of baby Theresa was the beginning of the ethical debate over anencephalic infant organ donation. The story of baby Theresa remains a focus of basic moral philosophy. Baby Theresa was born with anencephaly in 1992. Her parents, knowing that their child was going to die, requested that her organs be given for transplantation. Although her physicians agreed, Florida law prohibited the infant's organs from being removed while she was still alive. By the time she died nine days after birth, her organs had deteriorated past the point of being viable.
United States uniform acts
The Uniform Determination of Death Act (UDDA) is a model bill, adopted by many US states, stating that an individual who has sustained either 1) irreversible cessation of circulatory and respiratory functions or 2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. This bill was a result of much debate over the definition of death and is applicable to the debate over anencephaly. A related bill, the Uniform Anatomical Gift Act (UAGA), grants individuals and, after death, their family members the right to decide whether or not to donate organs. Because it is against the law for any person to pay money for an organ, the person in need of an organ transplant must rely on a volunteer.
There have been two state bills that proposed to change current laws regarding death and organ donation. California Senate Bill 2018 proposed to amend the UDDA to define anencephalic infants as already dead, while New Jersey Assembly Bill 3367 proposed to allow anencephalic infants to be organ sources even if they are not dead.
Some genetic research has been conducted to determine the causes of anencephaly. It has been found that cartilage homeoprotein (CART1) is selectively expressed in chondrocytes (cartilage cells). The CART1 gene to chromosome 12q21.3–q22 has been mapped. Also, it has been found that mice homozygous for deficiency in the Cart1 gene manifested acrania and meroanencephaly, and prenatal treatment with folic acid will suppress acrania and meroanencephaly in the Cart1-deficient mutants.
- "Anencephaly Information Page | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 10 January 2021.
- Tafuri, SM; Lui, F (January 2020). "Embryology, Anencephaly". PMID 31424828. Cite journal requires
- "Anencephaly". NORD (National Organization for Rare Disorders). Retrieved 10 January 2021.
- "Anencephaly Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". Archived from the original on 2 December 2016. Retrieved 2016-12-02.
- DIAMENT, Aron (1996). Neurologia Infantil. 3ª Edição. São Paulo: Atheneu. p. 745.
- Luyendijk, W; Treffers, PD (1992). "The smile in anencephalic infants". Clinical Neurology and Neurosurgery. 94 Suppl: S113-7. doi:10.1016/0303-8467(92)90042-2. PMID 1320482.
- Centers for Disease Control (CDC) (1991-08-02). "Use of folic acid for prevention of spina bifida and other neural tube defects--1983-1991". MMWR. Morbidity and Mortality Weekly Report. 40 (30): 513–516. ISSN 0149-2195. PMID 2072886.
- "Lancet 1991; 338:8760:131-137". www.sjsu.edu. Archived from the original on 2018-04-08. Retrieved 2018-12-10.
- Ratcliffe, Stephen D., ed. (2008). Family medicine obstetrics (3rd ed.). Philadelphia: Mosby Elsevier. ISBN 978-0-323-04306-9.[page needed]
- Shaffer, Lisa G.; Marazita, Mary L.; Bodurtha, Joann; Newlin, Anna; Nance, Walter E. (1990). "Evidence for a major gene in familial anencephaly". American Journal of Medical Genetics. 36 (1): 97–101. doi:10.1002/ajmg.1320360119. PMID 2333913.
- Kaneko, Kotaro J.; Kohn, Matthew J.; Liu, Chengyu; Depamphilis, Melvin L. (2007). "Transcription factor TEAD2 is involved in neural tube closure". Genesis. 45 (9): 577–87. doi:10.1002/dvg.20330. PMC 2765819. PMID 17868131.
- Cowchock, S.; Ainbender, E.; Prescott, G.; Crandall, B.; Lau, L.; Heller, R.; Muir, W. A.; Kloza, E.; et al. (1980). "The recurrence risk for neural tube defects in the United States: A collaborative study". American Journal of Medical Genetics. 5 (3): 309–14. doi:10.1002/ajmg.1320050314. PMID 7405962.
- "Archived copy". Archived from the original on 2011-03-04. Retrieved 2011-04-01.CS1 maint: archived copy as title (link)[full citation needed]
- "Anencephaly". Genetics Home Reference. National Institutes of Health. 22 August 2011. Archived from the original on 2011-08-05. Retrieved 28 August 2011.
- Badano, Jose L.; Mitsuma, Norimasa; Beales, Phil L.; Katsanis, Nicholas (2006). "The Ciliopathies: An Emerging Class of Human Genetic Disorders". Annual Review of Genomics and Human Genetics. 7: 125–48. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803.
- Joó JG, Beke A, Papp C, et al. (2007). "Neural tube defects in the sample of genetic counselling". Prenat. Diagn. 27 (10): 912–21. doi:10.1002/pd.1801. PMID 17602445.
- Cedergren M, Selbing A (2006). "Detection of fetal structural abnormalities by an 11-14-week ultrasound dating scan in an unselected Swedish population". Acta Obstetricia et Gynecologica Scandinavica. 85 (8): 912–5. doi:10.1080/00016340500448438. PMID 16862467.
- Isada, Nelson B.; Qureshi, Faisal; Jacques, Suzanne M.; Holzgreve, Wolfgang; Tout, Mary Jo; Johnson, Mark P.; Evans, Mark I. (1993). "Meroanencephaly: Pathology and Prenatal Diagnosis". Fetal Diagnosis and Therapy. 8 (6): 423–8. doi:10.1159/000263862. PMID 8286034.
- Murlimanju, N; Vishal, K; Maligi, AM; Naveen, NS (2010). "Craniorachischisis totalis". Journal of Neurosciences in Rural Practice. 1 (1): 54–5. doi:10.4103/0976-3147.63108. PMC 3137839. PMID 21799625.
- Gilbert, Scott F. (2010). Developmental biology (9th ed.). Sunderland, Mass.: Sinauer Associates. p. 338. ISBN 978-0878933846.
- "Anencephaly". PubMed Health. May 1, 2011. Archived from the original on 2014-03-28. Retrieved 2017-10-31.
- Neural Tube Defects : From Origin to Treatment: From Origin to Treatment. Oxford University Press. 2005. pp. 125–126. ISBN 9780199775149. Archived from the original on 2016-01-31. Retrieved 2015-08-09.
- Timson, J. (1970). "The sex ratio in anencephaly". Genetica. 41 (3): 457–65. doi:10.1007/BF00958926. PMID 4922971.
- Bard, Jennifer S. (1999). "The diagnosis is anencephaly and the parents ask about organ donation: Now what? A guide for hospital counsel and ethics committees". Western New England Law Review. 21 (1): 49–95. PMID 12774804. Archived from the original on 2014-03-26. Retrieved 2012-07-20.
- Meinke, Sue (June 1989). "Anencephalic Infants as Potential Organ Sources: Ethical and Legal Issues" (PDF). National Reference Center for Bioethics Literature. Archived (PDF) from the original on 2012-05-22. Retrieved 19 July 2012. Cite journal requires
- Glasson, John; Plows, Charles W.; Clarke, Oscar W.; Cosgriff, James H.; Kliger, Craig H.; Ruff, Victoria N.; Tenery, Robert M.; Wilkins, George T.; et al. (1995). "The Use of Anencephalic Neonates as Organ Donors". JAMA. 273 (20): 1614–8. doi:10.1001/jama.1995.03520440068039. PMID 7745776.
- Ahmad, Ferhaan (1992). "Anencephalic infants as organ donors: Beware the slippery slope". CMAJ. 146 (2): 236–241, 244. PMC 1488368. PMID 1735049.
-  Archived 2018-05-28 at the Wayback Machine. BBC News. Retrieved on 2015-04-23.
- "Archived copy" (PDF). Archived (PDF) from the original on 2013-10-15. Retrieved 2013-10-15.CS1 maint: archived copy as title (link)
- Beresford, H. Richard (July 1996). "Ethics in Neuroscience: Mind over Matter" (PDF). Indiana University. Archived from the original (PDF) on November 1, 2005.
- "The World's Abortion Laws Map 2013 Update" (PDF). Archived (PDF) from the original on 2015-12-02. Retrieved 2015-11-30.
- "Anencephaly in Brazil: A New Decision, Old Issues". Archived from the original on 13 May 2012. Retrieved 19 July 2012.
- Rachels, James. "What is Morality" (PDF). Archived (PDF) from the original on 2014-12-14. Retrieved 19 July 2012.
- "Uniform Declaration of Death Act (UDDA)". Archived from the original on 2013-09-06. Retrieved 2013-08-23.
- Chen, Chih-Ping (2008). "Syndromes, Disorders and Maternal Risk Factors Associated with Neural Tube Defects (III)". Taiwanese Journal of Obstetrics and Gynecology. 47 (2): 131–40. doi:10.1016/S1028-4559(08)60070-4. PMID 18603496.
- Zhao, Qi; Behringer, Richard R.; De Crombrugghe, Benoit (1996). "Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene". Nature Genetics. 13 (3): 275–83. doi:10.1038/ng0796-275. PMID 8673125.

domain: biology


text:
Cinderella escapes from her fairy tale, determined to lose her virginity with a handsome man in the mortal world! But Derek, king of the book realm of IsBn, vows to hunt her down. Her rebellion has stirred up other fictional characters. Derek decides he will seduce Cinderella and send her back to the story, restoring order once more.
Cinderella loathes the idea of scrubbing the castle floors and marrying a nancy boy prince. She'd much rather own a condominium, shop at Neiman Marcus, and be an electrician. But when she meets Derek reading a book by the condo's hot tub, she falls head over glass slipper heels.
Once he sets eyes upon the lovely cinder wench, Derek is lost in a haze of wild, uncontrollable desire. When the queen of the ash heap makes love with the king of all fiction, their passion turns into a raging inferno that threatens to scorch the very pages of the book world.

domain: artistic


text:
MySpace names Oz rockers AC/DC as world’s best band
Melbourne: Australian rock band AC/DC has been named as the best band in the world by MySpace.
Second on the list, which was released on October 7, was American rock band Nirvana followed by Red Hot Chilli Peppers in third place and the Beatles in fourth.
Surprisingly, the Rolling Stones failed to make the top ten bands.
U2 and Led Zeppelin also just made it on to the list, closing the ranks at number 9 and 10.
MySpace Content Manager, Dan Stapleton, said the results have highlighted the wide taste in music.
“These results demonstrate just how diverse MySpace’s user base is, and highlights Myspace as an entertainment destination that caters to all tastes in music,” the Herald Sun quoted him as saying.
“We’ve also taken the liberty of creating playlist for each of the Top Tens, so fans can listen to and share tracks by all their favourite artists,” he stated.
The top ten bands that made it to the list were:
3 Red Hot Chilli Peppers
5 Guns N Roses
10 Led Zeppelin
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domain: entertainment


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Front - Raw.


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CHAPTER 1 PAGE 1:
Alcohol Drugs Accident Prevention Training Course (ADAPT)
Introduction and Directions:
In 1989, the Florida Legislature passed section 322.095 of the Florida Statute. This Statute requires all First-Time applicants for a Florida Driver's License to attend a Traffic Law and Substance...
Technical Assistance Publication (TAP) Series
U.S. Department of Health and Human Services Substance Abuse and Mental Health Services Administration Center for Substance Abuse Treatment 1 Choke Cherry Road Rockville, MD 20857
A number of people deserve recognition for...
Alcoholism is a huge problem in the United States. How many times have you heard about the consequences of alcoholism? Alcoholism is one of the major problems in society today. Alcoholism has no age, no color or no size anyone can abuse the use of alcohol. Alcoholism is the extreme use of alcohol also known as...
violence” is heard, it is most likely that acts of physical abuse would enter the individual’s mind. It is essential to affirm that domestic violence refers to many forms of abusive behaviour, including emotional, sexual and economicabuse. Many individuals today, especially of female gender, are likely...
Tools for Analysing the Remote Environment Significance of Analysing the Remote Environment Tools for Analysing the Company Specific Industry Significance of Analysing the Industry Environment Tools for Analysing the Operating Environment Significance of Analysing the Operating Environment Analysing the Overall...
consequences and prohibition of certain drugs it’s highly relevant to consider all aspects which may be affected by this decision. What are the primary elements which may be deemed as a consequence. The salient factors are prohibition of drugs and the involvement of the criminal justice system, an increase...
homelessness or youth at risk of homelessness vary and include Domestic violence, a shortage of affordable housing , family breakdown, drug and alcoholabuse and in Mandy’s case Mental Illness. People at risk of being homeless are some of the most vulnerable and marginalized groups in our community....
or permanently disabled reminding them of the choices that they made when they decided to take that drink and then drive. It is a known factor that alcohol is a depressant that slows the nervous system down causing reaction time to be slower, decreases alertness, poor judgment, inattentive comprehension...
This chapter will cover the background of the study, problem statement and focus on the objectives and also the research question in order to get full findings of this study. It is also as the overview of what basically this study is all about. It...
Keywords: Health related behaviour, brief intervention, alcohol, stages of change, intervention mapping.
The health of people depends widely on their behaviour. Targeting unhealthy behaviours depends upon a number of factors since the health practitioner needs to take into account the beliefs...
Journal of Substance Abuse Treatment 46 (2014) 541–545
Contents lists available at ScienceDirect
Journal of Substance Abuse Treatment
The affordable care act and treatment for “Substance Use Disorders:” Implications of
ending segregated behavioral healthcare
A. Thomas McLellan...
4.Arguments and discussions3
5.In opposite to most European Countries (here Belgium)6
6.Courvoirsier – An example of responsible alcohol advertising7
IntroductionAlcohol abuse is becoming more...
LEARNING UNIT 1:
CONCEPTS AND THEORIES/MODELS IN COMMUNITY HEALTH
Theoretical thinking as a language
Choosing a theory/model to apply to community health
The dimensions model of community health nursing
Orem's self-care deficit theory...
Table of Contents
- Background 3
- Statement of the Problem4
- Objectives of dissertation research 5
- Specific research questions 5
- Assumptions and limitations 6
- Definition of Terms...
Intoxication with alcohol and drugs is commonly associated with crimes of violence. The relationship between intoxication and criminal culpability is complex especially if a mental condition legal defence is being considered. The apparent stimulating effect of alcohol is due solely to the fact...
weakens educators’ abilities to
recognize giftedness in its various forms (Ford & Grantham, 2003). The most devastating brand of this
sort of deficit thinking emerges when we mistake difference—particularly difference from ourselves—
for deficit. If one concentrates best while sitting still it may be difficult...
Alcohol the Legal killer
Alcohol is an ordinary name for a substance which is chemically known as ethyl alcohol, pure spirits or grain alcohol. Ethyl alcohol is a kind of wine which is produced for medical and other purposes. Alcohol drink is every beverage that has ethyl alcohol intoxicating quantities...
A. Statements of the Study 3
B. Scope of the study 4
C. Significance of the study 5
D. Definition of terms 6
Part III Main Discussion
Drug Addiction 45
Drug Problems in the Philippines 46
Drug Withdrawal 52 Drug Rehabilitation 53
Drug addiction in our society is a very difficult problem to tackle. It has so many detrimental repercussions throughout society. For the addict it can harm their mental and physical health, their financial wellbeing, pain and suffering due to quality of life being reduced, their social construct, family...

domain: psychology


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Showing April 6, 2012 on ESPN3Watch Upcoming EventApril 06, 2012


Sample MetaScenario: A Category 5 hurricane on the scale of Hurricane Andrew is fast approaching southern Florida, forcing mass evacuations in preparation for landfall. Even as the state takes its normal actions, hospitals across Florida and surrounding states are reporting unusually high numbers of patients exhibiting symptoms of a fatal and fast-spreading illness of unknown origin. Compounding both of these issues is a large population of non-English speaking residents and large elderly and disabled community. Clearly, both the pending hurricane and the rapidly spreading illness are critical priorities. All hospitals are full or in the hurricane path. Forty percent or more of the first responders are, or soon will, exhibit signs of illness, further weakening the resources typically used to help and further taxing the system. As the hurricane makes landfall, 7 million people across Florida are in an evacuation zone. Over 190,000 people are dead from the mystery illness, which is now believed to be food-born and not contagious, but still the source is unknown. Another 265,000 are requiring immediate medical attention. Furthermore, transportation workers, utility workers, and other key response workers are among those impacted by the illness, and are unable to keep up with power outages and other infrastructure failures.
Medical Response: After reading the above scenario, tell us how you think the private sector could support a rapid and widespread medical response in the first 72 hours, assuming all hospitals are full and healthcare professionals are beyond their capacity. Examples of how the government can work with the private sector to establish a more effective national capability to treat, stabilize, and provide for 265,000 casualties of this or another catastrophic event.
All of topics are designed to stimulate creative, out-of-the box thinking. We welcome your thoughts, ideas, or suggestions on all of the topics.
Global Peace Partners, bridges the turbulent waters of political, religious, cultural and social boundaries through medical diplomacy. Taking the lead before disaster strikes, our Care Convoy delivers Search, Rescue and Medical Equipment to enable nations to be better prepared for the disasters growing in frequency and intensity around the world.
Currently... more »
Stockpile resource - Pre arrange with local venders for supplies and equipment to ensure supply to these temporary facilities with MOI's and basic predetermined items.
Sister cities concept for EMS - Form a national program for EMS agencies as well as All Responder agencies that would create a network of sister cities. the agencies would be paired with 2 other comparable sized agencies and jurisdictional... more »
• Generate capacity lists from above as sites come on line
• Alert mutual aid partners and intrastate Mutual aid partners and confirm resources available to be brought in for medical transport to above facilities in addition, bring in any personal supplies such as food and bedding for those responding... more »
• Alert the following facilities that they may be called upon to house and shelter casualties... (pre selected and identified on county resource - annex list taken from their EOP's )
- Minimum security jails and detention centers
- Outpatient surgical centers
- Urgent care centers
- Large Inland hotels (with backup power systems to maintain operations )
• Activate the above facilities Using a modified COOP... more »
Fact and assumptions:
Major Resource and Demographic issues:
• Non-English speaking
• Large elderly and disabled community
• All hospitals are full or in the hurricane path
• Forty percent or more of the first responders are, or soon will... more »


Mumbai: Salman Khan and Arijit Singh had a fallout in 2016 since Arijit was roped in to sing ‘Jag Ghoomeya’ from ‘Sultan’, but Rahat Fateh Ali Khan’s voice ended up being added to the song.
It looks like Arijit has moved over it, as he not only sung Salman Khan’s ‘Tiger Zinda Hai’ song ‘Dil Diyan Gallan’ at a recently held event in Pune.
Arijit sung the song twice at the event, calling it a fan moment. ‘Dil Diyan Gallan’ was originally sung by Pakistani sensation Atif Aslam.
Directed by Ali Abbas Zafar, also starring Katrina Kaif, ‘Tiger Zinda Hai’ released in Christmas 2017, a few days after the Virushka wedding.


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By: Jim Philhower, Director Of Sales And Leadership Development, Henry Schein Dental
As dental benefits shift to PPOs and reimbursement rates continue to shrink, many offices are struggling with increasing overhead and decreasing cash flow and profit margins. Coding correctly is critical for maximizing reimbursement, increasing cash flow, and minimizing errors that could result in fines or worse. A thorough coding review should be conducted each year. Here are four places to start.
1. Fluoride Codes D1208 and D1206
Fluoride codes D1203 and D1204 for child and adult fluoride treatments were replaced with code D1208, which is used for child and adult applications. Many offices reporting the old codes are, most likely, not being reimbursed for the procedures.Restrictions to the fluoride varnish code D1206, which limited it to patients with moderate to high caries risk, have been eliminated. D1206 is applicable for child and adult reporting and pays a higher UCR than D1208.
2. D0140: Limited Oral Evaluation – Problem Focused or D9110 Palliative (Emergency) Treatment of Dental Pain
D9110 is an under-utilized code. Overwhelmingly, offices code D0140 for emergency visits when treating a patient for pain or discomfort. D0140 is an evaluation code and limited to “one evaluation per six months” or “two evaluations per year” rule. Consider reporting D9110 for minor non-definitive procedures to reduce discomfort, sensitivity, or pain at an emergency visit. D9110 is a procedure code and will not use one of the exam limitations. This palliative code pays a higher UCR than D0140. When reporting D9110, include the required narrative. Palliative D9110 should not be used in conjunction with a definitive procedure.
3. D0180: Comprehensive Periodontal Evaluation– New or Established Patient
This evaluation code may be reported for established periodontal patients, patients showing signs or symptoms of periodontal disease, and for patients with risk factors such as smoking and diabetes. D0180 requires a complete and detailed periodontal evaluation, including full-mouth probing and detailed charting. D0180 may be reported at the same visit as a D4910. However, it may be downgraded to a D0120 fee. Do not report D0180 in addition to a D0150 comprehensive evaluation. D0180 usually pays a slightly higher UCR than D0150.
4. D1352: Preventative Resin Restoration in a Moderate to High Caries Risk Patient– Permanent Tooth
D1352 is a conservative restoration of an active cavitated lesion in a pit or fissure that does not extend into dentin, and includes placement of a sealant in any radiating noncarious fissures or pits. Do not report this preventive type resin restoration if the prep and decay extend into dentin. See D2391 for one-surface composite. Do not report this preventative restoration if there is no active decay in the enamel. See D1351 for sealant. Do not report D1352 for a primary tooth. According to Dr. Charles Blair, some plans will pay more than two times the fee for a sealant but less than a one-surface composite and some plans will pay the alternate sealant benefit.
For a thorough coding review, visit www.henryscheinbusinesssolutions.com/practiceanalysis and request a practice analysis.

domain: medical


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The 'Angry Birds' movie trailer is not a great way to relax
Look, we all knew this was coming. Let's just sit down for two minutes and 36 seconds and get through the first trailer for The Angry Birds Movie together, OK?
The animated offshoot of Rovio's smash-hit mobile game series (get it? Because you smash things by throwing irate avians at them) has been in development since 2013 and is set for release 20 May 2016. When it was originally announced, it was said Rovio wanted the long window to make sure they got the story right.
We'll just leave that comment right there.
From the looks of the trailer, the movie could almost be inspired by Woody Allen's oeuvre -- Red is a down on his luck bird doing bird things, frustrated by the little things in life. He's angry, almost. And a bird. His disenfranchisement with contemporary society leaps from the screen. He has friends though, most of whom you'll have flung at porcine constructs that wouldn't pass even a cursory health and safety inspection. Their seemingly idyllic island life is interrupted when the nefarious green pigs arrive though. The trailer doesn't show it, but we can only presume that internecine warfare ensues.
The Angry Birds Movie's voice cast includes Jason Sudeikis as main bird Red, Josh Gad as Chuck, Danny McBride as Bomb, Peter Dinklage as the Mighty Eagle, Maya Rudolph as Matilda, and Bill Hader as Leonard, a long-suffering pig lackey. Comedian Keegan-Michael Key and soon-to-be-Ghostbuster Kate McKinnon also appear. The film is directed by Clay Kaytis and Fergal Reilly, and written by Simpsons scribe Jon Vitti.
We have many questions regarding the movie, but the most pressing is why is Michael Jackson the musical focus? Bad, a song that came out in 1987, plays throughout the trailer. Most kids now probably think Angry Birds itself is ancient, and that was released six months after Michael Jackson died. Will the target audience even know who he is? Do kids want to be "bad" any more? Wouldn't it at least make more sense to use the track for a Bad Piggies movie than an Angry Birds one?
These and many other mysteries will hopefully be answered in cinemas next spring.


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Which a single is the greatest kind of tile for your subsequent project?
Ceramic tiles are excellent for wall tiling, the bulk of kitchen splash backs are carried out in a ceramic tile. These dimensions are typically 100mm x 100mm or 200mm x 100mm. The reason for the dimensions is due to the fact of the kitchen sockets.
Ceramic tiles are also a little bit hotter than porcelain tiles. This is since they are additional porous. This makes them a great alternative for bathroom partitions as you will not get fairly so a great deal condensation gathering on your tiles soon after a sizzling shower. Ceramic tiles are also generally less expensive to purchase, appear in far more styles and are less costly to install owing to getting simpler to slash and in good shape.
The only spot ceramic tiles lose out to porcelain is in its toughness, porcelain wins by a extended way in this area.
Porcelain tiles are a great deal more robust creating them the perfect choice for floor tiling. Primarily when it will come to tiling about a flexible picket floor which you would commonly uncover in a bathroom.
The most frequent measurements for porcelain floor tiles are 600mm x 600mm or 600mm x 300mm.
To sum up we would usually often advise ceramic tiles for the walls and porcelain for the floor.
For much more facts, assist with designs or a no cost quotation be sure to never hesitate to get hold of us currently through our web site AG Tiling Northampton or contact us via
e mail firstname.lastname@example.org
We protect the greater part of Hampshire and Northampton and are now based mostly in Fleet.

domain: design


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Effect Code Special course Hold Select and press Left on the course selection screen.
Effect Code Get $50,000 Hold Select and press II on the course selection screen.
Effect Code See winning time Hold Select and press Right on the course selection screen.
Effect Code Music select Hold Select and press I or II while the game is paused
Track Select (Japanese Version)
At the intro, where it shows the cars racing, hold the following buttons:
Effect Code Alternative Brazil Goiania Course Hold Down + II and press Run Alternative USA Laguna Seca Course Hold Down + I and press Run Brazil Goiania Course Hold Up + II and press Run Suburb Course Hold I + Select and press Run Trap Course Hold I + II and press Run USA Laguna Seca Course Hold Up + I and press Run
Contributed By: ReyVGM.
Effect Password Sound test Input MUSIC or ART88 as a player name.
Know Something We Don't?
You can submit new cheats for this game and help our users gain an edge.
Have We Been Fooled?
You can submit a problem report for any non-working or fake code in the lists above.

domain: game


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Original Steam Engine Name Plates (Various)
A selection of name plates available from a huge collection, which includes original builders name plates from UK built road railway steam engines. Please enquire for details.
Selection of Pre-War Lorry Wheels and Tyres
Some 24 assorted pressed wheels and tyres, from Sentinel and other pre-war lorries, most ex-Liverpool docks.

domain: hobby


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Top of Mind with Julie Rose - Radio Archive, Episode 176 , Segment 5
Episode: Cheatgrass, Marriage and Health, Smart Grids, Digital Education
- Nov 10, 2015 10:00 pm
- 22:14 mins
Guest: David Wiley, PhD, Education Fellow at Creative Commons, Adjunct Faculty in Brigham Young University's graduate program in Instructional Psychology and Technology, Co-founder and Chief Academic Officer of Lumen Learning The average college textbook will run you about 100 bucks – some are much more. And the reliance on those big heavy, worth-their-weight-in-goal texts hasn’t changed, even as just about everything else in our lives has gone digital. But there is a movement afoot to make open source, digital textbooks the norm in college. Several recent studies find students can learn just as much from the open, digital textbook and get grades that are just as high as their peers using the old-school $100-a-pop textbook.

domain: library


We’ve hit the week where cuts are happening and preseason games means make of break for those fighting for a roster spot. The Chicago Blackhawks preseason schedule kicks off this week and there’s plenty of names vying for a spot on that final roster. Thursday begins that process.
Some teams have already gotten closer to their decision making. In Detroit, top prospect Simon Edvinsson is first to point to himself for not making it last year. Will it change this year?
As we draw closer to the season, there will be predictions, analysis on the past and how it correlates to this season, and with the rebuild. I’ll be there Thursday for the game against the Blues and the other home games as well. But each game will come with in-depth coverage on a number of different angles. We can all watch the recaps–but let’s see what else was there that might have been missed.
Blackhawks In Case You Missed It
- Blackhawks by the Numbers looks at the goal differential since the playoff team in 2020. It won’t be surprising, but some of the analysis put into context certainly is interesting
- The Blackhawks wrap wishes a preseason’s greeting to everyone–as real hockey is finally around the corner
- Taylor Hall’s words show that general manager Kyle Davidson’s vision of leadership is right on target
Hockey Now Network
Boston Hockey Now: Prospect Brandon Bussi isn’t going to break camp with the Boston Bruins. But he’s enjoying the moment as he’s up there now.
Detroit Hockey Now: Simon Edvinsson is one of the Detroit Red Wings best prospects. He also points to himself as the reason he’s not playing full time in the Motor City yet. On his attitude and how he plans to crack the lineup this season.
Florida Hockey Now: Gracyn Sawchuk is making his preseason debut for the Florida Panthers. The 2023 second-round pick is looking to make some noise and showing that the “small guy” isn’t afraid of anyone.
Montreal Hockey Now: Many Montreal Canadiens fans howled when the Habs took David Reinbacher in the 2023 NHL Draft. He’ll be a top pairing defenseman in today’s preseason tilt–maybe they’ll be howling for different reasons if he turns out to be the real deal down the road?
San Jose Hockey Now: Henry Thrun nets two in the San Jose Sharks victory over the Vegas Golden Knights


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Food Network Staffers Share Their 2020 Food Resolutions
Here's what we're doing (and eating) in 2020.
Get The All-New Food Network Kitchen App
Download Food Network Kitchen now to sign up and take advantage of the latest offer and get 40+ live classes a week, hundreds of on-demand cooking classes, in-app grocery ordering and so much more.
With 2020 just a few short days away, there's no better time than now to reflect on the past year and think ahead. Whether you're looking to change up your diet or perfect a new technique in the kitchen, food-based resolutions are a great way to ensure your year kicks off on the right note. This week, we asked Food Network staffers to share their resolutions for 2020. From eating less sugar and meat, to throwing picnics in the living room, here's what they had to share. Happy New Year!
Another Year of Whole30
I always love to start the year with Whole30. It’s challenging but it’s my third year now and I find that it’s the best way to start the year. Once I slay my sugar dragon, I have SO much more energy to attack those simple tasks. By the end of the month, my apartment is more organized, projects are done and I’m feeling great. It is tough, though. I love meeting up with friends for happy hour so being on Whole30 makes socializing difficult, but others are doing Dry January and similar diets that so that makes it feel slightly easier. Then at the end of the month, I eat way less sugar and far more veggies and it’s all been worth it. Helps me appreciate each food more and realize what types of foods my body appreciates.
- Laura Eshelman, Supervising Producer
Eat Less Meat
Like so many other people (probably many on this list!), I’m planning to eat more vegetables and less meat in the new year — not only for the sake of my body, but also the planet. This means I’m already knee deep in recipes like this Tex-Mex Tofu Bowl, these Smoky Roasted Mushrooms, and this (admittedly indulgent) Mushroom-Spinach Baked Egg Casserole. Luckily, I’ve never met a crunchy salad I don’t like and I’m putting some new ones in rotation, like this Carrot-Coconut Salad and this Pear and Fennel Salad. And I plan on using this delicious Kale Salad Dressing on everything — kale or not!
- Lygeia Grace, Director, Culinary Editorial
Cut Back on Sugar
For the past few years, I’ve tried to start the Whole30 diet in January with minimal success. Cutting out gluten, dairy, sugar, legumes and more becomes too daunting, and after a week of stressful mealtimes, I cave and eat all the cheese. This year, instead of trying to give up everything all at once, I’m picking one “bad” thing to cut back on: added sugar. After a December full of cookies, chocolate and cocktails galore, I’m hoping to keep my sugar crashes to a minimum to start 2020. These Banana and Peanut Butter Dippers are a great place to start.
- T.K Brady, Senior Editor
Use Up Pantry Condiments
My fridge and pantry are wastelands of mostly full oil bottles, mustard jars and assorted nut butters. I resolve to figure out better ways to use them while they’re still good, creating more salad dressings, vegetable sautés and improv dishes utilizing what I have at hand. Molly Yeh’s Magic Sauce is just the ticket, calling for tahini, soy sauce, sesame oil and honey in one fell swoop, which she uses to coat crisp-tender green beans. Take that, pantry stalwarts!
- Erin Hartigan, Senior Managing Editor
Throw More Indoor Picnics
I resolve to have more indoor picnics with my 3-year-old son. He adores when we spread out a blanket on the living room floor and graze on platters of room temperature goodies. He’s less picky and eats healthier — plus we get to look for pretend ants.
- Leah Brickley, Senior Editor
Prep Those Veggies
This year, I’m resolving to prep my veggies as soon as I get them home from the grocery store. I’m never going to be the type of person who meal preps an entire week’s worth of dinners on Sunday — my cravings are too fickle and I don’t want cooking to feel like a marathon each week. But I’ve realized that if I can at least get some veggies cleaned and sliced in advance, I’m halfway through the most time-consuming part of cooking — and maybe I’ll actually hit up Seamless less often!
- Lauren Piro, Director, Editorial
Make Cooking Fun
My food resolution is trying to start making cooking less of a chore. I love meal prepping because it makes my weekdays less stressful, but by this point in the year, I feel like I’ve run out of ideas and my lunches have been pretty lame for the past month or so. So how am I making it more fun? By making it interactive! I’m tuning into cooking classes in the Food Network Kitchen app. I’ve been working in (and with!) food for the better part of a decade, but watching these videos always gives me fresh ideas for dinner and cooking along in real time improves my technique. I love watching Amanda Freitag, who teaches you how to nail basic (but important!) cooking techniques that might have seemed a little intimidating. Some of my favorites include her Seared Scallops and her Shrimp Cocktail classes.
- Julie Hines, Managing Editor
I made a resolution to cook and bake as much as possible in 2019, and I'm planning on renewing that same resolution again for 2020. Not only has it helped me become a better chef, I now avoid ordering takeout whenever the craving for stir-fry or tacos hit. Instead, I just run to the kitchen and make my own! And with the new Food Network Kitchen app there to help guide me throughout 2020, the possibilities are truly and deliciously endless.
- Michelle Baricevic, Online Editorial Coordinator, Food Network Magazine

domain: food


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Read the Original Article at http://www.informationweek.com/news/showArticle.jhtml?articleID=22102505
An across-the-board rally attributed to optimism about Iraqi sovereignty petered out Monday after economic (and maybe political) realities intruded. Traders eventually realized that the Fed is still going to raise interest rates and the economy still has weak spots (such as auto sales for GM).
At the close, techs were down the most. Our InformationWeek 100 index fell 0.5%, or 1.47 points, to rest at 320.11, and the Nasdaq fell 0.3%, or 5.65 points, to 2,019.82. The Dow fell 0.1%, or 14.75 points, to 10,357.09. Holding up best was the S&P 500, which fell 0.08%, or 0.91 of a point, to 1,133.52.
The Nasdaq-100 tracking stock fell 0.8%, or 31 cents, to $37.02, on middling volume of 94 million shares.
See the full listing of all the companies in the InformationWeek 100 and the top 5 percentage winners and losers for the last closing at informationweek.com/stocks.

domain: news


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Elton John has collaborated with a number of different artists this year but the most important for him was playing piano and lending vocals on ‘The Pink Phantom’ for Gorillaz’ latest project ‘Song Machine, Season One: Strange Timez’ because he enjoyed working with the frontman so much.
He said: “This year I’ve worked with Ozzy Osbourne, Lady Gaga, Surfaces and a Charlie Puth track that hasn’t come out yet.
“I’ve been in a Teyana Taylor video. But Damon really is special. He’s someone who I really, really admire.”
Elton hailed Damon a “British jewel” for his diverse body of work and throwing himself into projects that interest him, rather than focusing on what will be commercially successful.
He told Record Collector magazine: “When you see what he’s done, when you compare him and Blur with Oasis – including the last Blur album [2015’s ‘Magic Whip’], which is a masterpiece – and then you look at what he’s done outside of Blur, he’s just done so many different things.
“And he’s just finished an opera that just opened in Paris.
“I think he’s a British jewel because he just does what he wants and, for him, success is just working with great musicians like Tony Allen, just doing things that interest him.
“I mean, for fuck’s sake, he did an album with Bobby Womack! So this is a mind I admire because he’s always looking forward.”
When writing a song, Elton likes to seize an idea quickly and found Damon opts for a similar process.
He explained: “Damon Albarn is the same. I was talking to him about the first Gorillaz album, which I love.
“I said, ‘How did you do it?’ And he said, ‘I just wrote it when I felt like it.’ You have to be in the mood.”
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Evolution USA has been appointed as the North American licensing and merchandising agent for Yo Kai Watch.
The firm will premiere the popular multi-media franchise property at next week’s Licensing Expo in Las Vegas, with products and retail promotions hitting stores from autumn next year.
Under the new deal, Evolution USA will also represent Little Battlers Experience to the USA and Canadian markets.
Hasbro has been previously announced as the Yo Kai Watch master toy licensee for the USA, Canada, Europe, New Zealand, Australia, Mexico, Central and South America and will develop new toy lines for spring 2016.
Meanwhile, Viz Media has been granted the publishing rights for Manga under the Perfect Square imprint.
“As leaders in the licensing industry, Evolution is the perfect partner to license and manage these amazing properties in the North American market as we expand the franchises globally,” said Marc Harrington, senior vice president of global strategy and development.
Travis J Rutherford, president licensing and retail at Evolution, added: “Yo Kai Watch has taken the Japanese retail market by storm selling excess of $1.0 billion of toys and other merchandise in Japan, not counting games, music or publishing.
“Plans are well underway for a major rollout of this sensational franchise across North American market and our team looks forward to supporting all the efforts of Hasbro, Nintendo and Viz Media to maximise this opportunity across all retail channels.”


The National - Police in southern India arrested an airline passenger from Dubai who concealed nearly a kilogram of gold in his body.
The passenger arrived at Kerala's Kannur airport on a GoAir flight with 972 grams of the flattened precious metal that he had inserted into his body.
Officials at the Air Intelligence Unit extracted the gold from the man, the state agency aid on Tuesday.
Know the term "...shit a gold brick"? Well before now that was just some foolish southernism to describe being shocked out of your mind at something.
But now, in 2020, it's a real possibility.
And is it any surprise this occurred in India?
The land that gave us tree man and all those other oddity greatest-hits that defy reality? If Ripleys believe it or not was a country it’d be India.
But why on earth would somebody do such a thing you ask?
The goods and services tax on gold in India is 18 per cent, making smuggling the precious metal into the country profitable for illegal networks.
In recent months, police uncovered gangs and caught passengers trying to bring gold into the country.
Over the past week, several airports in India reported seizing gold between 300g and 3kg stuffed into capsules in paste form or lined in underwear.
I realize that taking an 18% haircut on gold bullion is steep. But at what point do you weigh the trade-off of having to shove these giant gold rods up your asshole? For me its 99%. The tax rate would have to be 99% for me to have to jam these things up my rectum and attempt to walk through the airport undetected. Anything less than 99% and I'm taking the hit. Just not worth it.
Please discuss below -


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The company is aiming to increase its workspace capacity by 10pc to 15pc this year, compared to 5pc in 2009, with six new sites in the UK.
Mark Dixon, founder and chief executive, said he was "cautiously optimistic" about the overall outlook, despite revenues falling 2pc to £1.06bn, and pre-tax peofit declining 42pc to £86.9m in 2009.
Mr Dixon also said he is seeking to renegotiate rental deals in the UK with regard to "the interests of all concerned". Regus has come under criticism from landlords for threatening to place some of its sites into administration if it could not agree changes to its rental payments, despite having net cash of £237m.
Mr Dixon said Regus is "seeking to renegotiate a small number of leases where this is critical to improving a centre's performance and where the historic rent is not reflective of current market conditions".
The final dividend has been increased by 33pc to 1.6p, and will be paid on May 28. Regus shares rose by 13.3, or 15pc, to 100½p.

domain: finance


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Aamir Khan posted a funny video in his Twitter account. This video shows how much of a perfectionist is he while at work. He is seen taking too many shots to get the desired effect.
PK is directed by Rajkumar Hirani who has done 3 Idiots with Aamir Khan earlier. the director-actor combo has worked wonders before and we hope it hits the right chord even this time around.
With people guessing about the story of PK, it has already made a lot of attention from the poster releases to the teaser trailer.
This video was posted by the actor and it shows the making of a funny scene. It is about a fat barber and his funny scene.
Aamir Khan is all set to give another blockbuster this December when PK releases on 16th. Like Dhoom 3 which raked in a lot of money last year, we believe PK will cross his own Box Office records.
PK also features Anushka Sharma, Sanjay Dutt and Sushant Singh Rajput in pivotal roles.
Watch the funny video here.


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Established in 2014, Alighieri celebrates the work of one of Italy’s finest poets, Dante and his work The Divine Comedy, where each piece draws inspiration from one of the 100 poems within the collection. These hoop earrings are hand-crafted in the UK to a chunky shape with the signature rocky texture, which the brand uses as a symbol of overcoming life’s sometimes rocky path.
Made in United Kingdom
- gold plated
- textured finish
- chunky hoop design
- post-back fastening
- for pierced ears
- These earrings come as a pair.
- We've partnered with Good On You — an independent agency that rates how brands perform in relation to their impact on the planet, people and animals, with a multi-criteria rating simplified to a five points scale. In order to be awarded our conscious label, larger brands need to score a minimum of four out of five ('Good'), while smaller brands must score at least three out of five ('It's a start').
- This item comes from a brand rated four out of five ('Good') by Good on You at the time it was added on FARFETCH. Please note, this is a brand-level rating and does not guarantee that this product is made with conscious materials.
- Learn more about what makes a product Conscious on our Conscious Criteria page
Gold Plated Brass
The model is 1.78 m wearing size OS
FARFETCH ID: 22147491
Brand style ID: FJ5530A


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Angiogenesis after administration of basic fibroblast growth factor induces proliferation and differentiation of mesenchymal stem cells in elastic perichondrium in an in vivo model: mini review of three sequential republication-abridged reports
Cellular & Molecular Biology Letters volume 23, Article number: 49 (2018)
To date, studies on mesenchymal tissue stem cells (MSCs) in the perichondrium have focused on in vitro analysis, and the dynamics of cartilage regeneration from the perichondrium in vivo remain largely unknown. We have attempted to apply cell and tissue engineering methodology for ear reconstruction using cultured chondrocytes. We hypothesized that by inducing angiogenesis with basic fibroblast growth factor (bFGF), MSCs or cartilage precursor cells would proliferate and differentiate into cartilage in vivo and that the regenerated cartilage would maintain its morphology over an extended period. As a result of a single administration of bFGF to the perichondrium, cartilage tissue formed and proliferated while maintaining its morphology for at least 3 months. By day 3 post bFGF treatment, inflammatory cells, primarily comprising mononuclear cells, migrated to the perichondrial region, and the proliferation of matrix metalloproteinase 1 positive cells peaked. During week 1, the perichondrium thickened and proliferation of vascular endothelial cells was noted, along with an increase in the number of CD44-positive and CD90-positive cartilage MSCs/progenitor cells. Neocartilage was formed after 2 weeks, and hypertrophied mature cartilage was formed and maintained after 3 months. Proliferation of the perichondrium and cartilage was bFGF concentration-dependent and was inhibited by neutralizing antibodies. Angiogenesis induction by bFGF was blocked by the administration of an angiogenesis inhibitor, preventing perichondrium proliferation and neocartilage formation. These results suggested that angiogenesis may be important for the induction and differentiation of MSCs/cartilage precursor cells in vivo, and that morphological changes, once occurring, are maintained.
Ear reconstruction using cell and tissue engineering methods involving cultured chondrocytes has been attempted. Although cultured mature cells possess a high ability to form cartilage tissue, there are defects in long-term maintenance because of a low capacity for regeneration . Kobayashi et al. succeeded in purifying mature cartilage tissue by identifying mesenchymal stem cells (MSCs) and progenitor cells among human auricular cartilage cells, and in culturing the cells . Using a similar method, Kagimoto et al. injected cultured human and monkey perichondrial cells into immunodeficient mice and confirmed that mature cartilage tissue is not absorbed by 3 months after production . They reported that the self-renewal ability of MSCs makes it possible to maintain long-term morphological function. In addition, Takebe et al. revealed that vascular endothelial cells are important for MSC differentiation into cartilaginous tissue in the perichondrium, and demonstrated in vitro that self-regeneration of MSCs occurred as a result of vascular endothelial cell formation . To date, studies on MSCs in the perichondrium have focused on in vitro analyses, with the details of cartilage regeneration from the perichondrium in vivo remaining largely undefined [2, 5].
We hypothesized that by inducing angiogenesis, MSCs/cartilage precursor cells would proliferate and differentiate into cartilage in vivo and that the regenerated cartilage would maintain its morphology over an extended period of time. Accordingly, we conducted an experimental investigation using basic fibroblast growth factor (bFGF) to induce angiogenesis. The growth factor bFGF promotes the proliferation, differentiation, and migration of various cells; exhibits strong angiogenic action ; and has been studied as a major component in the wound healing process . The specific aims of the current study were to determine whether bFGF would induce cartilage proliferation in vivo in the rabbit elastic perichondrium, and to investigate the involvement of MSCs and angiogenesis in this model system.
Materials and methods
All experimental protocols involving animals and their tissues were approved by the Ethics Committee of Kanazawa Medical University School of Medicine. Japanese white male rabbits were purchased from Sankyo Labo Service Corporation (Toyama, Japan); 57 rabbits (aged 14–16 weeks; weighing 2.5–3.5 kg) were housed in individual cages under a 12 h/12 h light/dark cycle with free access to food and water. All the rabbits were anesthetized with pentobarbital (25 mg/kg) through ear marginal vein injection prior to the surgical procedure. The details of the surgical procedures have been mentioned in each experiment section. At the end of the experiment, the rabbits were euthanized. After euthanasia, the experimental areas and a nonexperimental area of the rabbits’ ears were excised, fixed in 10% buffered formalin, and embedded in paraffin.
Histological and immunohistochemical analyses
Paraffin-embedded sections were subjected to hematoxylin and eosin (HE) staining using standard procedures. Immunohistochemical staining was performed using the streptavidin-biotin-peroxidase-complex method (Histofine SAB-PO kit, Nichirei Co., Tokyo Japan). Tissue sections were deparaffinized and rehydrated prior to immunostaining. Tissues sections were treated with proteinase K (20 mg/ml; Dako Cytomation, Carpinteria, CA, USA) for 10 min at room temperature for antigen activation, except for Ki67 staining in which antigen activation was performed using tris-acetate-EDTA buffer (Target Retrieval Solution, Dako Cytomation, Carpinteria, CA, USA) for 4 h at 37 °C, endogenous peroxidase activity was quenched with 3% hydrogen peroxide in methanol, and tissue sections were blocked with 10% serum-free protein block. Primary peroxidase-conjugated antibodies included anti-type 1 collagen (0.25 μg/ml; Daiichi Fine Chemical, Toyama, Japan) for the primary extracellular-matrix component of the perichondrium, anti-type 2 collagen (2.5 μg/ml; Daiichi Fine Chemical) for the primary extracellular-matrix component of chondrium, anti-CD44 (1 μg/ml; Eptimics, Burlingame, CA, USA), anti-CD34 (2 μg/ml; Leica, UK) as a negative marker, anti-MMP-1 (1.25 μg/ml; Daiichi Fine Chemical, Toyama, Japan), anti-CD31 antibody JC/70A (5 μg/ml; Novus Biologicals, Littleton, CO, USA), and anti-Ki67 antibody MIB-1 (10 μg/ml; Dako Cytomation, Carpinteria, CA, USA). The experimental tissue sections were incubated with the primary antibodies at 4 °C overnight. For colorimetric detection, 3,3′-diaminobenzidine (DAB) was used as the peroxidase substrate. The specimens were counterstained with Mayer’s hematoxylin.
Thickness of cartilage and perichondrium
Immunohistochemical staining of type 1 and 2 collagen expression was performed for evaluation of the perichondrium and chondrogenesis, respectively. Thickness of cartilage and perichondrium was measured using Image J (version 1.45) image analysis software (National Institutes of Health, Bethesda, MD, USA).
Temporal quantification of MMP-1-, CD31-, Ki67-, and CD90-positive cells
Cells positive for MMP-1, CD31, Ki67, and CD90 were counted in randomly chosen microscopic visual fields (× 200) of the perichondrium layer and the subcutaneous layer close to the perichondrium (a width of 200 μm). Vessels with a diameter less than 50 μm were counted to quantitate the level of neovascularization.
Effect of a single administration of bFGF
In brief, 18 animals received 0.1 ml of recombinant human bFGF (100 μg/ml, Kaken, Japan) by subcutaneous injection into the perichondrium tissue of the auricular region using insulin syringes (29G × 13 mm, Terumo, Tokyo, Japan). Each rabbit received injections in four locations. At 1, 3, 7, and 14 days, and at 1 month and 3 months post-injection, three rabbits per group were euthanized. Three microscopic visual fields were randomly chosen for 12 tissue specimens from each of three rabbits (n = 36). In a preliminary study, there was no histological difference between control saline-injected (0.1 ml) areas and noninjected areas at each time point; therefore, the control groups throughout the remainder of the study were noninjected areas. The thickness of cartilage was measured and cells positive for MMP-1, CD31, Ki67, and CD90 were counted.
Effect of bFGF concentration on auricular chondrogenesis
To determine the importance of bFGF concentration, 0.1 ml of bFGF in normal saline at concentrations of 1, 5, 10, 25, 50, and 100 μg/ml was injected subcutaneously into the perichondrium in the auricular region of the rabbits. The noninjected areas were treated as the control areas. Three rabbits were used, and each rabbit received injections in six locations (each bFGF concentration for each rabbit). At 1 month post-injection, the injected region was excised. Each section was stained with HE. The thickness of new cartilage and the origin of cartilage production were evaluated at five points (n = 15) in randomly chosen microscopic fields. The rate of new cartilage formation was calculated using the following equation:
Blocking bFGF stimulation using a neutralizing antibody
Fifteen rabbits were randomly divided into five groups of three rabbits each. bFGF in normal saline (0.1 ml; 5 μg/ml) was injected subcutaneously into the perichondrium in the auricular region of each rabbit, followed by the injection of 0.25 ml of an anti-bFGF neutralizing monoclonal antibody (1 mg/ml, R&D systems, USA) into the same region at the various time points indicated. The groups of animals were injected with the neutralizing antibody as follows: group 1 (G1), immediately after the bFGF injection; group 2 (G2), immediately and 1 week post bFGF-injection; group 3 (G3), immediately and 2 weeks post bFGF-injection; group 4 (G4), 1 week post bFGF-injection; and group 5 (G5), 2 weeks post bFGF-injection. The injected area and the noninjected control areas were excised 1 month post bFGF-injection, fixed in 10% buffered formalin, and embedded in paraffin. The areas not injected with the neutralizing antibody after bFGF-injection were the control areas. Sections were HE-stained, and the neogenesis cartilage rate was calculated.
bFGF (0.1 ml, 100 μg/ml) was injected subcutaneously into the perichondrium in the auricular region of ten rabbits. At 24-h after the bFGF treatment, 0.10 ml of 6.25 mM MMP inhibitor (Wako, Osaka, Japan), or the DMSO carrier alone (as a negative control), was locally injected into each ear. The dosing and timing for the MMP treatment were based on preliminary experiments. Each rabbit received injections in four locations (2 experimental and 2 control regions). Each of 5 rabbits was euthanized at 1-week and 2-weeks post MMP treatment (n = 10 per time point). The tissue was sectioned on a microtome and stained with HE. The thickness of new cartilage was measured at the center of the region of injection, and cells positive for CD31 were counted in five randomly chosen microscopic visual fields (× 200).
Eleven rabbits were treated with 0.10-ml subcutaneous injections of bFGF (100 μg/ml) in the perichondrium in the auricular region. Based on preliminary experiments, 0.10 ml of localized treatment of VEGF-neutralizing antibody (25 mg/ml; Chugai, Tokyo, Japan), or normal saline as a negative control, was administered by three subcutaneous injections into the same region at 30 min, 24 h, and 48 h post bFGF treatment. Each rabbit received injections in four locations (2 experimental and 2 control regions). Five rabbits were euthanized 1 week later (n = 10 per time point), and six rabbits were euthanized at 2 weeks after the initial bFGF stimulation (n = 12 per time point). Measurement of the thickness of new cartilage and the number of CD31-positive cells was performed as described above.
Experiment of a single administration of FGF: two-way analysis of variance (ANOVA) was performed to compare the means of two or more groups for the objective study period. A t-test or one-way ANOVA was also conducted to compare the means of two or more groups on each day of measurement. Scheffe’s method of multiple comparisons was used as a post hoc analysis to evaluate the differences in all combinations of two individual groups for data from each day of measurement using the StatView 5.0 software (Cary, NC).
Experiment of bFGF concentration and blocking bFGF stimulation using a neutralizing antibody: nonparametric testing for variance by Kruskal–Wallis analysis was performed to determine significance in cartilage neogenesis rate using StatView software version 5.0 (Cary, NC). Post hoc comparisons by Scheffe’s test and Tukey HSD test were performed when necessary.
Experiment of MMP inhibition and VEGF neutralization: Student’s t-tests were used to assess for significance using SPSS v. 20 (IBM Corp, Japan).
Results were considered statistically significant if p < 0.05.
Results and discussion
BFGF-induced proliferation and differentiation of MSCs or cartilage precursor cells in ear cartilage in vivo model
Representative findings from the evaluation of the in vivo rabbit model with a single bFGF treatment are shown in Fig. 1. One to 3 days after the injection of 10 μg of bFGF (100 μg/ml), infiltration of mononuclear cells, comprising mostly macrophages, and an expansion in the volume of the perichondrium layer in the superficial perichondrium and the subcutaneous layer near the perichondrium were observed. One week after the injection, proliferation of perichondrium cells with spindle and spider shapes, and extracellular matrix with type 1 collagen fibers were observed. Two weeks after the injection, the superficial perichondrium layer and the deep neo-chondrium layer with neocartilage cells were differentiated from pericartilage cells. Additionally, by 2 weeks, type 2 collagen fibers in the extracellular matrix were observed. From one to 3 months after the injection, neocartilage cells with hypertrophy of the cytoplasm and abundant extracellular matrix were present. The new cartilage was morphologically similar to mature tissue.
The average thickness of the cartilage stained with an anti-type 2 collagen antibody (Fig. 1) was 171 ± 26 μm for the control, 177 ± 35 μm at 1 day, 206 ± 30 μm at 3 days, 213 ± 58 μm at 1 week, 703 ± 100 μm at 2 weeks, 835 ± 84 μm at 1 month (not shown in Fig. 1), and 933 ± 18.8 μm at 3 months. The differences in the thickness of cartilage between 1 week and 2 weeks were statistically significant (P < 0.0001).
CD31-positive cells were seldom observed around the perichondrium layer in the noninjected group (Fig. 2). Mononuclear cells and small vascular endothelial cells were observed on day 3 following the administration of bFGF. During the first week, proliferation of vascular endothelial cells was noted and the vessels extended vertically into the perichondrial region. Vascular endothelial cells were not observed in the deep layer of perichondrium, but were located in the superficial layer during week 2.
As shown in Fig. 2, a small number of MMP-1-positive cells in the perichondrium was observed in the noninjected control group. During day 3, a large number of mononuclear cells and pericartilage cells stained positive for MMP-1 in the perichondrium and the outer layer of perichondrium. Only mononuclear cells stained positive for MMP-1 in the superficial layer of the perichondrium during the first week following bFGF treatment.
CD44 and CD90 are markers for MSCs of auricular cartilage, whereas CD34 is not and served as a negative control. The protein Ki-67 is a cellular marker for proliferation.
As shown in Fig. 3, a small number of CD44-positive and CD90-positive cells was observed in the noninjected group, but a large number of CD44-positive and CD90-positive cells was observed 1 week after the injection of bFGF. Almost all the observed spindle- and spider-shaped cells in the perichondrium layer stained positive for CD44 and CD90. These positively stained cells decreased in number 2 weeks after the injection. No CD34-positive cells were detected in any of the experimental groups. Ki-67-positive cells were scarcely observed in noninjected controls at 1 day after the injection. During week 1, Ki67-positive perichondrial cells were observed in the outer region of the perichondrial inner-layer/outer-layer boundary. In the superficial layer of perichondrium during week 2, only perichondrial cells stained positive for Ki-67.
Immunohistochemical staining with the anti-MMP-1 antibody was performed to evaluate type 1 collagenolytic activity. The average number of positive cells per microscopic visual field was 2.4 ± 2.0 for the control, 12.0 ± 3.3 at 1 day, 40.1 ± 14.4 at 3 days, 18.2 ± 4.1 at 1 week, 13.5 ± 2.7 at 2 weeks, 3.6 ± 2.1 at 1 month, and 1.7 ± 1.6 at 3 months. The differences in the number of MMP-1-positive cells from the control to 1 day, 1 day to 3 days, and 3 days to 1 week were statistically significant (P < 0.0001) (Fig. 4a). Immunohistochemical staining with the anti-CD31 antibody was performed to evaluate angiogenesis. The average number of positive cells per visual field was 2.0 ± 0.8 for the control, 2.9 ± 1.3 at 1 day, 12.3 ± 4.6 at 3 days, 35.3 ± 8.2 at 1 week, 17.8 ± 3.6 at 2 weeks, 4.3 ± 2.7 at 1 month, and 1.2 ± 0.7 at 3 months. The differences in the number of CD31-positive cells from 1 day to 3 days, 3 days to 1 week, and 1 week to 2 weeks were statistically significant (P < 0.0001) (Fig. 4b). Immunohistochemical staining with the anti-Ki67 antibody was performed to evaluate proliferation. The average number of positive cells per visual field was 0.1 ± 0.3 for the control, 0.6 ± 0.7 at 1 day, 1.4 ± 0.8 at 3 days, 35.3 ± 8.3 at 1 week, 10.4 ± 3.3 at 2 weeks, 0.2 ± 0.4 at 1 month, and 0.1 ± 0.4 at 3 months. The differences in the number of Ki67-positive cells from 3 days to 1 week, and 1 week to 2 weeks were statistically significant (P < 0.0001) (Fig. 4c). Immunohistochemical staining using the anti-CD90 antibody was conducted to evaluate MSCs. The average numbers of positive cells were 1.6 ± 0.8 for the control, 1.8 ± 1.1 at 1 day, 2.8 ± 1.0 at 3 days, 35.5 ± 7.7 at 1 week, 10.4 ± 3.3 at 2 weeks, 2.4 ± 1.2 at 1 month, and 2.3 ± 1.0 at 3 months. The differences in the number of CD90-positive cells from 3 days to 1 week, and from 1 week to 2 weeks were statistically significant (P < 0.0001) (Fig. 4d).
A single administration of bFGF to the perichondrium resulted in the proliferation of precursor cells, and cartilage tissue formation with prolonged maintenance of cartilage morphology for at least 3 months. Inflammatory cells comprising mononuclear cells migrated into the treatment site by day 3 following administration of bFGF; moreover, by this time the proliferation of MMP1-positive cells peaked. During week 1, thickening of the perichondrium occurred and proliferation of vascular endothelial cells in the perichondrial region was observed. The bFGF treatment stimulated CD44-positive and CD90-positive cartilage MSCs or progenitor cells in the perichondrium to proliferate. Subsequently, neocartilage was formed after 2 weeks, and after 3 months hypertrophied mature cartilage was formed and maintained.
It has been reported that bFGF is a growth factor for fibroblasts present in bovine-brain extract ; it promotes the proliferation, differentiation, and migration of various cells and is a growth factor with strong angiogenic action . The growth-promoting effect of administration of bFGF on mature chondrocytes has been previously reported, but the effects on perichondrial tissue or perichondrial cells have not been elucidated. Moreover, it is unknown which cells in the perichondrium are involved in proliferation and differentiation into cartilage [9, 10]. The bFGF-stimulated cartilage-proliferation rabbit model in this study showed that perichondrial cells, rather than chondrocytes, were more likely to proliferate and differentiate into cartilage. Based on the proliferation activity of perichondrial cells analyzed by Ki67 labeling, it was suggested that the perichondrial cells in the outer layer of the perichondrial inner-layer/outer-layer boundary may have been involved in the observed proliferation. The perichondrium is composed of two layers: an outer layer in which small fibrocyte-like cells are interspersed between histologically sparse collagenous fibers, and an inner layer in which somewhat rounded cells in compact fibers have an irregular layer structure composed of three to four layers . Kobayashi et al. demonstrated by immunostaining for the auricular-perichondrial MSC markers CD44 and CD90 in an in vitro study using human auricular perichondrial cells that in the inactive perichondrium, MSCs exist as elongated spindle-shaped cells located at the inner layer-layer/outer-layer boundary . It has been shown that CD44-positive and CD90-positive MSCs in the perichondrial inner-layer/outer-layer boundary are activated by bFGF, become active chondrocyte precursor cells with short spindle shapes to star-like shapes, and participate in proliferation and chondrocyte differentiation . It has also been shown that MSCs in the proliferated cartilage membrane are able to maintain long-term morphology by reforming the perichondrial membrane, with one of the roles of MSCs in the regeneration process of the perichondrium having been elucidated in this in vivo study.
Verifying the effect of chondrogenesis following bFGF administration
The effect of bFGF concentration on auricular chondrogenesis was shown in Fig. 5a. The average neogenesis cartilage rates were 0.046 ± 0.025 (control with no bFGF), 0.040 ± 0.020 (1 μg/ml bFGF), 0.28 ± 0.064 (5 μg/ml), 0.38 ± 0.11 (10 μg/ml), 0.70 ± 0.06 (25 μg/ml), 0.71 ± 0.061 (50 μg/ml), and 0.78 ± 0.07 (100 μg/ml). Kruskal-Wallis analysis revealed a highly significant difference among the groups (P < 0.0001). Post hoc comparisons by Fisher test indicated significant differences between the treatment groups that received more than 5 μg/ml of bFGF and the control group. However, the difference between the group that received 1 μg/ml bFGF and the control group was not statistically significant (P = 0.51).
The blockage of bFGF-induced chondrogenesis with an anti-bFGF neutralizing antibody was shown in Fig. 5b. The average cartilage neogenesis rates based on the ratio of new cartilage to total cartilage were 0.061 ± 0.024 in G1 (anti-bFGF neutralizing antibody injected immediately after bFGF injection), 0.055 ± 0.021 in G2 (anti-bFGF neutralizing antibody injected immediately after bFGF injection and at 1 week post injection), 0.046 ± 0.019 in G3 (anti-bFGF neutralizing antibody injected immediately after bFGF injection and at 2 weeks post injection), 0.44 ± 0.13 in G4 (anti-bFGF neutralizing antibody injected at 1 week post-bFGF injection), 0.33 ± 0.07 in G5 (anti-bFGF neutralizing antibody injected at 2 weeks post-bFGF injection), and 0.27 ± 0.06 for controls not receiving any anti-bFGF neutralizing antibody injections after the bFGF injection. Kruskal-Wallis analysis revealed a significant difference among the three groups immediately after injection of bFGF (G1–3) and the control group (P < 0.01), but suppression of chondrogenesis at 1 week and 2 weeks after bFGF injection was not recognized in comparison with the control group. The difference in the neogenesis rates between G1, G2, and G3, and between G4 and G5 were not significant.
The results from the current study confirmed that bFGF-induced chondrogenesis was concentration-dependent, with the highest concentration tested of 100 μg/ml yielding the highest levels of cartilage formation. It has been reported in vitro that the bFGF concentration at which chondrocytes show proliferation-promoting activity is 10 ng/ml [11, 12]. In our study, the concentration of bFGF that induced the highest degree of chondrogenesis was the same as that used in clinical practice for intractable ulcers and burn ulcers, and appeared to be a reasonable concentration for cell stimulation in vivo. The results from the experiments using anti-bFGF neutralizing antibodies revealed that chondrogenesis was inhibited in the groups that received the neutralizing antibody immediately after bFGF treatment, whereas in the group that received the neutralizing antibody at 1 week and 2 weeks post bFGF-injection, cartilage formation was not inhibited. Therefore, the process by which injected bFGF binds to and releases proteoglycans in vivo and the possibility that bFGF from cells in the perichondrial region is continuously produced is unlikely. The concentration-dependent bFGF-induced cartilage proliferation and suppression of cartilage proliferation by anti-bFGF neutralizing antibodies suggests that the stimulation of perichondrial cells by the injection of high concentrations of bFGF may have turned on a switch that promoted sustained proliferation of tissue stem cells or perichondrial progenitor cells present in the perichondrium, as well as their differentiation into chondrocytes. Nonetheless, it is unlikely that the initial time lag for significant proliferation of CD44-positive and CD90-positive MSCs or cartilage precursor cells of the perichondrium that was observed after bFGF stimulation was due to the direct growth-stimulating effect of bFGF on MSCs. We speculated that this effect was caused by angiogenesis induced by bFGF. Therefore, we examined the effects of an MMP inhibitor that inhibits angiogenesis, and anti-VEGF neutralizing antibodies.
Verifying the inhibition of chondrogenesis through the inhibition of angiogenesis
The CD31 positive cells, the perichondrium and neocartilage thickness by administration of MMP inhabitation are shown in Fig. 6a. Immunohistochemical staining with the anti-CD31 antibody was performed to evaluate angiogenesis (Fig. 6a, graph panel a). The average numbers of positive cells per visual field in the control groups that received only an injection of the carrier DMSO were 19.8 ± 5.4 at 1 week and 20.8 ± 6.8 at 2 weeks, compared to 1.2 ± 0.8 at 1 week and 1.8 ± 1.6 at 2 weeks in the experimental groups that received the injections of a monoclonal antibody inhibiting MMP. The differences in the numbers of CD31-positive cells between the controls and the corresponding experimental groups were statistically significant (P < 0.001 at 1 week and < 0.001 at 2 weeks post treatment). The average perichondrium thickness per microscopic visual field in the control group was 127 ± 3 μm at 1 week, and 92 ± 26 μm at 2 weeks compared to 60 ± 17 μm at 1 week and 29 ± 15 μm at 2 weeks in the experimental group (Fig. 6a, graph panel b). The differences between the controls and the corresponding experimental groups were statistically significant (P < 0.01 at 1 week and < 0.01 at 2 weeks). The average neocartilage thickness per visual field in the control group was 20 ± 5 μm at 1 week and 183 ± 47 μm at 2 weeks, compared to 17 ± 10 μm at 1 week and 19 ± 9 μm at 2 weeks per field in the experimental groups (Fig. 6a, graph panel c). The differences between the controls and the experimental groups at 2 weeks post-treatment were statistically significant (P < 0.001). This differed from the results obtained at 1 week post-treatment, in which there was no significant difference between the control and experimental groups.
The CD31 positive cells, the perichondrium and neocartilage thickness by administration of VEGF neutralization are shown in Fig. 6b. The average number of positive cells per visual field in the control group that received injections of only the carrier DMSO was 20.0 ± 4.4 at 1 week and 20.6 ± 4.6 at 2 weeks post treatment, compared to 12.4 ± 4.6 at 1 week and 13 ± 3.4 at 2 weeks post treatment in the experimental groups (Fig. 6b, graph panel a). The differences in the numbers of CD31-positive cells between the controls and the corresponding experimental groups were statistically significant (P < 0.05 at 1 week and < 0.01 at 2 weeks post treatment). The average perichondrium thickness per visual field in the control groups was 152 ± 47 μm at 1 week and 110 ± 29 μm at 2 weeks post treatment, compared to 102 ± 25 μm at 1 week and 125 ± 39 μm at 2 weeks post treatment in the experimental groups (Fig. 6b, graph panel b). The differences between the control groups and the corresponding experimental groups at 1 week post-treatment were statistically significant (P < 0.05), but this did not continue, as no significant difference was detected at 2 weeks post treatment. The average neocartilage thickness per visual field in the control group was 28 ± 10 μm at 1 week and 163 ± 80 μm at 2 weeks post-treatment, whereas in the experimental groups it was 19 ± 6 μm at 1 week and 64 ± 25 μm at 2 weeks post treatment (Fig. 6b, graph panel c). The differences between the controls and the experimental groups at 2 weeks post-treatment were statistically significant (P < 0.001), but not at 1 week post-treatment where no significant difference was observed. Angiogenesis induced by bFGF was sensitive to an angiogenesis inhibitor, which suppressed bFGF-induced perichondrium proliferation and neocartilage formation.
The results from the MMP inhibitor and VEGF neutralization experiments showed that the proliferation of new blood vessels 1 week after bFGF stimulation and the proliferation of perichondrial cells 1 week after bFGF stimulation were both inhibited, similarly to cartilage formation 2 weeks after treatment. Therefore, it appears that new blood vessels were strongly involved in perichondrial proliferation and subsequent cartilage formation. Humanized anti-VEGF monoclonal antibody (common name, bevacizumab) utilizes VEGF as a target molecule and inhibits angiogenesis [13, 14]. It has also been reported that mononuclear cells express and secrete IL-1β, and induce VEGF genes of the vascular endothelium and fibroblasts . Because mononuclear cells accumulated in the perichondrial region 1 day after the administration of bFGF, it is possible that bFGF induced early-stage mononuclear cell infiltration that stimulated VEGF, which in turn may have been involved in the observed cartilage proliferation. In addition, the MMP inhibitor batimastat (chemical name) inhibits MT1-MMP, MMP-2, MMP-9, and angiogenesis , apparently resulting in inhibition of cartilage proliferation. Additionally, the MMP inhibitor suppressed the enzymatic activity of MMP-1, which degrades type I collagen, the main extracellular-matrix component of the perichondrium . Based on the results of our study, the reason for the observed strong inhibition of perichondrial proliferation and cartilage formation by the MMP inhibitor compared to the VEGF-neutralizing antibody may have been not only the inhibition of angiogenesis, but also the inhibition of invasion of MMP-1-positive cells on days 1 to 3 post bFGF-treatment. Takebe et al. found that early interactions with endothelial cells in establishing avascular tissues from human specific progenitors trigger the initial expansion of cartilage progenitor cells and promote the self-aggregation of a 3D condensation of progenitors without any scaffold materials in vitro, and the introduction of MSCs into immunodeficient mice results in angiogenesis within 3 days of grafting . They also found that cartilage precursor cells proliferated from day 2 to 7 post-grafting, and that the grafted cells differentiated into chondrocytes from days 10 to 20 . This is similar to the gradual changes observed in the bFGF-stimulated cartilage proliferation model analyzed in our study. They also reported that the onset of angiogenesis during the early stage of grafting is consistent with the timing of proliferation of MSCs. In fact, blocking of angiogenesis strongly inhibits the proliferation of cartilage progenitor cells and cartilage formation, and angiogenesis is essential for the proliferation of MSCs (cartilage precursor cells) derived from the perichondrium and their differentiation into chondrocytes . In the current study, the timing of angiogenesis and that of proliferation of MSCs were consistent, whereas cartilage formation and the proliferation of the cartilage membrane were suppressed as a result of angiogenesis inhibition. Therefore, it appears that MSCs were activated in vivo by angiogenesis induced by the administration of bFGF and that the activated MSCs caused perichondrial proliferation and cartilage formation.
The results of this study suggest that angiogenesis may be important for the induction of activation and differentiation of MSCs/cartilage precursor cells in vivo, and the maintenance of long-term tissue morphology. In the future, we hope to establish a novel reconstruction method for auricular cartilage using perichondrial MSCs, and clarify the details of the mechanisms involved.
Mesenchymal stem cell
Basic fibroblast growth factor
Matrix metalloproteinase 1
Hematoxylin and eosin
Analysis of variance
Isogai N, Asamura S, Higashi T, Ikeda Y, Hillyer J, Jacquet R, et al. Tissue engineering of an auricular cartilage model utilizing cultured chondrocyte-poly (L-lactide-epsiloncaprolactone) scaffolds. Tissue Eng. 2004;10:673–87.
Kobayashi S, Takebe T, Inui M, Iwai S, Kan H, Zheng YW, et al. Reconstruction of human elastic cartilage by a CD44+ CD90+ stem cell in the ear perichondrium. Proc Natl Acad Sci U S A. 2011;108:14479–84.
Kagimoto S, Takebe T, Kobayashi S, Yabuki Y, Hori A, Hirotomi K, et al. Autotransplantation of monkey ear perichondrium-derived progenitor cells for cartilage reconstruction. Cell Transplant. 2016;25:951–62.
Takebe T, Kobayashi S, Suzuki H, Mizuno M, Chang YM, Yoshizawa E, et al. Transient vascularization of transplanted human adult-derived progenitors promotes self-organizing cartilage. J Clin Invest. 2014;124:4325–34.
Togo T, Utani A, Naitoh M, Ohya M, Tsuji Y, Morikawa N, et al. Identification of cartilage progenitor cells in the adult ear perichondrium: utilization for cartilage reconstruction. Lab Investig. 2006;86:445–57.
Yun YR, Won JE, Jeon E, Lee S, Kang W, Jo H, et al. Fibroblast growth factors: biology, function, and application for tissue regeneration. J Tissue Eng. 2010;7:218142.
Hu C, Ding Y, Chen J, Liu D, Zhang Y, Ding M, et al. Basic fibroblast growth factor stimulates epithelial cell growth and epithelial wound healing in canine corneas. Vet Opthalmol. 2009;12:170–5.
Gospodarowics D, Ferrara N, Schweigerer L, Neufeld G. Structural characterization and biological functions of fibroblast growth factor. Endocr Rev. 1987;8:95–114.
Engvist O, Skoog V, Pastacaldi P, Yormuk E, Juhlin R. The cartilaginous potential of the perichondrium in rabbit ear and rib. A comparative study in vivo and in vitro. Scand J Plast Reconstr Surg Hand Surg. 1979;13:275–80.
Ohlsen L. Cartilage regeneration from perichondrium. Experimental studies and clinical applications. Plast Reconstr Surg. 1978;62:507–13.
Arévalo-Silva CA, Cao Y, Vacanti M, Weng Y, Vacanti CA, Eavey RD. Influence of growth factors on tissue engineered pediatric elastic cartilage. Arch Otolaryngol Head Neck Surg. 2000;126:1234–8.
Arévalo-Silva CA, Cao Y, Weng Y, Vacanti M, Rodríguez A, Vacanti CA, et al. The effect of fibroblast growth factor and transforming growth factor-beta on porcine chondrocytes and tissue-engineered autologous elastic cartilage. Tissue Eng. 2001;7:81–8.
Zondor SD, Medina PJ. Bevacizumab: an angiogenesis inhibitor with efficacy in colorectal and other malignancies. Ann Pharmacother. 2004;38:1258–64.
Tol J, Koopman M, Cats A, Rondenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–72.
Tateno K, Minamino T, Toko H, Akazawa H, Shimizu N, Takeda T, et al. Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization. Circ Res. 2006;98:1198–202.
Pepper MS. Extracellular proteolysis and angiogenesis. Thromb Haemost. 2001;86:346–55.
Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 2008;75:346–59.
The authors thank the members of the Department of Plastic Surgery and Pathology at Kanazawa Medical University. We are especially grateful to S. Kawakami.
This article is based on three sequential studies first reported in the Journal of Kanazawa Medical University (Koizumi et al., 2010; Yagishita et al., 2013; and Miyanaga et al., 2017).
Koizumi, N. (2010). Basic fibroblast growth factor stimulates proliferation and differentiation of perichondrocytes of rabbit auricular cartilage in vivo. Journal of Kanazawa Medical University, 35, 122–130.
Yagishita, M. (2013). Involvement of mesenchymal tissue stem cells and aquaporin 1 in rabbit auricular cartilage regeneration from perichondrium with full reference. Journal of Kanazawa Medical University, 38, 43–52.
Miyanaga, A. (2017). Transient vascularization promotes proliferation and cartilage-formation of perichondrial progenitor cells. Journal of Kanazawa Medical University, 42, 24–31.
This work was supported by the Japan Society for the Promotion of Science KAKENHI Grant Number 16H07307.
Availability of data and materials
The datasets used and/or analyzed during this study are available from the author for correspondence upon reasonable request.
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Miyanaga, T., Ueda, Y., Miyanaga, A. et al. Angiogenesis after administration of basic fibroblast growth factor induces proliferation and differentiation of mesenchymal stem cells in elastic perichondrium in an in vivo model: mini review of three sequential republication-abridged reports. Cell Mol Biol Lett 23, 49 (2018). https://doi.org/10.1186/s11658-018-0113-1


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