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Intensive Care Medicine. 38 (4): 577–591. doi:10.1007/s00134-012-2513-4. ISSN 1432-1238. PMID 22392031. - Richalet JP, Gratadour P, Robach P, et al. (2005).
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(2009). Kumar and Clark's clinical medicine. St. Louis, Mo: Elsevier Saunders. p. 783. ISBN 0-7020-2993-9. - Fagenholz PJ, Gutman JA, Murray AF, Harris NS (2007). "Treatment of high altitude pulmonary edema at 4240 m in Nepal".
Kumar and Clark's clinical medicine. St. Louis, Mo: Elsevier Saunders. p. 783. ISBN 0-7020-2993-9. - Fagenholz PJ, Gutman JA, Murray AF, Harris NS (2007). "Treatment of high altitude pulmonary edema at 4240 m in Nepal". High Alt.
St. Louis, Mo: Elsevier Saunders. p. 783. ISBN 0-7020-2993-9. - Fagenholz PJ, Gutman JA, Murray AF, Harris NS (2007). "Treatment of high altitude pulmonary edema at 4240 m in Nepal". High Alt. Med.
High Alt. Med. Biol. 8 (2): 139–46. doi:10.1089/ham.2007.3055. PMID 17584008. - Cleland JG, Yassin AS, Khadjooi K (2010).
Med. Biol. 8 (2): 139–46. doi:10.1089/ham.2007.3055. PMID 17584008. - Cleland JG, Yassin AS, Khadjooi K (2010). "Acute heart failure: focusing on acute cardiogenic pulmonary oedema".
8 (2): 139–46. doi:10.1089/ham.2007.3055. PMID 17584008. - Cleland JG, Yassin AS, Khadjooi K (2010). "Acute heart failure: focusing on acute cardiogenic pulmonary oedema". Clin Med. 10 (1): 59–64.
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"Acute heart failure: focusing on acute cardiogenic pulmonary oedema". Clin Med. 10 (1): 59–64. doi:10.7861/clinmedicine.10-1-59. PMID 20408310. - Vital FM, Ladeira MT, Atallah AN (2013). "Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema".
10 (1): 59–64. doi:10.7861/clinmedicine.10-1-59. PMID 20408310. - Vital FM, Ladeira MT, Atallah AN (2013). "Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema". Cochrane Database Syst Rev. 5: CD005351.
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"Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema". Cochrane Database Syst Rev. 5: CD005351. doi:10.1002/14651858.CD005351.pub3. PMID 23728654. - HeartFailureMatters.org Animation showing How Heart Failure causes Fluid Accumulation – Created by the European Heart Failure Association
When you have a child or children with autism, you probably spend more time with doctors and therapists than most other families. First, there’s the search for a diagnosis, then there are potential treatments, not to mention the other conditions—such as ADHD or gastrointestinal issues—sometimes associated with ASD. All this means you’ve almost certainly come into contact with the ICD-10-CM. What does this string of letters and numbers mean, and how does it connect to autism? In this article, we’ll explore the ICD and how it impacts autism diagnosis. What is the ICD-10-CM index?
All this means you’ve almost certainly come into contact with the ICD-10-CM. What does this string of letters and numbers mean, and how does it connect to autism? In this article, we’ll explore the ICD and how it impacts autism diagnosis. What is the ICD-10-CM index? The ICD-10-CM index is a version of the International Classification of Diseases, a tool created by the World Health Organization. It’s essentially a list of diseases, disorders, and other health conditions, all of which are categorized and labeled with a code made up of letters and numbers. The ICD got its start as the International Statistical Institute’s International List of Causes of Death in 1893.
What does this string of letters and numbers mean, and how does it connect to autism? In this article, we’ll explore the ICD and how it impacts autism diagnosis. What is the ICD-10-CM index? The ICD-10-CM index is a version of the International Classification of Diseases, a tool created by the World Health Organization. It’s essentially a list of diseases, disorders, and other health conditions, all of which are categorized and labeled with a code made up of letters and numbers. The ICD got its start as the International Statistical Institute’s International List of Causes of Death in 1893. Eventually, the World Health Organization took over its maintenance, and it was expanded to include all conditions, not just fatal ones.
The ICD got its start as the International Statistical Institute’s International List of Causes of Death in 1893. Eventually, the World Health Organization took over its maintenance, and it was expanded to include all conditions, not just fatal ones. Every country that is a member of WHO must use the ICD to compile national death and disease statistics. Member countries currently use the tenth edition of the ICD, called ICD-10. The International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) is a version created for use in the United States. The U.S. uses the ICD-10-CM to diagnose conditions and record patient information, and it uses the standard ICD-10 to classify data from death certificates. ICD-10 came into effect globally in 1990, but the United States didn’t begin using it for mortality information until 1999 and didn’t fully transition to the ICD-10-CM until 2015.
Eventually, the World Health Organization took over its maintenance, and it was expanded to include all conditions, not just fatal ones. Every country that is a member of WHO must use the ICD to compile national death and disease statistics. Member countries currently use the tenth edition of the ICD, called ICD-10. The International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) is a version created for use in the United States. The U.S. uses the ICD-10-CM to diagnose conditions and record patient information, and it uses the standard ICD-10 to classify data from death certificates. ICD-10 came into effect globally in 1990, but the United States didn’t begin using it for mortality information until 1999 and didn’t fully transition to the ICD-10-CM until 2015. That’s why some websites will list what tenth revision codes are equivalent to those from its predecessor, the ICD-9—although there aren’t exact matches, since the transition to the tenth edition added about 55,000 new codes.
Every country that is a member of WHO must use the ICD to compile national death and disease statistics. Member countries currently use the tenth edition of the ICD, called ICD-10. The International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) is a version created for use in the United States. The U.S. uses the ICD-10-CM to diagnose conditions and record patient information, and it uses the standard ICD-10 to classify data from death certificates. ICD-10 came into effect globally in 1990, but the United States didn’t begin using it for mortality information until 1999 and didn’t fully transition to the ICD-10-CM until 2015. That’s why some websites will list what tenth revision codes are equivalent to those from its predecessor, the ICD-9—although there aren’t exact matches, since the transition to the tenth edition added about 55,000 new codes. These codes have important purposes in the medical world.
Member countries currently use the tenth edition of the ICD, called ICD-10. The International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) is a version created for use in the United States. The U.S. uses the ICD-10-CM to diagnose conditions and record patient information, and it uses the standard ICD-10 to classify data from death certificates. ICD-10 came into effect globally in 1990, but the United States didn’t begin using it for mortality information until 1999 and didn’t fully transition to the ICD-10-CM until 2015. That’s why some websites will list what tenth revision codes are equivalent to those from its predecessor, the ICD-9—although there aren’t exact matches, since the transition to the tenth edition added about 55,000 new codes. These codes have important purposes in the medical world. On a larger scale, public health officials use the data to conduct research and keep track of trends.
The International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) is a version created for use in the United States. The U.S. uses the ICD-10-CM to diagnose conditions and record patient information, and it uses the standard ICD-10 to classify data from death certificates. ICD-10 came into effect globally in 1990, but the United States didn’t begin using it for mortality information until 1999 and didn’t fully transition to the ICD-10-CM until 2015. That’s why some websites will list what tenth revision codes are equivalent to those from its predecessor, the ICD-9—although there aren’t exact matches, since the transition to the tenth edition added about 55,000 new codes. These codes have important purposes in the medical world. On a larger scale, public health officials use the data to conduct research and keep track of trends. For patients and caregivers, codes are usually used in hospital billing and insurance claims.
These codes have important purposes in the medical world. On a larger scale, public health officials use the data to conduct research and keep track of trends. For patients and caregivers, codes are usually used in hospital billing and insurance claims. How is autism classified in the ICD-10-CM Index? Autism is labeled with the code F84.0. It is a “billable code,” meaning it’s detailed enough to constitute a medical diagnosis. It falls under the section for mental and behavioral disorders (codes F00 through F99), the subsection of pervasive and specific developmental disorders (F80 through F89), and the smaller subsection of pervasive developmental disorders (F84).
On a larger scale, public health officials use the data to conduct research and keep track of trends. For patients and caregivers, codes are usually used in hospital billing and insurance claims. How is autism classified in the ICD-10-CM Index? Autism is labeled with the code F84.0. It is a “billable code,” meaning it’s detailed enough to constitute a medical diagnosis. It falls under the section for mental and behavioral disorders (codes F00 through F99), the subsection of pervasive and specific developmental disorders (F80 through F89), and the smaller subsection of pervasive developmental disorders (F84). The ICD defines a pervasive developmental disorder as “severe distortions in the development of many basic psychological functions that are not normal for any stage in development.” F84 itself is a non-billable code, so it can’t be entered into any system as a diagnosis, but every code that falls under it (F84.0 through F84.9) can.
Autism is labeled with the code F84.0. It is a “billable code,” meaning it’s detailed enough to constitute a medical diagnosis. It falls under the section for mental and behavioral disorders (codes F00 through F99), the subsection of pervasive and specific developmental disorders (F80 through F89), and the smaller subsection of pervasive developmental disorders (F84). The ICD defines a pervasive developmental disorder as “severe distortions in the development of many basic psychological functions that are not normal for any stage in development.” F84 itself is a non-billable code, so it can’t be entered into any system as a diagnosis, but every code that falls under it (F84.0 through F84.9) can. Click here to find out more Looking at F84.0 autistic disorder The description of F84.0 autistic disorder in the ICD is basically the same as other descriptions of autism—children with ASD will have difficulties with social interaction, language and communication skills, and repetitive behavior that become evident in early childhood, particularly before the age of three. An ICD code may have “inclusion terms,” which are other conditions the code can be used for. Often, the inclusion terms are just synonyms of the primary one.
It is a “billable code,” meaning it’s detailed enough to constitute a medical diagnosis. It falls under the section for mental and behavioral disorders (codes F00 through F99), the subsection of pervasive and specific developmental disorders (F80 through F89), and the smaller subsection of pervasive developmental disorders (F84). The ICD defines a pervasive developmental disorder as “severe distortions in the development of many basic psychological functions that are not normal for any stage in development.” F84 itself is a non-billable code, so it can’t be entered into any system as a diagnosis, but every code that falls under it (F84.0 through F84.9) can. Click here to find out more Looking at F84.0 autistic disorder The description of F84.0 autistic disorder in the ICD is basically the same as other descriptions of autism—children with ASD will have difficulties with social interaction, language and communication skills, and repetitive behavior that become evident in early childhood, particularly before the age of three. An ICD code may have “inclusion terms,” which are other conditions the code can be used for. Often, the inclusion terms are just synonyms of the primary one. In the case of code F84.0, the inclusion terms are autism spectrum disorder, infantile autism, infantile psychosis, and Kanner’s syndrome.
Click here to find out more Looking at F84.0 autistic disorder The description of F84.0 autistic disorder in the ICD is basically the same as other descriptions of autism—children with ASD will have difficulties with social interaction, language and communication skills, and repetitive behavior that become evident in early childhood, particularly before the age of three. An ICD code may have “inclusion terms,” which are other conditions the code can be used for. Often, the inclusion terms are just synonyms of the primary one. In the case of code F84.0, the inclusion terms are autism spectrum disorder, infantile autism, infantile psychosis, and Kanner’s syndrome. The ICD also has Type 1 Excludes Notes, which indicate when two codes should never be diagnosed alongside each other. In this case, autism and asperger’s syndrome are considered to be mutually exclusive (a position not taken by all diagnostic authorities, as we’ll see later). Asperger’s syndrome is called code F84.5 instead of code F84.0.
An ICD code may have “inclusion terms,” which are other conditions the code can be used for. Often, the inclusion terms are just synonyms of the primary one. In the case of code F84.0, the inclusion terms are autism spectrum disorder, infantile autism, infantile psychosis, and Kanner’s syndrome. The ICD also has Type 1 Excludes Notes, which indicate when two codes should never be diagnosed alongside each other. In this case, autism and asperger’s syndrome are considered to be mutually exclusive (a position not taken by all diagnostic authorities, as we’ll see later). Asperger’s syndrome is called code F84.5 instead of code F84.0. The difference, according to the ICD, is that children with asperger’s don’t have the language and cognitive impairments that can be found in other autism spectrum disorders.
In the case of code F84.0, the inclusion terms are autism spectrum disorder, infantile autism, infantile psychosis, and Kanner’s syndrome. The ICD also has Type 1 Excludes Notes, which indicate when two codes should never be diagnosed alongside each other. In this case, autism and asperger’s syndrome are considered to be mutually exclusive (a position not taken by all diagnostic authorities, as we’ll see later). Asperger’s syndrome is called code F84.5 instead of code F84.0. The difference, according to the ICD, is that children with asperger’s don’t have the language and cognitive impairments that can be found in other autism spectrum disorders. ICD coding allows professionals to include an additional code in their diagnosis, so they can further specify the disorder or identify any associated medical condition such as an intellectual disability. In that case, the patient would be coded for F84.0 autistic disorder as well as a code between F70-F79, which represent mild, moderate, severe, and unspecified intellectual disabilities.
Asperger’s syndrome is called code F84.5 instead of code F84.0. The difference, according to the ICD, is that children with asperger’s don’t have the language and cognitive impairments that can be found in other autism spectrum disorders. ICD coding allows professionals to include an additional code in their diagnosis, so they can further specify the disorder or identify any associated medical condition such as an intellectual disability. In that case, the patient would be coded for F84.0 autistic disorder as well as a code between F70-F79, which represent mild, moderate, severe, and unspecified intellectual disabilities. Autism in the ICD-9 American children diagnosed with autism before 2015, when the ICD-9 phased out, may have received the code 299.0 or 299.1. Code 299.0 indicated “autistic disorder, current or active state” and 299.1 indicated “autistic disorder, residual state,” meaning the patient used to meet the criteria for an ASD diagnosis but no longer does. People with ASD in a residual state may still have symptoms found in autism, but not enough to maintain the diagnosis.
The difference, according to the ICD, is that children with asperger’s don’t have the language and cognitive impairments that can be found in other autism spectrum disorders. ICD coding allows professionals to include an additional code in their diagnosis, so they can further specify the disorder or identify any associated medical condition such as an intellectual disability. In that case, the patient would be coded for F84.0 autistic disorder as well as a code between F70-F79, which represent mild, moderate, severe, and unspecified intellectual disabilities. Autism in the ICD-9 American children diagnosed with autism before 2015, when the ICD-9 phased out, may have received the code 299.0 or 299.1. Code 299.0 indicated “autistic disorder, current or active state” and 299.1 indicated “autistic disorder, residual state,” meaning the patient used to meet the criteria for an ASD diagnosis but no longer does. People with ASD in a residual state may still have symptoms found in autism, but not enough to maintain the diagnosis. Either way, both codes now fall under F84.0 autistic disorder.
ICD coding allows professionals to include an additional code in their diagnosis, so they can further specify the disorder or identify any associated medical condition such as an intellectual disability. In that case, the patient would be coded for F84.0 autistic disorder as well as a code between F70-F79, which represent mild, moderate, severe, and unspecified intellectual disabilities. Autism in the ICD-9 American children diagnosed with autism before 2015, when the ICD-9 phased out, may have received the code 299.0 or 299.1. Code 299.0 indicated “autistic disorder, current or active state” and 299.1 indicated “autistic disorder, residual state,” meaning the patient used to meet the criteria for an ASD diagnosis but no longer does. People with ASD in a residual state may still have symptoms found in autism, but not enough to maintain the diagnosis. Either way, both codes now fall under F84.0 autistic disorder. Is the ICD-10-CM Index related to the DSM V?
Autism in the ICD-9 American children diagnosed with autism before 2015, when the ICD-9 phased out, may have received the code 299.0 or 299.1. Code 299.0 indicated “autistic disorder, current or active state” and 299.1 indicated “autistic disorder, residual state,” meaning the patient used to meet the criteria for an ASD diagnosis but no longer does. People with ASD in a residual state may still have symptoms found in autism, but not enough to maintain the diagnosis. Either way, both codes now fall under F84.0 autistic disorder. Is the ICD-10-CM Index related to the DSM V? The DSM V is the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatric Association. It has been in effect since 2013.
Code 299.0 indicated “autistic disorder, current or active state” and 299.1 indicated “autistic disorder, residual state,” meaning the patient used to meet the criteria for an ASD diagnosis but no longer does. People with ASD in a residual state may still have symptoms found in autism, but not enough to maintain the diagnosis. Either way, both codes now fall under F84.0 autistic disorder. Is the ICD-10-CM Index related to the DSM V? The DSM V is the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatric Association. It has been in effect since 2013. Unlike the ICD, it only covers mental conditions.
Either way, both codes now fall under F84.0 autistic disorder. Is the ICD-10-CM Index related to the DSM V? The DSM V is the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatric Association. It has been in effect since 2013. Unlike the ICD, it only covers mental conditions. But they have similar purposes in providing a shared, consistent set of terms and diagnostic criteria for health care professionals. Because they’re created by two separate organizations, there are some discrepancies between the two manuals.
Unlike the ICD, it only covers mental conditions. But they have similar purposes in providing a shared, consistent set of terms and diagnostic criteria for health care professionals. Because they’re created by two separate organizations, there are some discrepancies between the two manuals. For example, in the ICD-10, childhood disintegrative disorder, asperger’s syndrome, and pervasive developmental disorder-not otherwise specified each has its own code separate from autism. The American Psychiatric Association, however, collapsed each of these diagnoses under autism spectrum disorder. That said, the indexes have very similar definitions of ASD. Both emphasize repetitive behavior, struggles with social interaction and communication, and the appearance of symptoms in early childhood.
The main difference between the two is that DSM-V codes can not be submitted for insurance claims. They are only useful for identification and diagnosis. If an insurance claim is submitted in the United States without an ICD code, it will be rejected. Clearly, the ICD-10-CM is important for anyone with long-term medical diagnoses. As research is done and advances are made, the ICD will continue to change how we understand and classify conditions. In fact, the ICD-11 is already on its way—WHO member countries will be allowed to implement it in 2022, though the United States isn’t expected to fully adopt it until the latter end of the decade. Autism has a new code in the ICD-11: 6A02, now called “autism spectrum disorder” instead of “autistic disorder”.
If an insurance claim is submitted in the United States without an ICD code, it will be rejected. Clearly, the ICD-10-CM is important for anyone with long-term medical diagnoses. As research is done and advances are made, the ICD will continue to change how we understand and classify conditions. In fact, the ICD-11 is already on its way—WHO member countries will be allowed to implement it in 2022, though the United States isn’t expected to fully adopt it until the latter end of the decade. Autism has a new code in the ICD-11: 6A02, now called “autism spectrum disorder” instead of “autistic disorder”. There is a new range of codes from 6A02.0 to 6A02.5, indicating whether the individual has impaired intellectual development or functional language. ICD-11 has also followed the DSM-V’s lead in including asperger’s syndrome under ASD.
Clearly, the ICD-10-CM is important for anyone with long-term medical diagnoses. As research is done and advances are made, the ICD will continue to change how we understand and classify conditions. In fact, the ICD-11 is already on its way—WHO member countries will be allowed to implement it in 2022, though the United States isn’t expected to fully adopt it until the latter end of the decade. Autism has a new code in the ICD-11: 6A02, now called “autism spectrum disorder” instead of “autistic disorder”. There is a new range of codes from 6A02.0 to 6A02.5, indicating whether the individual has impaired intellectual development or functional language. ICD-11 has also followed the DSM-V’s lead in including asperger’s syndrome under ASD. We don’t know when ICD-11 will reach the U.S., or what, if any, modifications will be made to it.
As research is done and advances are made, the ICD will continue to change how we understand and classify conditions. In fact, the ICD-11 is already on its way—WHO member countries will be allowed to implement it in 2022, though the United States isn’t expected to fully adopt it until the latter end of the decade. Autism has a new code in the ICD-11: 6A02, now called “autism spectrum disorder” instead of “autistic disorder”. There is a new range of codes from 6A02.0 to 6A02.5, indicating whether the individual has impaired intellectual development or functional language. ICD-11 has also followed the DSM-V’s lead in including asperger’s syndrome under ASD. We don’t know when ICD-11 will reach the U.S., or what, if any, modifications will be made to it. Either way, this article has hopefully helped you understand its purpose.
In fact, the ICD-11 is already on its way—WHO member countries will be allowed to implement it in 2022, though the United States isn’t expected to fully adopt it until the latter end of the decade. Autism has a new code in the ICD-11: 6A02, now called “autism spectrum disorder” instead of “autistic disorder”. There is a new range of codes from 6A02.0 to 6A02.5, indicating whether the individual has impaired intellectual development or functional language. ICD-11 has also followed the DSM-V’s lead in including asperger’s syndrome under ASD. We don’t know when ICD-11 will reach the U.S., or what, if any, modifications will be made to it. Either way, this article has hopefully helped you understand its purpose. Whether ASD is known as code F84.0, 6A02, 299.0, or something else in the future, autistic people and their loved ones represent a vibrant, supportive community.
Autism has a new code in the ICD-11: 6A02, now called “autism spectrum disorder” instead of “autistic disorder”. There is a new range of codes from 6A02.0 to 6A02.5, indicating whether the individual has impaired intellectual development or functional language. ICD-11 has also followed the DSM-V’s lead in including asperger’s syndrome under ASD. We don’t know when ICD-11 will reach the U.S., or what, if any, modifications will be made to it. Either way, this article has hopefully helped you understand its purpose. Whether ASD is known as code F84.0, 6A02, 299.0, or something else in the future, autistic people and their loved ones represent a vibrant, supportive community. Autism Speaks.
ICD-11 has also followed the DSM-V’s lead in including asperger’s syndrome under ASD. We don’t know when ICD-11 will reach the U.S., or what, if any, modifications will be made to it. Either way, this article has hopefully helped you understand its purpose. Whether ASD is known as code F84.0, 6A02, 299.0, or something else in the future, autistic people and their loved ones represent a vibrant, supportive community. Autism Speaks. (n.d.). DSM-5 and Autism: Frequently Asked Questions.
Whether ASD is known as code F84.0, 6A02, 299.0, or something else in the future, autistic people and their loved ones represent a vibrant, supportive community. Autism Speaks. (n.d.). DSM-5 and Autism: Frequently Asked Questions. Autism Speaks. https://www.autismspeaks.org/dsm-5-and-autism-frequently-asked-questions Bielby, J. (2020, May 4).
(n.d.). DSM-5 and Autism: Frequently Asked Questions. Autism Speaks. https://www.autismspeaks.org/dsm-5-and-autism-frequently-asked-questions Bielby, J. (2020, May 4). ICD-10, ICD-10-CM, & ICD-10-PCS. A.R.
DSM-5 and Autism: Frequently Asked Questions. Autism Speaks. https://www.autismspeaks.org/dsm-5-and-autism-frequently-asked-questions Bielby, J. (2020, May 4). ICD-10, ICD-10-CM, & ICD-10-PCS. A.R. Dykes.
Autism Speaks. https://www.autismspeaks.org/dsm-5-and-autism-frequently-asked-questions Bielby, J. (2020, May 4). ICD-10, ICD-10-CM, & ICD-10-PCS. A.R. Dykes. https://guides.library.kumc.edu/icd10 Boyd, N. (n.d.).
A.R. Dykes. https://guides.library.kumc.edu/icd10 Boyd, N. (n.d.). Diagnostic Codes: DSM-5 vs ICD-10. KASA. https://kasa-solutions.com/diagnostic-codes-dsm-5-vs-icd-10/ Holman, T. (2018, October). ICD-10-CM (Clinical Modification).
https://guides.library.kumc.edu/icd10 Boyd, N. (n.d.). Diagnostic Codes: DSM-5 vs ICD-10. KASA. https://kasa-solutions.com/diagnostic-codes-dsm-5-vs-icd-10/ Holman, T. (2018, October). ICD-10-CM (Clinical Modification). TechTarget. https://searchhealthit.techtarget.com/definition/ICD-10-CM World Health Organization.
Diagnostic Codes: DSM-5 vs ICD-10. KASA. https://kasa-solutions.com/diagnostic-codes-dsm-5-vs-icd-10/ Holman, T. (2018, October). ICD-10-CM (Clinical Modification). TechTarget. https://searchhealthit.techtarget.com/definition/ICD-10-CM World Health Organization. (2021).
https://kasa-solutions.com/diagnostic-codes-dsm-5-vs-icd-10/ Holman, T. (2018, October). ICD-10-CM (Clinical Modification). TechTarget. https://searchhealthit.techtarget.com/definition/ICD-10-CM World Health Organization. (2021). International Statistical Classification of Diseases and Related Health Problems (ICD). World Health Organization.
World Health Organization. https://www.who.int/standards/classifications/classification-of-diseases World Health Organization. (2021). 2021 ICD-10-CM CODE F84.0. ICD List. https://icdlist.com/icd-10/F84.0 World Health Organization. (2021, May).
(2021). 2021 ICD-10-CM CODE F84.0. ICD List. https://icdlist.com/icd-10/F84.0 World Health Organization. (2021, May). 6A02 Autism spectrum disorder. ICD-11 for Mortality and Morbidity Statistics.
https://icdlist.com/icd-10/F84.0 World Health Organization. (2021, May). 6A02 Autism spectrum disorder. ICD-11 for Mortality and Morbidity Statistics. https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f437815624
For injuries that are serious enough to be recorded in the routine data collections or are identified by specific studies, there are some issues with their classification. The classification of injury has generally followed the World Health Organization's International Classification of Diseases (ICD), which includes particular attention to the external cause and intention of the injury. The 10th revision of the World Health Organization's International Classification of Diseases (ICD) is now applied in Australia to deaths and (in the somewhat more extensive ‘Australian Modification') to hospitalisation . The ICD-10 classification codes injuries in terms of their nature (for example, fracture of the vault of the skull) and the external cause of the injury (for example, assault by blunt instrument) . Because it is more useful for preventive purposes, most reporting of injury is in terms of external causes, the broad categories of which are as follows: • accidents - transport accidents (including motor-vehicle accidents) and other external causes of accidental injury (falls, burns, accidental poisoning, etc.) • intentional self-harm (including suicide) • assault (including homicide) • events of undetermined intent • legal interventions and operations of war • complications of medical and surgical care • sequelae of external causes of morbidity and mortality • supplementary factors related to causes of morbidity and mortality classified elsewhere. (this coding provides for factors like alcohol involvement, including blood alcohol levels if known).
Most studies that have sought to identify risk factors have failed to explore the interplay of risk factors (for example, young males' alcohol consumption, risk-taking, and exposure to hazardous environments) . If we are to understand how these factors influence each other, more longitudinal, in-depth research is required. Such research, with greater collaboration between fields of study, should also help us identify the point in the chain of events that can offer the greatest opportunity for intervention. © Australian Indigenous HealthInfoNet 2013 This product, excluding the Australian Indigenous HealthInfoNet logo, artwork, and any material owned by a third party or protected by a trademark, has been released under a Creative Commons BY-NC-ND 3.0 (CC BY-NC-ND 3.0) licence. Excluded material owned by third parties may include, for example, design and layout, images obtained under licence from third parties and signatures.
* To whom correspondence should be addressed. Received May 17, 2001; Revision received July 10, 2001 Cadherins are a family of membrane receptors that mediate calcium-dependent homophilic cell-cell adhesion. Cadherins play a key role in the regulation of organ and tissue development during embryogenesis. In adult organisms, these proteins are responsible for formation of stable cell-cell junctions and maintenance of normal tissue structure. Disruption in expression or function of cadherins may cause uncontrolled cell migration and proliferation during tumor development.
This review focuses on the structure and physiological functions of classical cadherins. KEY WORDS: cadherins, cell-cell adhesion, morphogenesis, signaling, oncogenesis STRUCTURE OF CLASSICAL CADHERINS The majority of members of the cadherin superfamily are transmembrane glycoproteins that pass the membrane only once. The N- and C-termini of the cadherin protein chain are located outside and inside the cell, respectively (Fig. 1). The extracellular portion of the cadherin molecule consists of a varying number of so-called cadherin domains that are highly homologous to each other. Each domain is comprised of approximately 110 amino acid residues . Classical cadherins contain five cadherin domains that are commonly designated as EC1-EC5 (beginning with the N-terminus of the molecule).
The N- and C-termini of the cadherin protein chain are located outside and inside the cell, respectively (Fig. 1). The extracellular portion of the cadherin molecule consists of a varying number of so-called cadherin domains that are highly homologous to each other. Each domain is comprised of approximately 110 amino acid residues . Classical cadherins contain five cadherin domains that are commonly designated as EC1-EC5 (beginning with the N-terminus of the molecule). The conformation of the cadherin molecule is stable only in the presence of Ca2+, whose binding with the extracellular portion of the polypeptide chain is prerequisite for cadherin-mediated cell-cell adhesion. Calcium-binding sites consisting of short highly conserved amino acid sequences are located between neighboring extracellular repeats .
Classical cadherins contain five cadherin domains that are commonly designated as EC1-EC5 (beginning with the N-terminus of the molecule). The conformation of the cadherin molecule is stable only in the presence of Ca2+, whose binding with the extracellular portion of the polypeptide chain is prerequisite for cadherin-mediated cell-cell adhesion. Calcium-binding sites consisting of short highly conserved amino acid sequences are located between neighboring extracellular repeats . The cytoplasmic domain of classical cadherins is associated with the cytoplasmic proteins catenins, which, in turn, serve as intermediate linkers between the cadherins and actin filaments [10-12]. It is this cadherin-catenin complex that is required for providing normal cell-cell adhesion. In principle, extracellular cadherin domains per se are capable of homophilic recognition and binding. It was shown that cells that express mutant cadherins lacking the cytoplasmic domains can bind with substrate covered with purified cadherin ectodomains.
It is this cadherin-catenin complex that is required for providing normal cell-cell adhesion. In principle, extracellular cadherin domains per se are capable of homophilic recognition and binding. It was shown that cells that express mutant cadherins lacking the cytoplasmic domains can bind with substrate covered with purified cadherin ectodomains. However, in this case adhesion is much weaker than in the case of cells bearing full-size cadherins [11, 13, 14]. These data indicate that the formation of stable cell-cell junctions depends on the presence in the cadherin molecule of functionally active cytoplasmic domain and association of the latter with the cytoskeleton. As mentioned above, cadherins mediate homophilic adhesion: during co-culturing of different types of cells, those cells first aggregate that bear identical cadherins on their surfaces . Similar dependence between cell sorting in the developing tissues and expression of different cadherins in them is observed during embryogenesis .
Similar dependence between cell sorting in the developing tissues and expression of different cadherins in them is observed during embryogenesis . The extracellular domains (primarily, the N-terminal domain EC1) play a key role in homophilic recognition between two cadherin molecules. It was shown that cells expressing chimerical E-cadherin, in which the EC1 domain was substituted with EC1 domain of P-cadherin, did not recognize the cells bearing native E-cadherin and aggregated with the P-cadherin-expressing cells . The site responsible for homophilic recognition contains 40 amino acid residues located in the C-terminal region of EC1. Blashchuk et al. assumed that sequence His-Ala-Val located in the C-terminal region of domain EC1 plays a key role in the interaction between cadherins because synthetic peptides containing this sequence effectively blocked mouse embryo blastomere assembling (a process that is mediated by cadherins). However, later it was shown that homophilic recognition also requires the presence of other regions located in the N-terminal domain.
assumed that sequence His-Ala-Val located in the C-terminal region of domain EC1 plays a key role in the interaction between cadherins because synthetic peptides containing this sequence effectively blocked mouse embryo blastomere assembling (a process that is mediated by cadherins). However, later it was shown that homophilic recognition also requires the presence of other regions located in the N-terminal domain. In addition, it was discovered that the sequence His-Ala-Val is contained only in the molecule of classical cadherins of type I that involves E- (epithelial), N- (neural), P- (placental), VE- (vascular endothelial), and R- (retinal) cadherins. The corresponding regions of type II classical cadherins that involve recently discovered cadherins designated by numbers 5-12 contain other amino acid residues [9, 10]. Type I and II cadherins also differ from each other in some amino acid residues. Fig. 1.
The corresponding regions of type II classical cadherins that involve recently discovered cadherins designated by numbers 5-12 contain other amino acid residues [9, 10]. Type I and II cadherins also differ from each other in some amino acid residues. Fig. 1. Structure of classical cadherins and their interaction with cytoplasmic proteins . It should be noted that some cadherins can also mediate weak heterophilic interactions. In particular, E- and N-cadherin can bind with the integrin alphaEbeta7 and receptor for fibroblast growth factor [20, 21], respectively.
1. Structure of classical cadherins and their interaction with cytoplasmic proteins . It should be noted that some cadherins can also mediate weak heterophilic interactions. In particular, E- and N-cadherin can bind with the integrin alphaEbeta7 and receptor for fibroblast growth factor [20, 21], respectively. The role of the four other cadherin repeats (EC2-4) in the cell-cell interaction remains obscure. Possibly, only EC1 domain directly participate in homophilic binding, whereas the remaining domains act as spacers providing the required distance between the junction and cell surface. Nevertheless, they are required for cadherin-dependent adhesion: in the absence of other extracellular domains, the N-terminal domain alone cannot maintain functional binding or adhesive activity .
Structure of classical cadherins and their interaction with cytoplasmic proteins . It should be noted that some cadherins can also mediate weak heterophilic interactions. In particular, E- and N-cadherin can bind with the integrin alphaEbeta7 and receptor for fibroblast growth factor [20, 21], respectively. The role of the four other cadherin repeats (EC2-4) in the cell-cell interaction remains obscure. Possibly, only EC1 domain directly participate in homophilic binding, whereas the remaining domains act as spacers providing the required distance between the junction and cell surface. Nevertheless, they are required for cadherin-dependent adhesion: in the absence of other extracellular domains, the N-terminal domain alone cannot maintain functional binding or adhesive activity . Numerous data that has accumulated to date show that the extracellular cadherin fragments exist in the form of stable parallel lateral dimers.
Based on the results of X-ray analysis of NCD1, Shapiro et al. proposed the existence of a zipper-like self-assembling structure. This molecular zipper model (Fig. 2) logically explains the mechanism whereby numerous weak bonds can ensure highly efficient binding in the cell layer. However, some authors believe that cadherin zipper is an in vitro artifact and suggest an alternative hypothesis that was formulated based on the results of electron microscopic analysis of adhesive zone preparations obtained by the freeze-fracture method . Separate protein cylinders extending from one cell surface to another and binding with the similar structures on the neighboring cell are seen on the images. According to the second model, cadherin molecules (dimers or oligomers) act as discrete units and do not form zipper-like ordered structures on the cell surface .
Separate protein cylinders extending from one cell surface to another and binding with the similar structures on the neighboring cell are seen on the images. According to the second model, cadherin molecules (dimers or oligomers) act as discrete units and do not form zipper-like ordered structures on the cell surface . Fig. 2. Two models of cadherin molecular organization in adhesive junctions. The molecular zipper model based on the results of X-ray analysis of N-cadherin EC1 domain is shown on the left. The model of cylindrical oligomers based on the results of electron microscopy of zonula adherens preparations obtained by the freeze-fracture method is shown on the right .
Two models of cadherin molecular organization in adhesive junctions. The molecular zipper model based on the results of X-ray analysis of N-cadherin EC1 domain is shown on the left. The model of cylindrical oligomers based on the results of electron microscopy of zonula adherens preparations obtained by the freeze-fracture method is shown on the right . The conclusion that cadherin complexes interact with the cytoskeleton was first made based on the data that cadherins cannot be extracted with non-ionic detergents that effectively solubilized other membrane proteins [13, 25, 26]. It was shown later that the major cytoplasmic proteins associated with the cytoplasmic domain of cadherins and participating in cell adhesion are alpha- and beta-catenins, which mediate the interaction between the cadherins and actin cytoskeleton [11, 13, 25, 27-30]. The catenin-binding site was mapped on E-cadherin. It is located at the distance of 56 amino acid residues from the C-terminus of the molecule [25, 31].
The molecular zipper model based on the results of X-ray analysis of N-cadherin EC1 domain is shown on the left. The model of cylindrical oligomers based on the results of electron microscopy of zonula adherens preparations obtained by the freeze-fracture method is shown on the right . The conclusion that cadherin complexes interact with the cytoskeleton was first made based on the data that cadherins cannot be extracted with non-ionic detergents that effectively solubilized other membrane proteins [13, 25, 26]. It was shown later that the major cytoplasmic proteins associated with the cytoplasmic domain of cadherins and participating in cell adhesion are alpha- and beta-catenins, which mediate the interaction between the cadherins and actin cytoskeleton [11, 13, 25, 27-30]. The catenin-binding site was mapped on E-cadherin. It is located at the distance of 56 amino acid residues from the C-terminus of the molecule [25, 31]. Biochemical analysis with the use of purified catenins and recombinant cytoplasmic domain of cadherins [32, 33] and expression of beta-catenin deletion mutants [34-36] showed that beta-catenin directly binds to the cytoplasmic cadherin fragment and serves as a linker for alpha-catenin attachment.
The conclusion that cadherin complexes interact with the cytoskeleton was first made based on the data that cadherins cannot be extracted with non-ionic detergents that effectively solubilized other membrane proteins [13, 25, 26]. It was shown later that the major cytoplasmic proteins associated with the cytoplasmic domain of cadherins and participating in cell adhesion are alpha- and beta-catenins, which mediate the interaction between the cadherins and actin cytoskeleton [11, 13, 25, 27-30]. The catenin-binding site was mapped on E-cadherin. It is located at the distance of 56 amino acid residues from the C-terminus of the molecule [25, 31]. Biochemical analysis with the use of purified catenins and recombinant cytoplasmic domain of cadherins [32, 33] and expression of beta-catenin deletion mutants [34-36] showed that beta-catenin directly binds to the cytoplasmic cadherin fragment and serves as a linker for alpha-catenin attachment. The crucial role of the cytoplasmic domain of cadherin (and the catenin-binding site, in particular) is corroborated by numerous experiments. It was shown that deletion of the cytoplasmic domain or the catenin-binding site suppresses stable cadherin-mediated adhesion of cultured cells [11, 13].
It was shown later that the major cytoplasmic proteins associated with the cytoplasmic domain of cadherins and participating in cell adhesion are alpha- and beta-catenins, which mediate the interaction between the cadherins and actin cytoskeleton [11, 13, 25, 27-30]. The catenin-binding site was mapped on E-cadherin. It is located at the distance of 56 amino acid residues from the C-terminus of the molecule [25, 31]. Biochemical analysis with the use of purified catenins and recombinant cytoplasmic domain of cadherins [32, 33] and expression of beta-catenin deletion mutants [34-36] showed that beta-catenin directly binds to the cytoplasmic cadherin fragment and serves as a linker for alpha-catenin attachment. The crucial role of the cytoplasmic domain of cadherin (and the catenin-binding site, in particular) is corroborated by numerous experiments. It was shown that deletion of the cytoplasmic domain or the catenin-binding site suppresses stable cadherin-mediated adhesion of cultured cells [11, 13]. Alternatively, overexpression of the catenin-binding site in the cultured cells , Xenopus laevis embryos , or in the intestinal cells of transgenic mice also entails disruption of cell-cell junctions.
It is located at the distance of 56 amino acid residues from the C-terminus of the molecule [25, 31]. Biochemical analysis with the use of purified catenins and recombinant cytoplasmic domain of cadherins [32, 33] and expression of beta-catenin deletion mutants [34-36] showed that beta-catenin directly binds to the cytoplasmic cadherin fragment and serves as a linker for alpha-catenin attachment. The crucial role of the cytoplasmic domain of cadherin (and the catenin-binding site, in particular) is corroborated by numerous experiments. It was shown that deletion of the cytoplasmic domain or the catenin-binding site suppresses stable cadherin-mediated adhesion of cultured cells [11, 13]. Alternatively, overexpression of the catenin-binding site in the cultured cells , Xenopus laevis embryos , or in the intestinal cells of transgenic mice also entails disruption of cell-cell junctions. Such unusual, at first glance, result (at least, in the case of Xenopus laevis) can be, apparently, explained by competition of the expressed catenin-binding site with the endogenous cadherin for catenin binding. The evidence for participation of alpha-catenin in cell adhesion was obtained on lung carcinoma cell culture that does not contain alpha-catenin and aggregates with each other very weakly despite the presence of cadherins on the cell surface.
Alternatively, overexpression of the catenin-binding site in the cultured cells , Xenopus laevis embryos , or in the intestinal cells of transgenic mice also entails disruption of cell-cell junctions. Such unusual, at first glance, result (at least, in the case of Xenopus laevis) can be, apparently, explained by competition of the expressed catenin-binding site with the endogenous cadherin for catenin binding. The evidence for participation of alpha-catenin in cell adhesion was obtained on lung carcinoma cell culture that does not contain alpha-catenin and aggregates with each other very weakly despite the presence of cadherins on the cell surface. However, transfection with alpha-catenin cDNA restores cadherin-mediated adhesion in these cells [27, 29]. Rim et al. showed that alpha-catenin directly binds to actin filaments both in vitro and in vivo in the cultured cells. The actin-binding protein alpha-actinin contained in adhesive junctions apparently also interacts with alpha-catenin .
showed that alpha-catenin directly binds to actin filaments both in vitro and in vivo in the cultured cells. The actin-binding protein alpha-actinin contained in adhesive junctions apparently also interacts with alpha-catenin . Participation of beta-catenin in cell adhesion was confirmed in experiments on Drosophila embryos using mutation analysis of protein armadillo, a homolog of beta-catenin . beta-Catenin is attached to the cytoplasmic domain of cadherin via its central region containing so-called armadillo repeats [34, 36]. These repeats (40 amino acid resides each) were first described in protein armadillo in Drosophila [40, 41]. alpha-Catenin binds to the N-terminus of beta-catenin [32, 34-36]. The role of a linker between cadherin and alpha-catenin is apparently the only function of beta-catenin in cell adhesion.
The actin-binding protein alpha-actinin contained in adhesive junctions apparently also interacts with alpha-catenin . Participation of beta-catenin in cell adhesion was confirmed in experiments on Drosophila embryos using mutation analysis of protein armadillo, a homolog of beta-catenin . beta-Catenin is attached to the cytoplasmic domain of cadherin via its central region containing so-called armadillo repeats [34, 36]. These repeats (40 amino acid resides each) were first described in protein armadillo in Drosophila [40, 41]. alpha-Catenin binds to the N-terminus of beta-catenin [32, 34-36]. The role of a linker between cadherin and alpha-catenin is apparently the only function of beta-catenin in cell adhesion. It was shown that a chimerical molecule where the cytoplasmic domain of E-cadherin is substituted with alpha-catenin ensures cell adhesion in the absence of beta-catenin as successfully as the whole protein complex .
Participation of beta-catenin in cell adhesion was confirmed in experiments on Drosophila embryos using mutation analysis of protein armadillo, a homolog of beta-catenin . beta-Catenin is attached to the cytoplasmic domain of cadherin via its central region containing so-called armadillo repeats [34, 36]. These repeats (40 amino acid resides each) were first described in protein armadillo in Drosophila [40, 41]. alpha-Catenin binds to the N-terminus of beta-catenin [32, 34-36]. The role of a linker between cadherin and alpha-catenin is apparently the only function of beta-catenin in cell adhesion. It was shown that a chimerical molecule where the cytoplasmic domain of E-cadherin is substituted with alpha-catenin ensures cell adhesion in the absence of beta-catenin as successfully as the whole protein complex . Plakoglobin (gamma-catenin) sometimes substitutes beta-catenin in the cadherin-catenin complex .
It was shown that a chimerical molecule where the cytoplasmic domain of E-cadherin is substituted with alpha-catenin ensures cell adhesion in the absence of beta-catenin as successfully as the whole protein complex . Plakoglobin (gamma-catenin) sometimes substitutes beta-catenin in the cadherin-catenin complex . However, its physiological role is not completely understood. Plakoglobin is the major component of the desmosomes , where it is associated with the desmosomal cadherins [44, 45]. The high extent of homology of plakoglobin to beta-catenin and armadillo [26, 46] implies that these proteins may have similar functions. However, mouse embryo cells lacking beta-catenin due to genetic recombination aggregate very weakly and readily dissociate despite the presence of plakoglobin in them . This is indicative of inability of plakoglobin to completely substitute for beta-catenin in cell adhesion.
Plakoglobin (gamma-catenin) sometimes substitutes beta-catenin in the cadherin-catenin complex . However, its physiological role is not completely understood. Plakoglobin is the major component of the desmosomes , where it is associated with the desmosomal cadherins [44, 45]. The high extent of homology of plakoglobin to beta-catenin and armadillo [26, 46] implies that these proteins may have similar functions. However, mouse embryo cells lacking beta-catenin due to genetic recombination aggregate very weakly and readily dissociate despite the presence of plakoglobin in them . This is indicative of inability of plakoglobin to completely substitute for beta-catenin in cell adhesion. Deletion of the plakoglobin gene, which was also caused by homologous recombination, entails lethal changes in the heart structure and early death of the embryos, presumably due to disruptions in desmosomal junction formation .
However, mouse embryo cells lacking beta-catenin due to genetic recombination aggregate very weakly and readily dissociate despite the presence of plakoglobin in them . This is indicative of inability of plakoglobin to completely substitute for beta-catenin in cell adhesion. Deletion of the plakoglobin gene, which was also caused by homologous recombination, entails lethal changes in the heart structure and early death of the embryos, presumably due to disruptions in desmosomal junction formation . Other cytoplasmic proteins directly associated with cadherin are tyrosine phosphatases [49, 50] and the substrate for src-kinase p120cas [51-53]. Interestingly, the level of cadherin expression in the cell may affect catenin expression. Transfection of L-cells with E-, N-, or P-cadherin cDNA results in a significant increase in the catenin content without changing the catenin mRNA content. Hence, the presence of cadherins regulates catenin expression at the post-translation level .
Transfection of L-cells with E-, N-, or P-cadherin cDNA results in a significant increase in the catenin content without changing the catenin mRNA content. Hence, the presence of cadherins regulates catenin expression at the post-translation level . It was also reported that cadherin cytoplasmic domain may mediate adhesion independently of catenins. Chimerical cadherin molecules in which cadherin cytoplasmic domain was substituted for the analogous domain of desmoglein-3 (one of desmosomal cadherins) that cannot bind catenins, mediates cadherin-dependent adhesion in the cultured cells . Thus, association with catenins is not the only way of participation of the intracellular cadherin domain in cell-cell adhesion. CELL-CELL JUNCTIONS CONTAINING CADHERINS Immunohistochemical analysis of tissues and cultured cells shows that cadherins most often are constituents of cell-cell adhesive junctions (Fig. 3).
Chimerical cadherin molecules in which cadherin cytoplasmic domain was substituted for the analogous domain of desmoglein-3 (one of desmosomal cadherins) that cannot bind catenins, mediates cadherin-dependent adhesion in the cultured cells . Thus, association with catenins is not the only way of participation of the intracellular cadherin domain in cell-cell adhesion. CELL-CELL JUNCTIONS CONTAINING CADHERINS Immunohistochemical analysis of tissues and cultured cells shows that cadherins most often are constituents of cell-cell adhesive junctions (Fig. 3). This type of junctions involves autotypic junctions between the layers of the same glial cell in the axon myelin sheath ; adhesive junctions in synapses, where cadherins link pre- and postsynaptic membranes in the regions adjacent to the neurotransmitter secretion areas [57, 58]; the intermediate disks between the cardiomyocytes ; and some other. The best-known type of cell-cell adhesive junctions is zonula adherens located at the apico-lateral border of the epithelial layer a little lower than the tight junctions. Actin bunches attached to the adhesive junctions girding the cell on the cytoplasmic side are located parallel to the membrane surface and form a united contracting network in the epithelial layer.
Thus, association with catenins is not the only way of participation of the intracellular cadherin domain in cell-cell adhesion. CELL-CELL JUNCTIONS CONTAINING CADHERINS Immunohistochemical analysis of tissues and cultured cells shows that cadherins most often are constituents of cell-cell adhesive junctions (Fig. 3). This type of junctions involves autotypic junctions between the layers of the same glial cell in the axon myelin sheath ; adhesive junctions in synapses, where cadherins link pre- and postsynaptic membranes in the regions adjacent to the neurotransmitter secretion areas [57, 58]; the intermediate disks between the cardiomyocytes ; and some other. The best-known type of cell-cell adhesive junctions is zonula adherens located at the apico-lateral border of the epithelial layer a little lower than the tight junctions. Actin bunches attached to the adhesive junctions girding the cell on the cytoplasmic side are located parallel to the membrane surface and form a united contracting network in the epithelial layer. Assembling of the belt-like zonula adherens is apparently the basis for the occurrence of the epithelial morphology of the cell layer [60-63].
This type of junctions involves autotypic junctions between the layers of the same glial cell in the axon myelin sheath ; adhesive junctions in synapses, where cadherins link pre- and postsynaptic membranes in the regions adjacent to the neurotransmitter secretion areas [57, 58]; the intermediate disks between the cardiomyocytes ; and some other. The best-known type of cell-cell adhesive junctions is zonula adherens located at the apico-lateral border of the epithelial layer a little lower than the tight junctions. Actin bunches attached to the adhesive junctions girding the cell on the cytoplasmic side are located parallel to the membrane surface and form a united contracting network in the epithelial layer. Assembling of the belt-like zonula adherens is apparently the basis for the occurrence of the epithelial morphology of the cell layer [60-63]. During morphogenesis, folding of the epithelial layers into tubes is often attained by contraction of actin filaments contained in the zonula adherens, which is associated with narrowing the apical end of each cell in the apical layer and results in the cell layer bending [64, 65]. Besides cadherins and catenins, adhesive junctions contain numerous proteins (such as vinculin, ezrin, moesin, and radixin), protein components of the actin cytoskeleton, and integral membrane proteins (e.g., epidermal growth factor receptor, EGF) . Genetic studies on Drosophila revealed other components required for adhesive junction assembly.
The best-known type of cell-cell adhesive junctions is zonula adherens located at the apico-lateral border of the epithelial layer a little lower than the tight junctions. Actin bunches attached to the adhesive junctions girding the cell on the cytoplasmic side are located parallel to the membrane surface and form a united contracting network in the epithelial layer. Assembling of the belt-like zonula adherens is apparently the basis for the occurrence of the epithelial morphology of the cell layer [60-63]. During morphogenesis, folding of the epithelial layers into tubes is often attained by contraction of actin filaments contained in the zonula adherens, which is associated with narrowing the apical end of each cell in the apical layer and results in the cell layer bending [64, 65]. Besides cadherins and catenins, adhesive junctions contain numerous proteins (such as vinculin, ezrin, moesin, and radixin), protein components of the actin cytoskeleton, and integral membrane proteins (e.g., epidermal growth factor receptor, EGF) . Genetic studies on Drosophila revealed other components required for adhesive junction assembly. In particular, the genes whose mutations lead to disruptions in the course of zonula adherens assembling were identified in studies on Drosophila embryos.
Besides cadherins and catenins, adhesive junctions contain numerous proteins (such as vinculin, ezrin, moesin, and radixin), protein components of the actin cytoskeleton, and integral membrane proteins (e.g., epidermal growth factor receptor, EGF) . Genetic studies on Drosophila revealed other components required for adhesive junction assembly. In particular, the genes whose mutations lead to disruptions in the course of zonula adherens assembling were identified in studies on Drosophila embryos. They involve the gene of beta-catenin homolog, armadillo, which is completely consistent with the view on the key role of this protein in cadherin-mediated adhesion [30, 67], as well as the genes crumb and stardust [67-69]. It was shown that gene crumb encodes the integral membrane protein that is required for epithelization of the ectodermic cells. In mutant individuals with inactive crumb gene normal cadherin-catenin complexes are expressed on the cell surface; however, their distribution is chaotic, leading to disruption in formation of mature zonula adherens in the epithelium [68-70]. Fig.
In particular, the genes whose mutations lead to disruptions in the course of zonula adherens assembling were identified in studies on Drosophila embryos. They involve the gene of beta-catenin homolog, armadillo, which is completely consistent with the view on the key role of this protein in cadherin-mediated adhesion [30, 67], as well as the genes crumb and stardust [67-69]. It was shown that gene crumb encodes the integral membrane protein that is required for epithelization of the ectodermic cells. In mutant individuals with inactive crumb gene normal cadherin-catenin complexes are expressed on the cell surface; however, their distribution is chaotic, leading to disruption in formation of mature zonula adherens in the epithelium [68-70]. Fig. 3. Cell-cell junctions formed by cadherins: a) epithelial zonula adherens; b) intermediate disks between the cardiomyocytes; c) adhesive junctions restricting the area of neurotransmitter secretion in the synapse; d) autotypic junctions between the glial cell layers in axon myelin sheath .
It was shown that gene crumb encodes the integral membrane protein that is required for epithelization of the ectodermic cells. In mutant individuals with inactive crumb gene normal cadherin-catenin complexes are expressed on the cell surface; however, their distribution is chaotic, leading to disruption in formation of mature zonula adherens in the epithelium [68-70]. Fig. 3. Cell-cell junctions formed by cadherins: a) epithelial zonula adherens; b) intermediate disks between the cardiomyocytes; c) adhesive junctions restricting the area of neurotransmitter secretion in the synapse; d) autotypic junctions between the glial cell layers in axon myelin sheath . It should be noted that in many cells cadherins can mediate adhesion without formation of morphologically pronounced adhesive junctions. Even in the epithelium of some organs, where cell-cell adhesion depends on E-cadherin, zonula adherens is absent .
It should be noted that in many cells cadherins can mediate adhesion without formation of morphologically pronounced adhesive junctions. Even in the epithelium of some organs, where cell-cell adhesion depends on E-cadherin, zonula adherens is absent . Cadherin-mediated adhesion without cadherin accumulation in the adhesive junctions was also described for blastomeres , nerve ridge cells , and fibroblasts transfected with different types of cadherins . REGULATION OF CADHERIN ACTIVITY Cadherin-mediated adhesion can be regulated by a variety of extracellular signals, including growth factors [72-74], peptide hormones [75, 76], signals from gap junctions , and cholinergic receptor agonists . In response to these external stimuli, different signals are generated in the cell, of which protein phosphorylation is, apparently, the most important for the regulation of cadherin function . Protein kinase C (PKC) participates in the activation of E-cadherin-dependent mouse embryo cell compacting, which was demonstrated with the use of a combination of pharmacological agonists and antagonists. Embryo compacting is accelerated by the addition of PKC-stimulating agents (e.g., phorbol ester and diacylglycerol) and inhibited by PKC-blocking agents , the PKC effect being blocked by the addition of anti-E-cadherin antibodies.
However, it was not determined which PKC-mediated way is activated in this case. Using a similar experimental approach, a potential inhibitory effect of tyrosine phosphorylation on cadherin function was shown. Several scientific groups discovered that enhancement of tyrosine phosphorylation (transfection with v-src or incubation of the cells with pervanadate) weakens cadherin-mediated cell-cell adhesion. Components of the cadherin-catenin complex (primarily beta-catenin) undergo tyrosine phosphorylation in response to v-src transfection and incubation with pervanadate [80-82]. Attenuation of adhesion in these experiments was blocked by herbimicin, which is also indicative of participation of tyrosine phosphorylation in the regulation of cadherin activity. It was also shown that v-src can affect cadherin-mediated adhesion irrespective of beta-catenin . The authors of this work used mutant E-cadherin that could directly bind with the C-terminal fragment of alpha-catenin and induce adhesion without the participation of beta-catenin.
Tyrosine phosphorylation of beta-catenin is observed when cells are treated with hepatocyte growth factor (HGF) and EGF (agents that can induce dissociation of epithelial cells) . Tyrosine kinases or their substrates can associate with the cadherin-catenin complex. It is known that p120cas, a member of the armadillo protein family, is a substrate for both src kinases and receptor tyrosine kinases . It was shown that p120cas directly binds to the distal part of the cytoplasmic domain of E-cadherin, forming a whole complex with cadherin and beta-catenin or plakoglobin [52, 53, 84, 85]. Activation of the Erb-2/Neu receptor tyrosine kinase in the epithelial cells causes disassembling of the cell-cell junctions formed by E-cadherin, which results in the loss of the epithelial phenotype by the cells . EGF receptor tyrosine kinase also can bind to the cadherin-catenin complex . In addition, it was shown that cadherin-catenin complex can interact with receptor-dependent tyrosine phosphatases [49, 50, 88].
Tyrosine kinases or their substrates can associate with the cadherin-catenin complex. It is known that p120cas, a member of the armadillo protein family, is a substrate for both src kinases and receptor tyrosine kinases . It was shown that p120cas directly binds to the distal part of the cytoplasmic domain of E-cadherin, forming a whole complex with cadherin and beta-catenin or plakoglobin [52, 53, 84, 85]. Activation of the Erb-2/Neu receptor tyrosine kinase in the epithelial cells causes disassembling of the cell-cell junctions formed by E-cadherin, which results in the loss of the epithelial phenotype by the cells . EGF receptor tyrosine kinase also can bind to the cadherin-catenin complex . In addition, it was shown that cadherin-catenin complex can interact with receptor-dependent tyrosine phosphatases [49, 50, 88]. Cadherin function may also be affected by cell-cell communication via gap junctions.
It was shown that p120cas directly binds to the distal part of the cytoplasmic domain of E-cadherin, forming a whole complex with cadherin and beta-catenin or plakoglobin [52, 53, 84, 85]. Activation of the Erb-2/Neu receptor tyrosine kinase in the epithelial cells causes disassembling of the cell-cell junctions formed by E-cadherin, which results in the loss of the epithelial phenotype by the cells . EGF receptor tyrosine kinase also can bind to the cadherin-catenin complex . In addition, it was shown that cadherin-catenin complex can interact with receptor-dependent tyrosine phosphatases [49, 50, 88]. Cadherin function may also be affected by cell-cell communication via gap junctions. Inhibition of cell-cell communication by expression of the chimerical protein connexin 32/connexin 43 inhibitor (a protein that forms gap junctions) in Xenopus embryo cells leads to blastomere separation. A similar effect is observed when mutant cadherin is expressed in the embryo cells.
EGF receptor tyrosine kinase also can bind to the cadherin-catenin complex . In addition, it was shown that cadherin-catenin complex can interact with receptor-dependent tyrosine phosphatases [49, 50, 88]. Cadherin function may also be affected by cell-cell communication via gap junctions. Inhibition of cell-cell communication by expression of the chimerical protein connexin 32/connexin 43 inhibitor (a protein that forms gap junctions) in Xenopus embryo cells leads to blastomere separation. A similar effect is observed when mutant cadherin is expressed in the embryo cells. This phenotype can be corrected by coexpression of connexin 37 that is insensitive to the inhibitor . Similarly, cell-cell junction assembling in Novikov hepatoma cells is suppressed by anti-connexin and anti-cadherin antibodies .
Cadherin function may also be affected by cell-cell communication via gap junctions. Inhibition of cell-cell communication by expression of the chimerical protein connexin 32/connexin 43 inhibitor (a protein that forms gap junctions) in Xenopus embryo cells leads to blastomere separation. A similar effect is observed when mutant cadherin is expressed in the embryo cells. This phenotype can be corrected by coexpression of connexin 37 that is insensitive to the inhibitor . Similarly, cell-cell junction assembling in Novikov hepatoma cells is suppressed by anti-connexin and anti-cadherin antibodies . The mechanism of signal transduction mediated by the gap junctions remains obscure. It is assumed that in this case cadherin-dependent adhesion and cell-cell junction assembling may be regulated via temporal increase in the concentration of Ca2+ and other small signal molecules (such as cyclic nucleotides or inositol phosphate) penetrating through the gap junctions and activating the intracellular processes that affect cadherin activity.
The mechanism of signal transduction mediated by the gap junctions remains obscure. It is assumed that in this case cadherin-dependent adhesion and cell-cell junction assembling may be regulated via temporal increase in the concentration of Ca2+ and other small signal molecules (such as cyclic nucleotides or inositol phosphate) penetrating through the gap junctions and activating the intracellular processes that affect cadherin activity. The strength of cell-cell interactions can be affected both by modulating cadherin activity and changing their expression level in the cell. It was demonstrated that an increase in cadherin content enhances cell adhesion [7, 90, 91]. It was also shown that cadherin expression in cultured cells is regulated by growth factors and peptide hormones [72, 73, 75, 76]. Another mechanism of regulation of cadherin activity is changing the extent of clustering of cadherin molecules in the junction area. As was mentioned above, lateral clustering of cadherin molecules can significantly affect the strength of cell-cell interaction.
It is assumed that in this case cadherin-dependent adhesion and cell-cell junction assembling may be regulated via temporal increase in the concentration of Ca2+ and other small signal molecules (such as cyclic nucleotides or inositol phosphate) penetrating through the gap junctions and activating the intracellular processes that affect cadherin activity. The strength of cell-cell interactions can be affected both by modulating cadherin activity and changing their expression level in the cell. It was demonstrated that an increase in cadherin content enhances cell adhesion [7, 90, 91]. It was also shown that cadherin expression in cultured cells is regulated by growth factors and peptide hormones [72, 73, 75, 76]. Another mechanism of regulation of cadherin activity is changing the extent of clustering of cadherin molecules in the junction area. As was mentioned above, lateral clustering of cadherin molecules can significantly affect the strength of cell-cell interaction. Changes in the extent of clustering can mediate rapid changes in cell adhesion strength.
Changes in the extent of clustering can mediate rapid changes in cell adhesion strength. For example, mouse embryo blastomere compacting is associated with E-cadherin redistribution in the region of cell-cell junctions without any change in protein expression . CADHERINS AND SIGNALING To date, numerous data indicate that cell adhesion receptors can affect cell form, motility, and growth not only due to mechanical attachment of the cells to each other or to the substrate, but also by activating internal signaling . Some papers report that many effects of cadherin on cell behavior are rapid and apparently caused by a series of short-term signals rather than by assembling stable long-term cell-cell junctions [4, 6, 94]. However, until recently only indirect evidence of cadherin ability to induce the production of secondary messengers in the cell have been known. For instance, it was shown that axon outgrowth stimulated by N-cadherin is associated with changes in the cytoplasmic Ca2+ concentration and activation of G-proteins and tyrosine kinases. However, it was not clear whether these signals result from the direct interaction of N-cadherin molecules [95, 96].