<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Complex post-traumatic stress disorder and can you explain it in depth? [/INST] Complex post-traumatic stress disorder (C-PTSD; also known as complex trauma disorder) is a psychological disorder that is theorized to develop in response to exposure to a series of traumatic events in a context in which the individual perceives little or no chance of escape, and particularly where the exposure is prolonged or repetitive. It is not yet recognized by the American Psychiatric Association or the DSM-5 as a valid disorder, although was added to the eleventh revision of the International Classification of Diseases (ICD-11). In addition to the symptoms of post-traumatic stress disorder (PTSD), an individual with C-PTSD experiences emotional dysregulation, negative self-beliefs and feelings of shame, guilt or failure regarding the trauma, and interpersonal difficulties. C-PTSD relates to the trauma model of mental disorders and is associated with chronic sexual, psychological, and physical abuse or neglect, or chronic intimate partner violence, bullying, victims of kidnapping and hostage situations, indentured servants, victims of slavery and human trafficking, sweatshop workers, prisoners of war, concentration camp survivors, and prisoners kept in solitary confinement for a long period of time, or defectors from authoritarian religions. Situations involving captivity/entrapment (a situation lacking a viable escape route for the victim or a perception of such) can lead to C-PTSD-like symptoms, which can include prolonged feelings of terror, worthlessness, helplessness, and deformation of ones identity and sense of self.C-PTSD has also been referred to as Enduring Personality Change after Catastrophic Event (EPCACE)  and/or Disorders of Extreme Stress - not otherwise specified (DESNOS)Some researchers believe that C-PTSD is distinct from, but similar to, PTSD, somatization disorder, dissociative identity disorder, and borderline personality disorder. Its main distinctions are a distortion of the persons core identity and significant emotional dysregulation. It was first described in 1992 by American psychiatrist and scholar Judith Lewis Herman in her book Trauma & Recovery and an accompanying article.
The disorder is included in the World Health Organizations (WHO) eleventh revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11). The C-PTSD criteria has not yet gone through the private approval board of the American Psychiatric Association (APA) for inclusion in the Diagnostic and Statistical Manual of Mental Disorders (DSM). Complex PTSD is also recognized by the United States Department of Veterans Affairs (VA), Healthdirect Australia (HDA), and the British National Health Service (NHS).

Symptoms
Children and adolescents
The diagnosis of PTSD was originally developed for adults who had suffered from a single-event trauma, such as rape, or a traumatic experience during a war. However, the situation for many children is quite different. Children can suffer chronic trauma such as maltreatment, family violence, dysfunction, or a disruption in attachment to their primary caregiver. In many cases, it is the childs caregiver who causes the trauma. The diagnosis of PTSD does not take into account how the developmental stages of children may affect their symptoms and how trauma can affect a childs development.The term developmental trauma disorder (DTD) has been proposed as the childhood equivalent of C-PTSD. This developmental form of trauma places children at risk for developing psychiatric and medical disorders. Bessel van der Kolk explains DTD as numerous encounters with interpersonal trauma such as physical assault, sexual assault, violence or death. It can also be brought on by subjective events such as abandonment, betrayal, defeat or shame.Repeated traumatization during childhood leads to symptoms that differ from those described for PTSD. Cook and others describe symptoms and behavioral characteristics in seven domains:
Attachment – "problems with relationship boundaries, lack of trust, social isolation, difficulty perceiving and responding to others emotional states"
Biology – "sensory-motor developmental dysfunction, sensory-integration difficulties, somatization, and increased medical problems"
Affect or emotional regulation – "poor affect regulation, difficulty identifying and expressing emotions and internal states, and difficulties communicating needs, wants, and wishes"
Dissociation – "amnesia, depersonalization, discrete states of consciousness with discrete memories, affect, and functioning, and impaired memory for state-based events"
Behavioral control – "problems with impulse control, aggression, pathological self-soothing, and sleep problems"
Cognition – "difficulty regulating attention; problems with a variety of executive functions such as planning, judgement, initiation, use of materials, and self-monitoring; difficulty processing new information; difficulty focusing and completing tasks; poor object constancy; problems with cause-effect thinking; and language developmental problems such as a gap between receptive and expressive communication abilities."
Self-concept – "fragmented and disconnected autobiographical narrative, disturbed body image, low self-esteem, excessive shame, and negative internal working models of self".

Adults
Adults with C-PTSD have sometimes experienced prolonged interpersonal traumatization beginning in childhood, rather than, or as well as, in adulthood. These early injuries interrupt the development of a robust sense of self and of others. Because physical and emotional pain or neglect was often inflicted by attachment figures such as caregivers or older siblings, these individuals may develop a sense that they are fundamentally flawed and that others cannot be relied upon. This can become a pervasive way of relating to others in adult life, described as insecure attachment. This symptom is neither included in the diagnosis of dissociative disorder nor in that of PTSD in the current DSM-5 (2013). Individuals with Complex PTSD also demonstrate lasting personality disturbances with a significant risk of revictimization.Six clusters of symptoms have been suggested for diagnosis of C-PTSD:
Alterations in regulation of affect and impulses
Alterations in attention or consciousness
Alterations in self-perception
Alterations in relations with others
Somatization
Alterations in systems of meaningExperiences in these areas may include:: 199–122
Changes in emotional regulation, including experiences such as persistent dysphoria, chronic suicidal preoccupation, self-injury, explosive or extremely inhibited anger (may alternate), and compulsive or extremely inhibited sexuality (may alternate).
Variations in consciousness, such as amnesia or improved recall for traumatic events, episodes of dissociation, depersonalization/derealization, and reliving experiences (either in the form of intrusive PTSD symptoms or in ruminative preoccupation).
Changes in self-perception, such as a sense of helplessness or paralysis of initiative, shame, guilt and self-blame, a sense of defilement or stigma, and a sense of being completely different from other human beings (may include a sense of specialness, utter aloneness, a belief that no other person can understand, or a feeling of nonhuman identity).
Varied changes in perception of the perpetrators, such as a preoccupation with the relationship with a perpetrator (including a preoccupation with revenge), an unrealistic attribution of total power to a perpetrator (though the individuals assessment may be more realistic than the clinicians), idealization or paradoxical gratitude, a sense of a special or supernatural relationship with a perpetrator, and acceptance of a perpetrators belief system or rationalizations.
Alterations in relations with others, such as isolation and withdrawal, disruption in intimate relationships, a repeated search for a rescuer (may alternate with isolation and withdrawal), persistent distrust, and repeated failures of self-protection.
Changes in systems of meaning, such as a loss of sustaining faith and a sense of hopelessness and despair.

Diagnostics
C-PTSD was considered for inclusion in the DSM-IV but was not included when the DSM-IV was published in 1994. It was also not included in the DSM-5, though post-traumatic stress disorder continues to be listed as a disorder.

Differential diagnosis
Post-traumatic stress disorder
Post-traumatic stress disorder (PTSD) was included in the DSM-III (1980), mainly due to the relatively large numbers of American combat veterans of the Vietnam War who were seeking treatment for the lingering effects of combat stress. In the 1980s, various researchers and clinicians suggested that PTSD might also accurately describe the sequelae of such traumas as child sexual abuse and domestic abuse. However, it was soon suggested that PTSD failed to account for the cluster of symptoms that were often observed in cases of prolonged abuse, particularly that which was perpetrated against children by caregivers during multiple childhood and adolescent developmental stages. Such patients were often extremely difficult to treat with established methods.PTSD descriptions fail to capture some of the core characteristics of C-PTSD. These elements include captivity, psychological fragmentation, the loss of a sense of safety, trust, and self-worth, as well as the tendency to be revictimized. Most importantly, there is a loss of a coherent sense of self: this loss, and the ensuing symptom profile, most pointedly differentiates C-PTSD from PTSD.: 199–122 C-PTSD is also characterized by attachment disorder, particularly the pervasive insecure, or disorganized-type attachment. DSM-IV (1994) dissociative disorders and PTSD do not include insecure attachment in their criteria. As a consequence of this aspect of C-PTSD, when some adults with C-PTSD become parents and confront their own childrens attachment needs, they may have particular difficulty in responding sensitively especially to their infants and young childrens routine distress – such as during routine separations, despite these parents best intentions and efforts. Although the great majority of survivors do not abuse others, this difficulty in parenting may have adverse repercussions for their childrens social and emotional development if parents with this condition and their children do not receive appropriate treatment.Thus, a differentiation between the diagnostic category of C-PTSD and that of PTSD has been suggested. C-PTSD better describes the pervasive negative impact of chronic repetitive trauma than does PTSD alone. PTSD can exist alongside C-PTSD; however a sole diagnosis of PTSD often does not sufficiently encapsulate the breadth of symptoms experienced by those who have experienced prolonged traumatic experience, and therefore C-PTSD extends beyond the PTSD parameters.C-PTSD also differs from continuous traumatic stress disorder (CTSD), which was introduced into the trauma literature by Gill Straker (1987). It was originally used by South African clinicians to describe the effects of exposure to frequent, high levels of violence usually associated with civil conflict and political repression. The term is also applicable to the effects of exposure to contexts in which gang violence and crime are endemic as well as to the effects of ongoing exposure to life threats in high-risk occupations such as police, fire and emergency services.

Traumatic grief
Traumatic grief or complicated mourning are conditions where both trauma and grief coincide. There are conceptual links between trauma and bereavement since loss of a loved one is inherently traumatic. If a traumatic event was life-threatening, but did not result in a death, then it is more likely that the survivor will experience post-traumatic stress symptoms. If a person dies, and the survivor was close to the person who died, then it is more likely that symptoms of grief will also develop. When the death is of a loved one, and was sudden or violent, then both symptoms often coincide. This is likely in children exposed to community violence.For C-PTSD to manifest traumatic grief, the violence would occur under conditions of captivity, loss of control and disempowerment, coinciding with the death of a friend or loved one in life-threatening circumstances. This again is most likely for children and stepchildren who experience prolonged domestic or chronic community violence that ultimately results in the death of friends and loved ones. The phenomenon of the increased risk of violence and death of stepchildren is referred to as the Cinderella effect.

Borderline personality disorder
C-PTSD may share some symptoms with both PTSD and borderline personality disorder (BPD). However, there is enough evidence to also differentiate C-PTSD from borderline personality disorder.
It may help to understand the intersection of attachment theory with C-PTSD and BPD if one reads the following opinion of Bessel A. van der Kolk together with an understanding drawn from a description of BPD:

Uncontrollable disruptions or distortions of attachment bonds precede the development of post-traumatic stress syndromes. People seek increased attachment in the face of danger. Adults, as well as children, may develop strong emotional ties with people who intermittently harass, beat, and, threaten them. The persistence of these attachment bonds leads to confusion of pain and love. Trauma can be repeated on behavioural, emotional, physiologic, and neuroendocrinologic levels. Repetition on these different levels causes a large variety of individual and social suffering.

However, C-PTSD and BPD have been found by some researchers to be distinctive disorders with different features. Those with C-PTSD do not fear abandonment or have unstable patterns of relations; rather, they withdraw. There are distinct and notably large differences between BPD and C-PTSD and while there are some similarities – predominantly in terms of issues with attachment (though this plays out in different ways) and trouble regulating strong emotional affects – the disorders are different in nature.

While the individuals in the BPD reported many of the symptoms of PTSD and CPTSD, the BPD class was clearly distinct in its endorsement of symptoms unique to BPD. The RR ratios presented in Table 5 revealed that the following symptoms were highly indicative of placement in the BPD rather than the CPTSD class: (1) frantic efforts to avoid real or imagined abandonment, (2) unstable and intense interpersonal relationships characterized by alternating between extremes of idealization and devaluation, (3) markedly and persistently unstable self-image or sense of self, and (4) impulsiveness. Given the gravity of suicidal and self-injurious behaviors, it is important to note that there were also marked differences in the presence of suicidal and self-injurious behaviors with approximately 50% of individuals in the BPD class reporting this symptom but much fewer and an equivalent number doing so in the CPTSD and PTSD classes (14.3 and 16.7%, respectively). The only BPD symptom that individuals in the BPD class did not differ from the CPTSD class was chronic feelings of emptiness, suggesting that in this sample, this symptom is not specific to either BPD or CPTSD and does not discriminate between them.

Overall, the findings indicate that there are several ways in which complex PTSD and BPD differ, consistent with the proposed diagnostic formulation of CPTSD. BPD is characterized by fears of abandonment, unstable sense of self, unstable relationships with others, and impulsive and self-harming behaviors. In contrast, in CPTSD as in PTSD, there was little endorsement of items related to instability in self-representation or relationships. Self-concept is likely to be consistently negative and relational difficulties concern mostly avoidance of relationships and sense of alienation.
In addition, 25% of those diagnosed with BPD have no known history of childhood neglect or abuse and individuals are six times as likely to develop BPD if they have a relative who was so diagnosed compared to those who do not. One conclusion is that there is a genetic predisposition to BPD unrelated to trauma. Researchers conducting a longitudinal investigation of identical twins found that "genetic factors play a major role in individual differences of borderline personality disorder features in Western society." A 2014 study published in European Journal of Psychotraumatology was able to compare and contrast C-PTSD, PTSD, Borderline Personality Disorder and found that it could distinguish between individual cases of each and when it was co-morbid, arguing for a case of separate diagnoses for each. BPD may be confused with C-PTSD by some without proper knowledge of the two conditions because those with BPD also tend to have PTSD or to have some history of trauma.
In Trauma and Recovery, Herman expresses the additional concern that patients with C-PTSD frequently risk being misunderstood as inherently dependent, masochistic, or self-defeating, comparing this attitude to the historical misdiagnosis of female hysteria. However, those who develop C-PTSD do so as a result of the intensity of the traumatic bond – in which someone becomes tightly biolo-chemically bound to someone who abuses them and the responses they learned to survive, navigate and deal with the abuse they suffered then become automatic responses, imbedded in their personality over the years of trauma – a normal reaction to an abnormal situation.

Treatment
While standard evidence-based treatments may be effective for treating post traumatic stress disorder, treating complex PTSD often involves addressing interpersonal relational difficulties and a different set of symptoms which make it more challenging to treat. According to the United States Department of Veteran Affairs:

The current PTSD diagnosis often does not fully capture the severe psychological harm that occurs with prolonged, repeated trauma. People who experience chronic trauma often report additional symptoms alongside formal PTSD symptoms, such as changes in their self-concept and the way they adapt to stressful events.

The utility of PTSD-derived psychotherapies for assisting children with C-PTSD is uncertain. This area of diagnosis and treatment calls for caution in use of the category C-PTSD. Dr. Julian Ford and Dr. Bessel van der Kolk have suggested that C-PTSD may not be as useful a category for diagnosis and treatment of children as a proposed category of developmental trauma disorder (DTD).: 60  According to Courtois & Ford, for DTD to be diagnosed it requires a

history of exposure to early life developmentally adverse interpersonal trauma such as sexual abuse, physical abuse, violence, traumatic losses or other significant disruption or betrayal of the childs relationships with primary caregivers, which has been postulated as an etiological basis for complex traumatic stress disorders. Diagnosis, treatment planning and outcome are always relational.

Since C-PTSD or DTD in children is often caused by chronic maltreatment, neglect or abuse in a care-giving relationship the first element of the biopsychosocial system to address is that relationship. This invariably involves some sort of child protection agency. This both widens the range of support that can be given to the child but also the complexity of the situation, since the agencys statutory legal obligations may then need to be enforced.
A number of practical, therapeutic and ethical principles for assessment and intervention have been developed and explored in the field:: 67
Identifying and addressing threats to the childs or familys safety and stability are the first priority.
A relational bridge must be developed to engage, retain and maximize the benefit for the child and caregiver.
Diagnosis, treatment planning and outcome monitoring are always relational (and) strengths based.
All phases of treatment should aim to enhance self-regulation competencies.
Determining with whom, when and how to address traumatic memories.
Preventing and managing relational discontinuities and psychosocial crises.

Adults
Trauma recovery model
Judith Lewis Herman, in her book, Trauma and Recovery, proposed a complex trauma recovery model that occurs in three stages:

Establishing safety
Remembrance and mourning for what was lost
Reconnecting with community and more broadly, societyHerman believes recovery can only occur within a healing relationship and only if the survivor is empowered by that relationship. This healing relationship need not be romantic or sexual in the colloquial sense of "relationship", however, and can also include relationships with friends, co-workers, ones relatives or children, and the therapeutic relationship.Complex trauma means complex reactions and this leads to complex treatments. Hence, treatment for C-PTSD requires a multi-modal approach.It has been suggested that treatment for complex PTSD should differ from treatment for PTSD by focusing on problems that cause more functional impairment than the PTSD symptoms. These problems include emotional dysregulation, dissociation, and interpersonal problems. Six suggested core components of complex trauma treatment include:
Safety
Self-regulation
Self-reflective information processing
Traumatic experiences integration
Relational engagement
Positive affect enhancementThe above components can be conceptualized as a model with three phases. Every case will not be the same, but one can expect the first phase to consist of teaching adequate coping strategies and addressing safety concerns. The next phase would focus on decreasing avoidance of traumatic stimuli and applying coping skills learned in phase one. The care provider may also begin challenging assumptions about the trauma and introducing alternative narratives about the trauma. The final phase would consist of solidifying what has previously been learned and transferring these strategies to future stressful events.

Neuroscientific and trauma informed interventions
In practice, the forms of treatment and intervention varies from individual to individual since there is a wide spectrum of childhood experiences of developmental trauma and symptomatology and not all survivors respond positively, uniformly, to the same treatment. Therefore, treatment is generally tailored to the individual. Recent neuroscientific research has shed some light on the impact that severe childhood abuse and neglect (trauma) has on a childs developing brain, specifically as it relates to the development in brain structures, function and connectivity among children from infancy to adulthood. This understanding of the neurophysiological underpinning of complex trauma phenomena is what currently is referred to in the field of traumatology as trauma informed which has become the rationale which has influenced the development of new treatments specifically targeting those with childhood developmental trauma.
Dr. Martin Teicher, a Harvard psychiatrist and researcher, has suggested that the development of specific complex trauma related symptomatology (and in fact the development of many adult onset psychopathologies) may be connected to gender differences and at what stage of childhood development trauma, abuse or neglect occurred. For example, it is well established that the development of dissociative identity disorder among women is often associated with early childhood sexual abuse.

Use of evidence-based treatment and its limitations
One of the current challenges faced by many survivors of complex trauma (or developmental trauma disorder) is support for treatment since many of the current therapies are relatively expensive and not all forms of therapy or intervention are reimbursed by insurance companies who use evidence-based practice as a criteria for reimbursement. Cognitive behavioral therapy, prolonged exposure therapy and dialectical behavioral therapy are well established forms of evidence-based intervention. These treatments are approved and endorsed by the American Psychiatric Association, the American Psychological Association and the Veterans Administration.
While standard evidence-based treatments may be effective for treating standard post-traumatic stress disorder, treating complex PTSD often involves addressing interpersonal relational difficulties and a different set of symptoms which make it more challenging to treat. The United States Department of Veterans Affairs acknowledges,

the current PTSD diagnosis often does not fully capture the severe psychological harm that occurs with prolonged, repeated trauma. People who experience chronic trauma often report additional symptoms alongside formal PTSD symptoms, such as changes in their self-concept and the way they adapt to stressful events.
For example, "Limited evidence suggests that predominantly [Cognitive behavioral therapy] CBT [evidence-based] treatments are effective, but do not suffice to achieve satisfactory end states, especially in Complex PTSD populations."

Treatment challenges
It is widely acknowledged by those who work in the trauma field that there is no one single, standard, one size fits all treatment for complex PTSD. There is also no clear consensus regarding the best treatment among the greater mental health professional community which included clinical psychologists, social workers, licensed therapists MFTs) and psychiatrists. Although most trauma neuroscientifically informed practitioners understand the importance of utilizing a combination of both top down and bottom up interventions as well as including somatic interventions (sensorimotor psychotherapy or somatic experiencing or yoga) for the purposes of processing and integrating trauma memories.
Survivors with complex trauma often struggle to find a mental health professional who is properly trained in trauma informed practices. They can also be challenging to receive adequate treatment and services to treat a mental health condition which is not universally recognized or well understood by general practitioners.
Allistair and Hull echo the sentiment of many other trauma neuroscience researchers (including Bessel van der Kolk and Bruce D. Perry) who argue:

Complex presentations are often excluded from studies because they do not fit neatly into the simple nosological categorisations required for research power. This means that the most severe disorders are not studied adequately and patients most affected by early trauma are often not recognised by services. Both historically and currently, at the individual as well as the societal level, "dissociation from the acknowledgement of the severe impact of childhood abuse on the developing brain leads to inadequate provision of services. Assimilation into treatment models of the emerging affective neuroscience of adverse experience could help to redress the balance by shifting the focus from top-down regulation to bottom-up, body-based processing."

Complex post trauma stress disorder is a long term mental health condition which is often difficult and relatively expensive to treat and often requires several years of psychotherapy, modes of intervention and treatment by highly skilled, mental health professionals who specialize in trauma informed modalities designed to process and integrate childhood trauma memories for the purposes of mitigating symptoms and improving the survivors quality of life. Delaying therapy for people with complex PTSD, whether intentionally or not, can exacerbate the condition.

Recommended treatment modalities and interventions
There is no one treatment which has been designed specifically for use with the adult complex PTSD population (with the exception of component based psychotherapy ) there are many therapeutic interventions used by mental health professionals to treat PTSD. As of February 2017, the American Psychological Association PTSD Guideline Development Panel (GDP) strongly recommends the following for the treatment of PTSD:
Cognitive behavioral therapy (CBT) and trauma focused CBT
Cognitive processing therapy (CPT)
Cognitive therapy (CT)
Prolonged exposure therapy (PE)The American Psychological Association also conditionally recommends
Brief eclectic psychotherapy (BEP)
Eye movement desensitization and reprocessing (EMDR)
Narrative exposure therapy (NET)While these treatments have been recommended, there is still on-going debate regarding the best and most efficacious treatment for complex PTSD. Many commonly used treatments are considered complementary or alternative since there still is a lack of research to classify these approaches as evidenced based. Some of these additional interventions and modalities include:

biofeedback
dyadic resourcing (used with EMDR)
emotionally focused therapy
emotional freedom technique (EFT) or tapping
equine-assisted therapy
expressive arts therapy
internal family systems therapy
dialectical behavior therapy (DBT)
family systems therapy
group therapy
neurofeedback
psychodynamic therapy
sensorimotor psychotherapy
somatic experiencing
yoga, specifically trauma-sensitive yoga

Arguments against diagnosis
Though acceptance of the idea of complex PTSD has increased with mental health professionals, the fundamental research required for the proper validation of a new disorder is insufficient as of 2013. The disorder was proposed under the name DES-NOS (Disorder of Extreme Stress Not Otherwise Specified) for inclusion in the DSM-IV but was rejected by members of the Diagnostic and Statistical Manual of Mental Disorders (DSM) committee of the American Psychiatric Association for lack of sufficient diagnostic validity research </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Copper toxicity and can you explain it in depth? [/INST] Copper toxicity (or Copperiedus) is a type of metal poisoning caused by an excess of copper in the body. Copperiedus could occur from consuming excess copper salts, but most commonly it is the result of the genetic condition Wilsons disease and Menkes disease, which are associated with mismanaged transport and storage of copper ions. Copper is essential to human health as it is a component of many proteins.
Chronic toxicity by copper is "rare".  The suggested safe level of copper in drinking water for humans varies depending on the source, but tends to be pegged at 1.3 mg/L.  So rare is the toxicity of copper that copper(II) sulfate is a routine reagent in undergraduate chemistry laboratories.

Signs and symptoms
Acute symptoms of copper poisoning by ingestion include vomiting, hematemesis (vomiting of blood), hypotension (low blood pressure), melena (black "tarry" feces), coma, jaundice (yellowish pigmentation of the skin), and gastrointestinal distress. Individuals with glucose-6-phosphate dehydrogenase deficiency may be at increased risk of hematologic effects of copper. Hemolytic anemia resulting from the treatment of burns with copper compounds is infrequent.Chronic (long-term) copper exposure can damage the liver and kidneys. Mammals have efficient mechanisms to regulate copper stores such that they are generally protected from excess dietary copper levels.Those same protection mechanisms can cause milder symptoms, which are often misdiagnosed as psychiatric disorders. There is a lot of research on the function of the Cu/Zn ratio in neurological, endocrinological, and psychological conditions. Many of the substances that protect us from excess copper perform important functions in our neurological and endocrine systems, leading to diagnostic difficulties. When they are used to bind copper in the plasma, to prevent it from being absorbed in the tissues, their own function may go unfulfilled. Such symptoms often include mood swings, irritability, depression, fatigue, excitation, difficulty focusing, and feeling out of control. To further complicate diagnosis, some symptoms of excess copper are similar to those of a copper deficit.
The U.S. Environmental Protection Agencys Maximum Contaminant Level (MCL) in drinking water is 1.3 milligrams per liter. The MCL for copper is based on the expectation that a lifetime of consuming copper in water at this level is without adverse effect (gastrointestinal). The US EPA lists copper as a micronutrient and a toxin. Toxicity in mammals includes a wide range of animals and effects such as liver cirrhosis, necrosis in kidneys and the brain, gastrointestinal distress, lesions, low blood pressure, and fetal mortality. The Occupational Safety and Health Administration (OSHA) has set a limit of 0.1 mg/m3 for copper fumes (vapor generated from heating copper) and 1 mg/m3 for copper dusts (fine metallic copper particles) and mists (aerosol of soluble copper) in workroom air during an eight-hour work shift, 40-hour work week. Toxicity to other species of plants and animals is noted to varying levels.

EPA cancer data
The EPA lists no evidence for human cancer incidence connected with copper, and lists animal evidence linking copper to cancer as "inadequate". Two studies in mice have shown no increased incidence of cancer. One of these used regular injections of copper compounds, including cupric oxide. One study of two strains of mice fed copper compounds found a varying increased incidence of reticulum cell sarcoma in males of one strain, but not the other (there was a slightly increased incidence in females of both strains). These results have not been repeated.

Pathophysiology
Indian childhood cirrhosis
One manifestation of copper toxicity, cirrhosis of the liver in children (Indian childhood cirrhosis), has been linked to boiling milk in copper cookware. The Merck Manual states that recent studies suggest that a genetic defect is associated with this particular cirrhosis.

Wilson disease
An inherited condition called Wilsons disease causes the body to retain copper, since it is not excreted by the liver into the bile. This disease, if untreated, can lead to brain and liver damage, and bis-choline tetrathiomolybdate is under investigation as a therapy against Wilsons disease.

Menkes disease
An X-linked recessive trait that is inherited named Menkes disease causes disruption of connective tissue due to mutations in genes. If severely affected the approximate span of life is three years. One treatment used to correct the mutation is copper-histidine treatment.

Alzheimers disease
Elevated free copper levels exist in Alzheimers disease, which has been hypothesized to be linked to inorganic copper consumption. Copper and zinc are known to bind to amyloid beta proteins in Alzheimers disease. This bound form is thought to mediate the production of reactive oxygen species in the brain.

Diagnosis
ICD-9-CM
ICD-9-CM code 985.8 Toxic effect of other specified metals includes acute & chronic copper poisoning (or other toxic effect) whether intentional, accidental, industrial etc.

In addition, it includes poisoning and toxic effects of other metals including tin, selenium, nickel, iron, heavy metals, thallium, silver, lithium, cobalt, aluminum and bismuth. Some poisonings, e.g. zinc phosphide, would/could also be included as well as under 989.4 Poisoning due to other pesticides, etc.
Excluded are toxic effects of mercury, arsenic, manganese, beryllium, antimony, cadmium, and chromium.

ICD-10-CM
SNOMED
Treatment
In cases of suspected copper poisoning, penicillamine is the drug of choice, and dimercaprol, a heavy metal chelating agent, is often administered. Vinegar is not recommended to be given, as it assists in solubilizing insoluble copper salts. The inflammatory symptoms are to be treated on general principles, as are the nervous ones. Treatment can also look like ozone oxidation for environmental toxicity problems, as well as removing sediment in water areas because sediment can be a home for toxicants to reside. There is some evidence that alpha-lipoic acid (ALA) may work as a milder chelator of tissue-bound copper. Alpha lipoic acid is also being researched for chelating other heavy metals, such as mercury.

Aquatic life
Too much copper in water may damage marine and freshwater organisms such as fish and molluscs. Fish species vary in their sensitivity to copper, with the LD50 for 96-h exposure to copper sulphate reported to be in the order of 58 mg per litre for Tilapia (Oreochromis niloticus) and 70 mg per litre for catfish (Clarias gariepinus)  The chronic effect of sublethal concentrations of copper on fish and other creatures is damage to gills, liver, kidneys and the nervous system. It also interferes with the sense of smell in fish, thus preventing them from choosing good mates or finding their way to mating areas.Copper-based paint is a common marine antifouling agent. In the United States, copper-based paint replaced tributyltin, which was banned due to its toxicity, as a way for boats to control organic growth on their hulls. In 2011, Washington state became the first U.S. state to ban the use of copper-based paint for boating, although it only applied to recreational boats. California has also pursued initiatives to reduce the effect of copper leaching, with the U.S. EPA pursuing research.Copper is an essential elemental for metabolic processes in marine algae. It is required for electron transport in photosynthesis and by various enzyme systems. Too much copper can also affect phytoplankton or marine algae in both marine and freshwater ecosystems. It has been show to inhibit photosynthesis, disrupt electron transport in photosystem 2, reduce pigment concentrations, restrict growth, reduce reproduction, etc. The toxicity of copper is widely recognized and is used to help prevent algal blooms. The effect of copper is solely dependent on the free copper the water is receiving. Its determined by the relative solubility and the concentration of the copper binding ligands.
Studies have shown that copper concentrations are toxic when marine phytoplankton are confined to areas that are heavily impacted by anthropogenic emissions. Some of the studies have used a marine amphipod to show how Copper affects it. This particular study said that the juveniles were 4.5 more times sensitive to the toxins than the adults </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Seabathers eruption and can you explain it in depth? [/INST] Seabathers eruption is an itching dermatitis caused by a hypersensitivity reaction to the immature nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (Edwardsiella lineata) and other larval cnidarians </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Callosity and can you explain it in depth? [/INST] A callosity is another name for callus, a piece of skin that has become thickened as a result of repeated contact and friction.

Primates
All Old World monkeys, gibbons, and some chimpanzees have pads on their rears known as ischial callosities. Ischial relates to the ischium: it forms the lower and back part of the hip bone.
The pads enable the monkeys to sleep sitting upright on thin branches, beyond reach of predators, without falling.
The ischial callosities are one of the most distinctive pelvic features which separates Old World monkeys from New World monkeys.

Right whales
In whales, the term callosity refers to the rough, calcified skin patches found on the heads of the three species of right whales.  These callosities are a characteristic feature of the whale genus Eubalaena; because they are found on the head of the whale and appear white against the dark background of the whales skin, they make it very easy to identify these species. The callosities themselves are grey; the white appearance is due to large colonies of whale lice, whale barnacles and parasitic worms which reside on them. Young whales and diseased individuals are often infested with a different species of cyamid, which gives an orange hue rather than white on these whales. Callosities arise naturally and are present even in late-term whale fetuses, although the work of lice digging into the surface of the skin may make them more jagged and hard over time.Callosities are found on the upper surface of the whales head, above the eyes, on the jawline and chin and surrounding the blowholes. Callosities form a unique pattern on every right whale and though callosities which are overgrown break off, the patterns do not change over a lifetime. This makes them a very useful tool for the purposes of photo-identification and conservation.The evolutionary significance of callosities is unknown. Male right whales have a higher density of callosities than females. Males have been observed scratching one another with their callosities and it has been suggested by Payne & Dorsey (1983) that they are a sexually dimorphic feature, used for intra-specific sexual aggression. That explanation is not entirely satisfactory, because it does not account for the appearance of callosities in females. It has been proposed that the barnacles attached to callosities are important in helping fend off attacks by orcas.

See also
Callus

Notes
References
Steudel, K (1981). "Functional Aspects of Primate Pelvic Structure: A Multivariate Approach" (PDF) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Chorditis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Subcutaneous granuloma annulare and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Condylomata lata and can you explain it in depth? [/INST]  </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Indian childhood cirrhosis and can you explain it in depth? [/INST] Indian childhood cirrhosis is a chronic liver disease of childhood characterised by cirrhosis of the liver associated with the deposition of copper in the liver </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Vertebral artery dissection and can you explain it in depth? [/INST] Vertebral artery dissection (VAD) is a flap-like tear of the inner lining of the vertebral artery, which is located in the neck and supplies blood to the brain. After the tear, blood enters the arterial wall and forms a blood clot, thickening the artery wall and often impeding blood flow. The symptoms of vertebral artery dissection include head and neck pain and intermittent or permanent stroke symptoms such as difficulty speaking, impaired coordination and visual loss. It is usually diagnosed with a contrast-enhanced CT or MRI scan.Vertebral dissection may occur after physical trauma to the neck, such as a blunt injury (e.g. traffic collision), or strangulation, or after sudden neck movements, i.e. coughing, but may also happen spontaneously. 1–4% of spontaneous cases have a clear underlying connective tissue disorder affecting the blood vessels. Treatment is usually with either antiplatelet drugs such as aspirin or with anticoagulants such as heparin or warfarin.Vertebral artery dissection is less common than carotid artery dissection (dissection of the large arteries in the front of the neck). The two conditions together account for 10–25% of non-hemorrhagic strokes in young and middle-aged people. Over 75% recover completely or with minimal impact on functioning, with the remainder having more severe disability and a very small proportion (about 2%) dying from complications. It was first described in the 1970s by the Canadian neurologist C. Miller Fisher.

Classification
Vertebral artery dissection is one of the two types of dissection of the arteries in the neck. The other type, carotid artery dissection, involves the carotid arteries. Vertebral artery dissection is further classified as being either traumatic (caused by mechanical trauma to the neck) or spontaneous, and it may also be classified by the part of the artery involved: extracranial (the part outside the skull) and intracranial (the part inside the skull).

Signs and symptoms
Head pain occurs in 50–75% of all cases of vertebral artery dissection. It tends to be located at the back of the head, either on the affected side or in the middle, and develops gradually. It is either dull or pressure-like in character or throbbing. About half of those with VAD consider the headache distinct, while the remainder have had a similar headache before. It is suspected that VAD with headache as the only symptom is fairly common; 8% of all cases of vertebral and carotid dissection are diagnosed on the basis of pain alone.Obstruction of blood flow through the affected vessel may lead to dysfunction of part of the brain supplied by the artery. This happens in 77–96% of cases. This may be temporary ("transient ischemic attack") in 10–16% of cases, but many (67–85% of cases) end up with a permanent deficit or a stroke. The vertebral artery supplies the part of the brain that lies in the posterior fossa of the skull, and this type of stroke is therefore called a posterior circulation infarct. Problems may include difficulty speaking or swallowing (lateral medullary syndrome); this occurs in less than a fifth of cases and occurs due to dysfunction of the brainstem. Others may experience unsteadiness or lack of coordination due to involvement of the cerebellum, and still others may develop visual loss (on one side of the visual field) due to involvement of the visual cortex in the occipital lobe. In the event of involvement of the sympathetic tracts in the brainstem, a partial Horners syndrome may develop; this is the combination of a drooping eyelid, constricted pupil, and an apparently sunken eye on one side of the face.If the dissection of the artery extends to the part of the artery that lies inside the skull, subarachnoid hemorrhage may occur (1% of cases). This arises due to rupture of the artery and accumulation of blood in the subarachnoid space. It may be characterized by a different, usually severe headache; it may also cause a range of additional neurological symptoms.13–16% of all people with vertebral or carotid dissection have dissection in another cervical artery. It is therefore possible for the symptoms to occur on both sides, or for symptoms of carotid artery dissection to occur at the same time as those of vertebral artery dissection. Some give a figure of multiple vessel dissection as high as 30%.

Causes
The causes of vertebral artery dissection can be grouped under two main categories, spontaneous and traumatic.

Spontaneous
Spontaneous cases are considered to be caused by intrinsic factors that weaken the arterial wall. Only a very small proportion (1–4%) have a clear underlying connective tissue disorder, such as Ehlers–Danlos syndrome type 4 and, more rarely, Marfan syndrome. However, ultrastructural abnormalities of the dermal connective tissue components are discernible in two out of three patients with spontaneous dissection. Ehlers–Danlos syndrome type 4, caused by mutations of the COL3A gene, leads to defective production of the collagen, type III, alpha 1 protein and causes skin fragility as well as weakness of the walls of arteries and internal organs. Marfan syndrome results from mutations in the FBN1 gene, defective production of the protein fibrillin-1, and a number of physical abnormalities including aneurysm of the aortic root.There have also been reports in other genetic conditions, such as osteogenesis imperfecta type 1, autosomal dominant polycystic kidney disease and pseudoxanthoma elasticum, α1 antitrypsin deficiency and hereditary hemochromatosis, but evidence for these associations is weaker. Genetic studies in other connective tissue-related genes have mostly yielded negative results. Other abnormalities to the blood vessels, such as fibromuscular dysplasia, have been reported in a proportion of cases. Atherosclerosis does not appear to increase the risk.There have been numerous reports of associated risk factors for vertebral artery dissection; many of these reports suffer from methodological weaknesses, such as selection bias. Elevated homocysteine levels, often due to mutations in the MTHFR gene, appear to increase the risk of vertebral artery dissection. People with an aneurysm of the aortic root and people with a history of migraine may be predisposed to vertebral artery dissection. Vascular tortuosity or redundancy in young patients is associated with an increased risk of spontaneous dissection.

Traumatic
Traumatic vertebral dissection may follow blunt trauma to the neck, such as in a traffic collision, direct blow to the neck, strangulation, or whiplash injury. 1–2% of those with major trauma may have an injury to the carotid or vertebral arteries. In many cases of vertebral dissection, people report recent very mild trauma to the neck or sudden neck movements, e.g. in the context of playing sports. Others report a recent infection, particularly respiratory tract infections associated with coughing. Trauma has been reported to have occurred within a month of dissection in 40% with nearly 90% of the traumas being minor. It has been difficult to prove the association of vertebral artery dissection with mild trauma and infections statistically. It is likely that many "spontaneous" cases may in fact have been caused by such relatively minor insults in someone predisposed by other structural problems to the vessels. A more likely theory, also as yet unproven, is that the low-energy traumatic dissections are actually spontaneous dissections brought to medical attention by the onset of neurological symptoms. These neurological events represent embolic phenomena due to loosening or breakdown of the clot at the site of the dissection, which can be triggered by low energy trauma or even occur spontaneously. The fragments travel within the arterial system downstream to the brain to cause stroke or stroke-like symptoms.
Vertebral artery dissection has also been reported in association with some forms of neck manipulation. There is significant controversy about the level of risk of stroke from neck manipulation. It may be that manipulation can cause dissection, or it may be that the dissection is already present in some people who seek manipulative treatment. At this time, conclusive evidence does not exist to support either a strong association between neck manipulation and stroke, or no association.  However, the two most authoritative articles on the subject, recent literature reviews and analyses, conclude that although there exists an association between stroke from vertebral artery dissection and chiropractic adjustment, there is insufficient evidence to indicate that the adjustment caused the dissection. A recent meta-analysis of the published data on the topic also looked to apply Hills criteria for assigning causation in biological systems to the relationship between chiropractic adjustment and cervical artery dissection, finding that the relationship did not fulfill the required criteria for causality.

Mechanism
The vertebral arteries arise from the subclavian artery, and run through the transverse foramen of the upper six vertebrae of the neck. After exiting at the level of the first cervical vertebra, its course changes from vertical to horizontal, and then enters the skull through the foramen magnum. Inside the skull, the arteries merge to form the basilar artery, which joins the circle of Willis. In total, three quarters of the artery are outside the skull; it has a high mobility in this area due to rotational movement in the neck and is therefore vulnerable to trauma. Most dissections happen at the level of the first and second vertebrae. The vertebral artery supplies a number of vital structures in the posterior cranial fossa, such as the brainstem, the cerebellum and the occipital lobes. The brainstem harbors a number of vital functions (such as respiration) and controls the nerves of the face and neck. The cerebellum is part of the diffuse system that coordinates movement. Finally, the occipital lobes participate in the sense of vision.Dissection occurs when blood accumulates in the wall of the blood vessel. This is most likely due to a tear in the tunica intima (the inner layer), allowing blood to enter the tunica media, although other lines of evidence have suggested that the blood may instead arise from the vasa vasorum, the small blood vessels that supply the outer layer of larger blood vessels. Various theories exist as to whether people who sustain carotid and vertebral artery dissection, even if they do not have a connective tissue disorder, have an underlying vulnerability. Biopsy samples of skin and other arteries has indicated that this might be a possibility, but no genetic defect in collagen or elastin genes has been convincingly proven. Other studies have indicated inflammation of the blood vessels, as measured by highly sensitive C-reactive protein (hsCRP, a marker of inflammation) in the blood.Once dissection has occurred, two mechanisms contribute to the development of stroke symptoms. Firstly, the flow through the blood vessel may be disrupted due to the accumulation of blood under the vessel wall, leading to ischemia (insufficient blood supply). Secondly, irregularities in the vessel wall and turbulence increase the risk of thrombosis (the formation of blood clots) and embolism (migration) of these clots of the brain. From various lines of evidence, it appears that thrombosis and embolism is the predominant problem.Subarachnoid hemorrhage due to arterial rupture typically occurs if the dissection extends into the V4 section of the artery. This may be explained by the fact that the arterial wall is thinner and lacks a number of structural supports in this section.

Diagnosis
Various diagnostic modalities exist to demonstrate blood flow or absence thereof in the vertebral arteries. The gold standard is cerebral angiography (with or without digital subtraction angiography). This involves puncture of a large artery (usually the femoral artery) and advancing an intravascular catheter through the aorta towards the vertebral arteries. At that point, radiocontrast is injected and its downstream flow captured on fluoroscopy (continuous X-ray imaging). The vessel may appear stenotic (narrowed, 41–75%), occluded (blocked, 18–49%), or as an aneurysm (area of dilation, 5–13%). The narrowing may be described as "rats tail" or "string sign". Cerebral angiography is an invasive procedure, and it requires large volumes of radiocontrast that can cause complications such as kidney damage. Angiography also does not directly demonstrate the blood in the vessel wall, as opposed to more modern modalities. The only remaining use of angiography is when endovascular treatment is contemplated (see below).More modern methods involve computed tomography (CT angiography) and magnetic resonance imaging (MR angiography). They use smaller amounts of contrast and are not invasive. CT angiography and MR angiography are more or less equivalent when used to diagnose or exclude vertebral artery dissection. CTA has the advantage of showing certain abnormalities earlier, tends to be available outside office hours, and can be performed rapidly. When MR angiography is used, the best results are achieved in the T1 setting using a protocol known as "fat suppression". Doppler ultrasound is less useful as it provides little information about the part of the artery close to the skull base and in the vertebral foramina, and any abnormality detected on ultrasound would still require confirmation with CT or MRI.

Treatment
Treatment is focused on reducing stroke episodes and damage from a distending artery. Four treatment modalities have been reported in the treatment of vertebral artery dissection. The two main treatments involve medication: anticoagulation (using heparin and warfarin) and antiplatelet drugs (usually aspirin). More rarely, thrombolysis (medication that dissolves blood clots) may be administered, and occasionally obstruction may be treated with angioplasty and stenting. No randomized controlled trials have been performed to compare the different treatment modalities. Surgery is only used in exceptional cases.

Anticoagulation and aspirin
From analysis of the existing small treatment trials of cervical artery dissection (carotid and vertebral) it appears that aspirin and anticoagulation (heparin followed by warfarin) are equally effective in reducing the risk of further stroke or death. Anticoagulation is regarded as more powerful than antiplatelet therapy, but anticoagulants may increase the size of the hematoma and worsen obstruction of the affected artery. Anticoagulation may be relatively unsafe if a large stroke has already occurred, as hemorrhagic transformation is relatively common, and if the dissection extends into V4 (carrying a risk of subarachnoid hemorrhage). Anticoagulation may be appropriate if there is rapid blood flow (through a severely narrowed vessel) on transcranial doppler despite the use of aspirin, if there is a completely occluded vessel, if there are recurrent stroke-like episodes, or if free-floating blood clot is visible on scans. Warfarin is typically continued for 3–6 months, as during this time the flow through the artery usually improves, and most strokes happen within the first 6 months after the development of the dissection. Some regard 3 months as sufficient.Professional guidelines in the UK recommend that patients with VA dissection should be enrolled in a clinical trial comparing aspirin and anticoagulation if possible. American guidelines state that the benefit of anticoagulation is not currently established.

Thrombolysis, stenting and surgery
Thrombolysis, stenting and surgery are not used as widely as anticoagulation or antiplatelet drugs. These treatments are invasive, and are typically reserved for situations where symptoms worsen despite medical treatment, or where medical treatment may be unsafe (e.g. an unacceptable bleeding tendency).Thrombolysis is enzymatic destruction of blood clots. This is achieved by the administration of a drug (such as urokinase or alteplase) that activates plasmin, an enzyme that occurs naturally in the body and digests clots when activated. Thrombolysis is an accepted treatment for heart attacks and stroke unrelated to dissection. In cervical artery dissection, only small case series are available. The thrombolytic drug is administered either intravenously or during cerebral angiography through a catheter directly into the affected artery. The data indicates that thrombolysis is safe, but its place in the treatment of VAD is uncertain.Stenting involves the catheterization of the affected artery during angiography, and the insertion of a mesh-like tube; this is known as "endovascular therapy" (inside the blood vessel). This may be performed to allow the blood to flow through a severely narrowed vessel, or to seal off an aneurysm. However, it is unclear whether the technical success of the procedure translates into improved outcomes, as in both cases the problem often resolves spontaneously over time. Stenting, as well as the insertion of coils by means of angiography, may be performed if there is an aneurysm and/or extension of the dissection into the V4 section of the artery.Surgery carries a high risk of complications, and is typically only offered in case of inexorable deterioration or contraindications to any of the other treatments. Various arterial repair procedures have been described.

Prognosis
Prognosis of spontaneous cervical arterial dissection involves neurological and arterial results. The overall functional prognosis of individuals with stroke due to cervical artery dissection does not appear to vary from that of young people with stroke due to other causes. The rate of survival with good outcome (a modified Rankin score of 0–2) is generally about 75%, or possibly slightly better (85.7%) if antiplatelet drugs are used. In studies of anticoagulants and aspirin, the combined mortality with either treatment is 1.8–2.1%.After the initial episode, 2% may experience a further episode within the first month. After this, there is a 1% annual risk of recurrence. Those with high blood pressure and dissections in multiple arteries may have a higher risk of recurrence. Further episodes of cervical artery dissection are more common in those who are younger, have a family history of cervical artery dissection, or have a diagnosis of Ehlers-Danlos syndrome or fibromuscular dysplasia.

Epidemiology
The annual incidence is about 1.1 per 100,000 annually in population studies from the United States and France </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Valvular heart disease and can you explain it in depth? [/INST] Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These conditions occur largely as a consequence of aging, but may also be the result of congenital (inborn) abnormalities or specific disease or physiologic processes including rheumatic heart disease and pregnancy.Anatomically, the valves are part of the dense connective tissue of the heart known as the cardiac skeleton and are responsible for the regulation of blood flow through the heart and great vessels. Valve failure or dysfunction can result in diminished heart functionality, though the particular consequences are dependent on the type and severity of valvular disease. Treatment of damaged valves may involve medication alone, but often involves surgical valve repair or valve replacement.

Classification
Stenosis and insufficiency/regurgitation represent the dominant functional and anatomic consequences associated with valvular heart disease. Irrespective of disease process, alterations to the valve occur that produce one or a combination of these conditions. Insufficiency and regurgitation are synonymous terms that describe an inability of the valve to prevent backflow of blood as leaflets of the valve fail to join (coapt) correctly. Stenosis is characterized by a narrowing of the valvular orifice that prevents adequate outflow of blood. Stenosis can also result in insufficiency if thickening of the annulus or leaflets results in inappropriate leaf closure.

Aortic and mitral valve disorders
Aortic and mitral valve disorders are left heart diseases that are more prevalent than diseases of the pulmonary or tricuspid valve in the right heart due to the higher pressures in the left heart.Stenosis of the aortic valve is characterized by a thickening of the valvular annulus or leaflets that limits the ability of blood to be ejected from the left ventricle into the aorta. Stenosis is typically the result of valvular calcification but may be the result of a congenitally malformed bicuspid aortic valve. This defect is characterized by the presence of only two valve leaflets. It may occur in isolation or in concert with other cardiac anomalies.Aortic insufficiency, or regurgitation, is characterized by an inability of the valve leaflets to appropriately close at the end systole, thus allowing blood to flow inappropriately backward into the left ventricle. Causes of aortic insufficiency in the majority of cases are unknown, or idiopathic. It may be the result of connective tissue or immune disorders, such as Marfan syndrome or systemic lupus erythematosus, respectively. Processes that lead to aortic insufficiency usually involve dilation of the valve annulus, thus displacing the valve leaflets, which are anchored in the annulus.Mitral stenosis is caused largely by rheumatic heart disease, though is rarely the result of calcification. In some cases, vegetations form on the mitral leaflets as a result of endocarditis, an inflammation of the heart tissue. Mitral stenosis is uncommon and not as age-dependent as other types of valvular disease.Mitral insufficiency can be caused by dilation of the left heart, often a consequence of heart failure. In these cases, the left ventricle of the heart becomes enlarged and causes displacement of the attached papillary muscles, which control the mitral.

Pulmonary and tricuspid valve disorders
Pulmonary and tricuspid valve diseases are right heart diseases. Pulmonary valve diseases are the least common heart valve disease in adults.Pulmonary valve stenosis is often the result of congenital malformations and is observed in isolation or as part of a larger pathologic process, as in Tetralogy of Fallot, Noonan syndrome, and congenital rubella syndrome. Unless the degree of stenosis is severe, individuals with pulmonary stenosis usually have excellent outcomes and better treatment options. Often patients do not require intervention until later in adulthood as a consequence of calcification that occurs with aging.Pulmonary valve insufficiency occurs commonly in healthy individuals to a very mild extent and does not require intervention. More appreciable insufficiency is typically the result of damage to the valve due to cardiac catheterization, intra-aortic balloon pump insertion, or other surgical manipulations. Additionally, insufficiency may be the result of carcinoid syndrome, inflammatory processes such a rheumatoid disease or endocarditis, or congenital malformations. It may also be secondary to severe pulmonary hypertension.Tricuspid valve stenosis without co-occurrent regurgitation is highly uncommon and typically the result of rheumatic disease. It may also be the result of congenital abnormalities, carcinoid syndrome, obstructive right atrial tumors (typically lipomas or myxomas), or hypereosinophilic syndromes.Minor tricuspid insufficiency is common in healthy individuals. In more severe cases it is a consequence of dilation of the right ventricle, leading to displacement of the papillary muscles which control the valves ability to close. Dilation of the right ventricle occurs secondary to ventricular septal defects, right to left shunting of blood, eisenmenger syndrome, hyperthyroidism, and pulmonary stenosis. Tricuspid insufficiency may also be the result of congenital defects of the tricuspid valve, such as Ebsteins anomaly.

Signs and symptoms
Aortic stenosis
Symptoms of aortic stenosis may include heart failure symptoms, such as dyspnea on exertion (most frequent symptom), orthopnea and paroxysmal nocturnal dyspnea, angina pectoris, and syncope, usually exertional.Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries.

Aortic regurgitation
Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock.Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present

Mitral stenosis
Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancyOn auscultation of a patient with mitral stenosis, typically the most prominent sign is a loud S1. Another finding is an opening snap followed by a low-pitched diastolic rumble with presystolic accentuation. The opening snap follows closer to the S2 heart tone with worsening stenosis. The murmur is heard best with the bell of the stethoscope lying on the left side and its duration increases with worsening disease. Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension (presenting with a loud P2). Signs increase with exercise and pregnancy.

Mitral regurgitation
Patients with mitral regurgitation may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations,  or pulmonary edema.On auscultation of a patient with mitral stenosis, there may be a holosystolic murmur at the apex, radiating to the back or clavicular area, a third heart sound, and a loud, palpable P2, heard best when lying on the left side. Patients also commonly have atrial fibrillation. Patients may have a laterally displaced apex beat, often with heave In acute cases, the murmur and tachycardia may be only distinctive signs.

Tricuspid regurgitation
Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension.Signs of tricuspid regurgitation include pulsatile liver, prominent V waves and rapid y descents in jugular venous pressure. Auscultatory findings include inspiratory third heart sound at left lower sternal border (LLSB) and a blowing holosystolic murmur at LLSB, intensifying with inspiration, and decreasing with expiration and Valsalva maneuver. Patients may have a parasternal heave along LLSB. Atrial fibrillation is usually present in patients with tricuspid regurgitation

Causes
Calcific disease
Calcification of the leaflets of the aortic valve is a common with increasing age, but the mechanism is likely to be more related to increased lipoprotein deposits and inflammation than the "wear and tear" of advance age. Aortic stenosis due to calcification of tricuspid aortic valve with age comprises >50% of the disease. Aortic stenosis due to calcification of a bicuspid aortic valve comprises about 30-40% of the disease. Hypertension, diabetes mellitus, hyperlipoproteinemia and uremia may speed up the process of valvular calcification.

Dysplasia
Heart valve dysplasia is an error in the development of any of the heart valves, and a common cause of congenital heart defects in humans as well as animals; tetralogy of Fallot is a congenital heart defect with four abnormalities, one of which is stenosis of the pulmonary valve. Ebsteins anomaly is an abnormality of the tricuspid valve, and its presence can lead to tricuspid valve regurgitation. A bicuspid aortic valve is an aortic valve with only 2 cusps as opposed to the normal 3. It is present in about 0.5% to 2% of the general population and causes increased calcification due to higher turbulent flow through the valve.

Connective tissue disorders
Marfans Syndrome is a connective tissue disorder that can lead to chronic aortic or mitral regurgitation. Osteogenesis imperfecta is a disorder in formation of type I collagen and can also lead to chronic aortic regurgitation.

Inflammatory disorders
Inflammation of the heart valves due to any cause is called valvular endocarditis; this is usually due to bacterial infection but may also be due to cancer (marantic endocarditis), certain autoimmune conditions (Libman-Sacks endocarditis, seen in systemic lupus erythematosus) and hypereosinophilic syndrome (Loeffler endocarditis). Endocarditis of the valves can lead to regurgitation through that valve, which is seen in the tricuspid, mitral, and aortic valves. Certain medications have been associated with valvular heart disease, most prominently ergotamine derivatives pergolide and cabergoline.Valvular heart disease resulting from rheumatic fever is referred to as rheumatic heart disease. Acute rheumatic fever, which frequently manifests with carditis and valvulitis, is a late sequela of Group A beta-hemolytic streptococcus infection in the throat, often lagging the initial infection by weeks to months. Cardiac involvement is dependent on the cross-reaction of antibodies directed against M proteins produced by bacteria with human proteins present in the myocardium or endocardium (although acute rheumatic fever may present as pancarditis with additional involvement of the pericardium). This results in generalized inflammation in the heart, producing acute erosions and vegetations with fibrin deposition in the mitral valve that may be followed by chronic changes over years to decades, including shortening of the chordae tendinae and thickening or fusion of the mitral leaflets, leading to a severely compromised "buttonhole" or "fish mouth" valve.In 70% of cases rheumatic heart disease involves only the mitral valve, while 25% of cases involve both the aortic and mitral valves. Involvement of other heart valves without damage to the mitral is exceedingly rare. Mitral stenosis is almost always caused by rheumatic heart disease. Less than 10% of aortic stenosis is caused by rheumatic heart disease. Rheumatic fever can also cause chronic mitral and aortic regurgitation.While developed countries once had a significant burden of rheumatic fever and rheumatic heart disease, medical advances and improved social conditions have dramatically reduced their incidence. Many developing countries, as well as indigenous populations within developed countries, still carry a significant burden of rheumatic fever and rheumatic heart disease and there has been a resurgence in efforts to eradicate the diseases in these populations.  Among persons who have experienced rheumatic fever, long-term intramuscular antibiotic therapy is used as secondary prophylaxis against additional streptococcal infections, which can contribute to progression of rheumatic heart disease.  In people with severe valvular disease, however, short-term risks of cardiovascular compromise after intramuscular injections may outweigh the benefits, and oral therapy may be considered instead of IM injections in this subset of patients.Diseases of the aortic root can cause chronic aortic regurgitation. These diseases include syphilitic aortitis, Behçets disease, and reactive arthritis.

Heart disease
Tricuspid regurgitation is usually secondary to right ventricular dilation which may be due to left ventricular failure (the most common cause), right ventricular infarction, inferior myocardial infarction, or cor pulmonale Other causes of tricuspid regurgitation include carcinoid syndrome and myxomatous degeneration.

Diagnosis
Aortic stenosis
Patients with aortic stenosis can have chest X-ray findings showing dilation of the ascending aorta, but they may also have a completely normal chest X-ray. Direct visualization of calcifications on chest X-ray is uncommon. Other findings include dilation of the left ventricle. ECG typically shows left ventricular hypertrophy in patients with severe stenosis, but it may also show signs of left heart strain. Echocardiography is the diagnostic gold standard, which shows left ventricular hypertrophy, leaflet calcification, and abnormal leaflet closure.

Aortic regurgitation
Chest X-ray is not as sensitive as other tests, but it may show aortic root dilation (especially in causes involving the aortic root) and apex displacement. An ECG may show left ventricular hypertrophy and signs of left heart strain. Left axis deviation can be a sign of advanced disease. An echocardiogram can be helpful in determining the root cause of the disease, as it will clearly show aortic root dilation or dissection if it exists. Typically the pump function of the heart during systole is normal, but an echocardiogram will show flow reversal during diastole. This disease is classified using regurgitant fraction (RF), or the amount of volume that flows back through the valve divided by the total forward flow through the valve during systole. Severe disease has an RF of >50%, while progressive aortic regurgitation has an RF of 30–49%.

Mitral stenosis
Chest x-ray in mitral stenosis will typically show an enlarged left atrium, and may show dilation of the pulmonary veins. ECG can show left atrial enlargement, due to increased pressures in the left atrium. Echocardiography is helpful in determining the severity of the disease by estimating the pulmonary artery systolic pressure. This test can also show leaflet calcification and the pressure gradient over the mitral valve. Severe mitral stenosis is defined as a mitral valve area <1.5 cm2. Progressive mitral stenosis has a normal valve area but will have increased flow velocity across the mitral valve.

Mitral regurgitation
Chest x-ray in mitral regurgitation can show an enlarged left atrium, as well as pulmonary venous congestion. It may also show valvular calcifications specifically in combined mitral regurgitation and stenosis due to rheumatic heart disease. ECG typically shows left atrial enlargement, but can also show right atrial enlargement if the disease is severe enough to cause pulmonary hypertension. Echocardiography is useful in visualizing the regurgitant flow and calculating the RF. It can also be used to determine the degree of calcification, and the function and closure of the valve leaflets. Severe disease has an RF of >50%, while progressive mitral regurgitation has an RF of <50%.

Treatment
Some of the most common treatments of valvular heart disease are avoiding smoking and excessive alcohol consumption, antibiotics, antithrombotic medications such as aspirin, anticoagulants, balloon dilation, and water pills.
In some cases, surgery may be necessary.

Aortic stenosis
Treatment of aortic stenosis is not necessary in asymptomatic patients, unless the stenosis is classified as severe based on valve hemodynamics. Both asymptomatic severe and symptomatic aortic stenosis are treated with aortic valve replacement (AVR) surgery. Trans-catheter Aortic Valve Replacement (TAVR) is an alternative to AVR and is recommended in high risk patients who may not be suitable for surgical AVR. Any angina is treated with short-acting nitrovasodilators, beta-blockers and/or calcium blockers. Any hypertension is treated aggressively, but caution must be taken in administering beta-blockers. Any heart failure is treated with digoxin, diuretics, nitrovasodilators and, if not contraindicated, cautious inpatient administration of ACE inhibitors. Moderate stenosis is monitored with echocardiography every 1–2 years, possibly with supplementary cardiac stress test. Severe stenosis should be monitored with echocardiography every 3–6 months.

Aortic regurgitation
Aortic regurgitation is treated with aortic valve replacement, which is recommended in patients with symptomatic severe aortic regurgitation. Aortic valve replacement is also recommended in patients that are asymptomatic but have chronic severe aortic regurgitation and left ventricular ejection fraction of less than 50%. Hypertension is treated in patients with chronic aortic regurgitation, with the anti-hypersensives of choice being calcium channel blockers, ACE inhibitors, or ARBs. Also, endocarditis prophylaxis is indicated before dental, gastrointestinal or genitourinary procedures. Mild to moderate aortic regurgitation should be followed with echocardiography and a cardiac stress test once every 1–2 years. In severe moderate/severe cases, patients should be followed with echocardiography and cardiac stress test and/or isotope perfusion imaging every 3–6 months.

Mitral stenosis
For patients with symptomatic severe mitral stenosis, percutaneous balloon mitral valvuloplasty (PBMV) is recommended. If this procedure fails, then it may be necessary to undergo mitral valve surgery, which may involve valve replacement, repair, or commisurotomy. Anticoagulation is recommended for patients that have mitral stenosis in the setting of atrial fibrillation or a previous embolic event. No therapy is required for asymptomatic patients. Diuretics may be used to treat pulmonary congestion or edema.

Mitral regurgitation
Surgery is recommended for chronic severe mitral regurgitation in symptomatic patients with left ventricular ejection fraction (LVEF) of greater than 30%, and asymptomatic patients with LVEF of 30-60% or left ventricular end diastolic volume (LVEDV) > 40%. Surgical repair of the leaflets is preferred to mitral valve replacement as long as the repair is feasible. Mitral regurgitation may be treated medically with vasodilators, diuretics, digoxin, antiarrhythmics, and chronic anticoagulation. Mild to moderate mitral regurgitation should be followed with echocardiography and cardiac stress test every 1–3 years. Severe mitral regurgitation should be followed with echocardiography every 3–6 months.

Epidemiology
In the United States, about 2.5% of the population has moderate to severe valvular heart disease. The prevalence of these diseases increase with age, and 75 year-olds in the United States have a prevalence of about 13%. In industrially underdeveloped regions, rheumatic disease is the most common cause of valve diseases, and it can cause up to 65% of the valve disorders seen in these regions.

Aortic stenosis
Aortic stenosis is typically the result of aging, occurring in 12.4% of the population over 75 years of age, and represents the most common cause of outflow obstruction in the left ventricle. Bicuspid aortic valves are found in up to 1% of the population, making it one of the most common cardiac abnormalities.

Aortic regurgitation
The prevalence of aortic regurgitation also increases with age </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Edwards syndrome and can you explain it in depth? [/INST] Edwards syndrome, also known as trisomy 18, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features include a small head, small jaw, clenched fists with overlapping fingers, and severe intellectual disability.Most cases of Edwards syndrome occur due to problems during the formation of the reproductive cells or during early development. The rate of disease increases with the mothers age. Rarely, cases may be inherited from a persons parents. Occasionally, not all cells have the extra chromosome, known as mosaic trisomy, and symptoms in these cases may be less severe. An ultrasound during pregnancy can increase suspicion for the condition, which can be confirmed by amniocentesis.Treatment is supportive. After having one child with the condition, the risk of having a second is typically around one percent. It is the second-most common condition due to a third chromosome at birth, after Down syndrome.Edwards syndrome occurs in around 1 in 5,000 live births. Many of those affected die before birth. Some studies suggest that more babies that survive to birth are female. Survival beyond a year of life is around 5–10%. It is named after English geneticist John Hilton Edwards, who first described the syndrome in 1960.

Signs and symptoms
Children born with Edwards syndrome may have some or all of these characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, intellectual disability, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).Some physical malformations associated with Edwards syndrome include small head (microcephaly) accompanied by a prominent back portion of the head (occiput), low-set, malformed ears, abnormally small jaw (micrognathia), cleft lip/cleft palate, upturned nose, narrow eyelid openings (blepharophimosis), widely spaced eyes (ocular hypertelorism), drooping of the upper eyelids (ptosis), a short breast bone, clenched hands, choroid plexus cysts, underdeveloped thumbs and/or nails, absent radius, webbing of the second and third toes, clubfoot or rocker bottom feet, and in males, undescended testicles.In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common intracranial anomaly is the presence of choroid plexus cysts, which are pockets of fluid on the brain. These are not problematic in themselves, but their presence may be a marker for trisomy 18. Sometimes, excess amniotic fluid or polyhydramnios is exhibited. Although uncommon in the syndrome, Edwards syndrome causes a large portion of prenatally diagnosed cases of Dandy–Walker malformation.

Genetics
Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or in part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations, but is more prevalent in female offspring.A healthy egg and/or sperm cell contains individual chromosomes, each of which contributes to the 23 pairs of chromosomes needed to form a normal cell with a typical human karyotype of 46 chromosomes. Numerical errors can arise at either of the two meiotic divisions and cause the failure of a chromosome to segregate into the daughter cells (nondisjunction). This results in an extra chromosome, making the haploid number 24 rather than 23. Fertilization of eggs or insemination by sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo has 47 chromosomes, with three copies of chromosome 18.A small percentage of cases occur when only some of the bodys cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected individuals have two copies of chromosome 18 plus extra material from chromosome 18 attached to another chromosome. With a translocation, a person has a partial trisomy for chromosome 18, and the abnormalities are often less severe than for the typical Edwards syndrome.

Diagnosis
Ultrasound can increase suspicion for the condition, which can be confirmed by CVS or amniocentesis.Levels of PAPP-A, AFP, uE3, free β-hCG, all of which are generally decreased during pregnancy.

Prognosis
About 95% of pregnancies that are affected do not result in a live birth. Major causes of death include apnea and heart abnormalities. It is impossible to predict an exact prognosis during pregnancy or the neonatal period </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Intraoperative floppy iris syndrome and can you explain it in depth? [/INST]  </s>