<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Dysgraphia and explain in detail? [/INST] Dysgraphia is a learning disability of written expression, that affects the ability to write, primarily handwriting, but also coherence. It is a specific learning disability (SLD) as well as a transcription disability, meaning that it is a writing disorder associated with impaired handwriting, orthographic coding and finger sequencing (the movement of muscles required to write). It often overlaps with other learning disabilities and neurodevelopmental disorders such as speech impairment, attention deficit hyperactivity disorder (ADHD) or developmental coordination disorder (DCD).In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), dysgraphia is characterized as a learning disability in the category of written expression, when ones writing skills are below those expected given a persons age measured through intelligence and age-appropriate education. The DSM is unclear in whether writing refers only to the motor skills involved in writing, or if it also includes orthographic skills and spelling.Dysgraphia should be distinguished from agraphia (sometimes called acquired dysgraphia), which is an acquired loss of the ability to write resulting from brain injury, progressive illness, or a stroke.The prevalence of dysgraphia throughout the world is not known, due to difficulties in diagnosis and lack of research.

Etymology
The word dysgraphia comes from the Greek words dys meaning "impaired" and γραφία graphía meaning "writing by hand".

Development
There are at least two stages in the act of writing: the linguistic stage and the motor-expressive-praxic stage. The linguistic stage involves the encoding of auditory and visual information into symbols for letters and written words. This is mediated through the angular gyrus, which provides the linguistic rules which guide writing. The motor stage is where the expression of written words or graphemes is articulated. This stage is mediated by Exners writing area of the frontal lobe.The condition can cause individuals to struggle with feedback and anticipating and exercising control over rhythm and timing throughout the writing process.People with dysgraphia can often write on some level and may experience difficulty with other activities requiring reciprocal movement of their fingers and other fine motor skills, such as; tying shoes, fastening buttons or playing certain musical instruments. However, dysgraphia does not affect all fine motor skills. People with dysgraphia often have unusual difficulty with handwriting and spelling which in turn can cause writing fatigue. Unlike people without transcription disabilities, they tend to fail to preserve the size and shape of the letters they produce if they cannot look at what they are writing. They may lack basic grammar and spelling skills (for example, having difficulties with the letters p, q, b, and d), and often will write the wrong word when trying to formulate their thoughts on paper. The disorder generally emerges when the child is first introduced to writing. There is accumulating evidence that in many cases individuals with SLDs and DCD do not outgrow their disorders. Accordingly, it has been found that adults, teenagers, and children alike are all subject to dysgraphia.  Studies have shown that higher education students with developmental dysgraphia still experience significant difficulty with hand writing, fine motor skills and motor-related daily functions when compared to their peers without neurodevelopmental disorders.

Classification
Dysgraphia is nearly always accompanied by other learning disabilities and/or neurodevelopmental disorders such as dyslexia, attention deficit disorder or oral and written language learning disability (OWL LD)  and this can impact the type of dysgraphia a person has. Tourette syndrome, ASD and dyspraxia are also common diagnoses among dysgraphic individuals. Developmental dysgraphia was originally described as being a disorder that occurs solely in dyslexic individuals. Dysgraphia was not studied as a separate entity until mid-20th century when researchers discovered there were different types that occur without dyslexia. Dyslexics and dysgraphics experience similar synchronization difficulties and issues with spelling. However, dyslexia does not seem to impair physical writing ability or dramatically impact fine motor skills and dysgraphia does not impact reading comprehension. Methods for evaluating, managing and remedying dysgraphia are still evolving, but there are three principal subtypes of dysgraphia that are recognized. There is little information available about different types of dysgraphia and there are likely more subtypes than the ones listed below. Some people may have a combination of two or more of these, and individual symptoms may vary in presentation from what is described here. Most common presentation is a motor agraphia resulting from damage to some part of the motor cortex in the parietal lobes.

Dyslexic
There are several features that distinguish dyslexic-dysgraphia (sometimes called linguistic dysgraphia) from the other types. People with dyslexic-dysgraphia typically have poor oral and written spelling that is typically phonemic in nature. Their spontaneously written work is often illegible, has extra or deleted syllables or letters, and contains unnecessary capitalization or large spaces in the middle of words which can make each individual word unrecognizable. They may also insert symbols that do not resemble any letter of the alphabet. Writing production generally requires long periods of contemplation and correction.Dyslexic-dysgraphic individuals have fairly good copied work, and their ability to draw is also preserved. Their finger tapping speed (a method for identifying fine motor problems) is normal, indicating that the deficit does not likely stem from cerebellar damage. Impaired verbal executive functioning has also been related to this form of the disorder.One study found that boys with ADHD and dysgraphia struggle primarily with motor planning rather than have a linguistic impairment but the prevalence of linguistic/dyslexic-dysgraphia compared to other subtypes is uncertain.

Motor
Motor dysgraphia (sometimes called peripheral dysgraphia) is due to deficient fine motor skills, poor dexterity, poor muscle tone or unspecified motor clumsiness. Motor dysgraphia impairs both motor patterns and motor memory. Letter formation may be acceptable in very short samples of writing, but this requires extreme effort and an unreasonable amount of time to accomplish, and it cannot be sustained for a significant length of time, as it can cause arthritis-like tensing of the hand. Overall, their written work is poor to illegible even if copied by sight from another document, and drawing is impaired. Oral spelling for these individuals is normal, and their finger tapping speed is below normal. This shows that there are problems within the fine motor skills of these individuals. People with developmental coordination disorder may be dysgraphic and motor-dysgraphia may serve as a marker of dyspraxia. Motor-dysgraphics struggle with proper finger grip and writing is often slanted due to holding a pen or pencil incorrectly. Average writing speed is slower than that of non-dysgrapic individuals, but this seems to improve with age. Motor skill deficits appears to be a common cause of dysgraphia; 78% of children with the disorder present kinematic difficulties, while 58% of them display issues with pressure skills.

Spatial
A person with spatial dysgraphia has a defect in the understanding of space. This impaired spatial perception causes illegible spontaneously written work, illegible copied work, abnormal spacing between letters and majorly impaired drawing abilities. They have normal oral spelling and normal finger tapping speed, suggesting that this subtype is not fine motor based. Symptoms in actuality may vary in presentation from what is listed here. Spatial dysgraphia may develop in individuals with lesions on the right hemisphere of the brain.

Miscellaneous
Other subtypes and informal classification systems have been proposed by researchers; this includes but is not limited to phonological dysgraphia, deep dysgraphia and surface dysgraphia.

Signs and symptoms
The symptoms to dysgraphia are often overlooked or attributed to the student being lazy, unmotivated, careless or anxious. The condition may also be dismissed as simply being an expression of attention deficiency or having delayed visual-motor processing. In order to be diagnosed with dysgraphia, one must have a cluster, but not necessarily all, of the following symptoms:

The symptoms of dysgraphia can change as one ages.  Dysgraphia may cause students emotional trauma often due to the fact that no one can read their writing, and they are aware that they are not performing to the same level as their peers. Emotional problems that may occur alongside dysgraphia include impaired self-esteem, lowered self-efficacy, reduced motivation, poorer social functioning, heightened anxiety, and depression. They may put in extra efforts in order to have the same achievements as their peers, but often get frustrated because they feel that their hard work does not pay off. Dysgraphia is a hard disorder to detect as it does not affect specific ages, gender, or intelligence. The main concern in trying to detect dysgraphia is that people hide their disability behind their verbal fluency/comprehension and strong syntax coding  because they are ashamed that they cannot achieve the same goals as their peers. Having dysgraphia is not related to a lack of cognitive ability, and it is not uncommon in intellectually gifted individuals, but due to dysgraphia their intellectual abilities are often not identified.

Associated conditions
There are some common problems not related to dysgraphia but often associated with dysgraphia, the most common of which is stress. Developing an aversion to writing is another common issue. Often children (and adults) with dysgraphia will become extremely frustrated with the task of writing specially on plain paper (and spelling); younger children may cry, pout, or refuse to complete written assignments. This frustration can cause the student a great deal of stress and can lead to stress-related illnesses. This can be a result of any symptom of dysgraphia.

Causes
The underlying causes of the disorder are not fully understood  But dysgraphia is as well known to be a biologically based disorder with genetic and brain bases. More specifically, it is a working memory problem caused by specific neurodevelopmental dysfunction. In dysgraphia, individuals fail to develop normal connections among different brain regions needed for writing. People with dysgraphia have difficulty in automatically remembering and mastering the sequence of motor movements required to write letters or numbers. Dysgraphia is also in part due to underlying problems in orthographic coding, the orthographic loop, and graphmotor output (the movements that result in writing) by ones hands, fingers and executive functions involved in letter writing. The orthographic loop is when written words are stored in the minds eye, connected through sequential finger movement for motor output through the hand with feedback from the eye.Family history of specific learning disabilities may play a role. Children with developmental dysphasia, developmental dysgraphia and developmental dyslexia may be more likely to have family members with one of these conditions. Genetic studies suggest that verbal executive function tasks, orthographic skills, and spelling ability may have a genetic basis. Genes on chromosomes 6 and 15 may play some role with SLDs as they have linked to poorer reading, poorer spelling and lower phonemic awareness.

Diagnosis
Unlike specific learning disabilities and neurodevelopmental disorders that have been more extensively studied, there is no gold standard for diagnosing dysgraphia. This is likely due to writing systems often differing substantially between countries and languages and there being considerable heterogeneity among the therapists who are charged with diagnosing dysgraphia. Consequently, there are several tests that are used to diagnose dysgraphia like Ajuriaguerra scale, BHK for children or teenagers, the Minnesota Handwriting Assessment, ETCH, SCRIPT, DASH and HHE scale.With devices like drawing tablets, it is now possible to measure the position, tilt, and pressure in real time. From these features, it is possible to compute automatic features like speed and shaking and train a classifier to diagnose automatically children with atypical writing. The features extracted have different importances in the classification through development and allow to characterize different subtypes of dysgraphia that could have different origins, outcomes and could require different remediation strategies.It is not uncommon for dysgraphic individuals to be intellectually gifted, possess a rich vocabulary and have strong comprehension of language when speaking or reading, though their disorder is often not detected or treated; which may also be in part to developmental dyslexia receiving far more academic and medical attention than developmental dysgraphia. In addition, gifted children with transcription disabilities seldom receive programming for their intellectual talents due to their difficulties in completing written assignments.

Treatment
Treatment for dysgraphia varies and may include treatment for motor disorders to help control writing movements. Helping dysgraphic students overcome writing avoidance and accept the purpose and necessity of writing may be needed. The use of occupational therapy can be effective in the school setting, and teachers should be well informed about dysgraphia to aid in carry-over of the occupational therapists interventions. Treatments may address impaired memory or other neurological problems. Some physicians recommend that individuals with dysgraphia use computers to avoid the problems of handwriting. Dysgraphia can sometimes be partially overcome with appropriate and conscious effort and training. The International Dyslexia Association suggests the use of kinesthetic memory through early training by having the child overlearn how to write letters and to later practice writing with their eyes closed or averted to reinforce the feel of the letters being written. They also suggest teaching the students cursive writing as it has fewer reversible letters and can help lessen spacing problems, at least within words, because cursive letters are generally attached within a word.

Prevalence
It has been estimated that up to 10% of children in the world are affected by disabilities like dysgraphia, dyslexia, dyscalculia and dyspraxia. Estimates on the true prevalence of dysgraphia are not available due to lack of research on the disorder.

School
There is no special education category for students with dysgraphia; in the United States, The National Center for Learning Disabilities suggests that children with dysgraphia be handled in a case-by-case manner with an Individualized Education Program, or provided individual accommodation to provide alternative ways of submitting work and modify tasks to avoid the area of weakness. Students with dysgraphia often cannot complete written assignments that are legible, appropriate in length and content, or within given time. It is suggested that students with dysgraphia receive specialized instructions that are appropriate for them. Children will mostly benefit from explicit and comprehensive instructions, help translating across multiple levels of language, and review and revision of assignments or writing methods. Direct, explicit instruction on letter formation and guided practice will help students achieve automatic handwriting performance before they use letters to write words, phrases, and sentences. Some older children may benefit from the use of a personal computer or a laptop in class so that they do not have to deal with the frustration of falling behind their peers.It is also suggested by Berninger that teachers with dysgraphic students decide if their focus will be on manuscript writing (printing) or keyboarding. In either case, it is beneficial that students are taught how to read cursive writing as it is used daily in classrooms by some teachers </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Necrobiotic xanthogranuloma and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Laryngopharyngeal reflux and explain in detail? [/INST] Laryngopharyngeal reflux (LPR) is the retrograde flow of gastric contents into the larynx, oropharynx and/or the nasopharynx. LPR causes respiratory symptoms such as cough and wheezing and is often associated with head and neck complaints such as dysphonia, globus pharyngis, and dysphagia.  LPR may play a role in other diseases, such as sinusitis, otitis media, and rhinitis, and can be a comorbidity of asthma.  While LPR is commonly used interchangeably with gastroesophageal reflux disease (GERD), it presents with a different pathophysiology.LPR reportedly affects approximately 10% of the U.S. population. However, LPR occurs in as many as 50% of individuals with voice disorders.

Signs and symptoms
Extraesophageal symptoms result from exposure of the upper aerodigestive tract to gastric contents. This causes a variety of symptoms, including hoarseness, postnasal drip, sore throat, difficulty swallowing, indigestion, wheezing, globus pharyngeus, and chronic throat-clearing. Some people with LPR have heartburn, while others have little to no heartburn as refluxed stomach contents do not remain in the esophagus long enough to irritate the surrounding tissue. Individuals with more severe forms of LPR may experience abrasion of tooth enamel due to intermittent presence of gastric contents in the oral cavity.Additionally, LPR can cause inflammation in the vocal tract which results in the symptom of dysphonia or hoarseness. Hoarseness is considered to be one of the primary symptoms of LPR and is associated with complaints such as strain, vocal fatigue, musculoskeletal tension, and hard glottal attacks, all of which can reduce a persons ability to communicate effectively.  Moreover, LPR patients may try to compensate for their hoarseness by increasing muscular tension in their vocal tract. This hyper-functional technique adopted in response to the inflammation caused by LPR can lead to a condition called muscle tension dysphonia and may persist even after the hoarseness and inflammation has disappeared. A speech-language pathologist will often need to be involved to help resolve this maladaptive, compensatory pattern through the implementation of voice therapy.LPR presents as a chronic and intermittent disease in children. LPR in children and infants tends to manifest with a unique set of symptoms.  Symptoms seen in children with LPR include a cough, hoarseness, stridor, sore throat, asthma, vomiting, globus sensation, wheezing, aspiration and recurrent pneumonia. Common symptoms of LPR in infants include wheezing, stridor, persistent or recurrent cough, apnea, feeding difficulties, aspiration, regurgitation, and failure to thrive. Moreover, LPR in children is commonly concomitant with laryngeal disorders such as laryngomalacia, subglottic stenosis, and laryngeal papillomatosis.

Relationship to GERD
LPR is often regarded as a subtype of GERD that occurs when stomach contents flow upward through the esophagus and reach the level of the larynx and pharynx. However, LPR is associated with a distinct presentation of symptoms. LPR and GERD frequently differ in the relative prevalence of heartburn and throat clearing. While heartburn is present in over 80% of GERD cases, it occurs in only 20% of LPR cases. Throat clearing shows the opposite prevalence pattern, occurring in approximately 87% of LPR cases and in fewer than 5% of GERD cases. Unlike GERD, LPR also poses a risk for bronchitis or pneumonitis as reflux of stomach acid to the level of the larynx can result in aspiration. LPR is also commonly associated with erythema, or redness, as well as edema in the tissues of the larynx that are exposed to gastric contents. In contrast, most cases of GERD are nonerosive, with no apparent injury to the mucosal lining of the esophageal tissue exposed to the refluxed material.Differences in the molecular structure of the epithelial tissue lining the laryngopharyngeal region may be partly responsible for the different symptomatic manifestations of LPR in comparison to GERD. In contrast to the resistant stratified squamous epithelium lining the esophagus, the larynx is lined by ciliated respiratory epithelium, which is more fragile and susceptible to damage. While the epithelium lining the esophagus is capable of withstanding as many as 50 instances of exposure to gastric contents each day, which is the uppermost estimate considered to be within the range of normal physiologic functioning, injury to laryngeal epithelium can occur following exposure to only small amounts of acidic gastric contents.

Diagnosis
LPR presents with non-specific symptoms and signs that make differential diagnosis difficult to achieve. Furthermore, symptoms of the disorder overlap greatly with symptoms of other disorders. Therefore, LPR is under-diagnosed and under-treated. As there are multiple potential etiologies for the respiratory and laryngeal symptoms of LPR, diagnosing LPR based on symptoms alone is unreliable. Laryngoscopic findings such as erythema, edema, laryngeal granulomas, and interarytenoid hypertrophy have been used to establish the diagnosis; however, these findings are nonspecific and have been described in the majority of asymptomatic subjects undergoing laryngoscopy. Response to acid-suppression therapy has been suggested as a diagnostic tool for confirming diagnosis of LPR, but studies have shown that the response to empirical trials of such therapy (as with proton-pump inhibitors) in these patients is often disappointing. Several studies have emphasized the importance of measuring proximal esophageal, or ideally pharyngeal acid exposure, in patients with clinical symptoms of LPR to document reflux as the cause of the symptoms.Additionally, several potential biomarkers of LPR have been investigated. These include inflammatory cytokines, carbonic anyhydrase, E-cadherin and mucins; however, their direct implications in LPR are still being established. The presence of pepsin, an enzyme produced in the stomach, in the hypopharynx has also become an increasingly researched biomarker for LPR. Research suggests that the stomach enzyme pepsin plays a crucial role in the complex mechanism behind LPR. Once present in the larynx pepsin is active at a low pH, but persists even when inactive.  Pepsin can manifest both extracellularly and intracellularly; however, damage is realized differently in these two environments. Intracellularly, pepsin enters the laryngeal tissue through endocytosis and causes damage that accumulates over time. Pepsin has implications on cellular transcription and therefore, gene expression, which subsequently leads to the recruitment of inflammatory cells, but inhibition of protective mechanisms such as growth factors. Structurally, pepsin plays a role in increasing viscosity of the vibratory portion of the vocal folds and decreasing cellular water retention, which reduces the overall thickness of the vocal folds. These morphological changes result in decreased vibratory amplitude, increasing demands for initiating vibration and ultimately, impacting voice quality.Before a diagnosis can be made, a physician will need to record the patients medical history and ask for details about the presenting symptoms. Questionnaires such as the Reflux Symptom Index (RSI), Quality-of-Life Index (QLI) for LPR, Glottal Closure/Function Index (GCI) and Voice Handicap Index (VHI) can be administered to gain information about the patients medical history as well as their symptomatology. A physical examination will then need to be performed with particular concentration around the head and neck. A scope with a specialized camera lens made of fiber optic strands is gently fed down the throat and feeds back images to a monitor. This provides a clear view of the throat and larynx. Signs of LPR include redness, swelling, and obvious irritation. Other, more invasive tests, such as fibre-optic transnasal laryngoscopy, 24-hour ambulatory dual probe pHmetry, pharyngeal pHmetry, transnasal esophagoscopy (TNE) and biopsy may be used. A noninvasive test for diagnosis of LPR is the collection of refluxate where the refluxed material is collected and analyzed. Another noninvasive diagnostic test that can be used is an empirical trial of proton-pump inhibitor therapy; however, this test is mostly successful in diagnosing GERD.There is no agreed-upon assessment technique to identify LPR in children. Of the debated diagnostic tools, multichannel intraluminal impedance with pH monitoring (MII-pH) is used as it recognizes both acid and non-acid reflux. A more common technique that is used is 24-hour dual probe pH monitoring. Both of these tools are expensive and are therefore not widely used.

Treatment
Management of symptoms for patients within this subgroup of the GERD spectrum is difficult. Once these patients are identified, behavioural and dietary changes are advised. Dietary modifications may include limiting the intake of chocolate, caffeine, acidic food and liquids, gaseous beverages and foods high in fat. Behavioral changes may include weight loss, cessation of smoking, limiting alcohol consumption and avoiding the ingestion of food shortly before bed. Lifestyle changes in children diagnosed with LPR include dietary modifications to avoid foods that will aggravate reflux (e.g., chocolate or acidic and spicy food), altering positioning (e.g., sleeping on your side), modifying the textures of foods (e.g., thickening feeds to heighten awareness of the passing bolus), and eliminating the intake of food before bed.Proton pump inhibitors (PPIs) are the leading pharmaceutical intervention chosen for the relief and reduction of LPR and are typically recommended for ongoing use twice a day for a period of 3–6 months. PPIs have been shown to be ineffective in very young children and are of uncertain efficacy in older children, for whom their use has been discouraged.
While PPIs may provide limited clinical benefits in some adults, there is insufficient evidence to support routine use. Many studies show that PPIs are not more effective than placebos in treating LPR.When medical management fails, Nissen fundoplication can be offered. However, patients should be advised that surgery may not result in complete elimination of LPR symptoms and even with immediate success, recurrence of symptoms later on is still possible.One way to assess treatment outcomes for LPR is through the use of voice quality measures. Both subjective and objective measures of voice quality can be used to assess treatment outcomes </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hyperlysinemia and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Verrucous perforating collagenoma and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Aarskog–Scott syndrome and explain in detail? [/INST] Aarskog–Scott syndrome is a rare disease inherited as X-linked and characterized by short stature, facial abnormalities, skeletal and genital anomalies. This condition mainly affects males, although females may have mild features of the syndrome.

Signs and symptoms
People with Aarskog–Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widows peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Other abnormalities in people with Aarskog–Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).Most males with Aarskog–Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).The intellectual development of people with Aarskog–Scott syndrome varies widely. Some may have mild learning and behavior problems, while others have normal intelligence. In rare cases, severe intellectual disability has been reported.

Genetics
Mutations in the FGD1 gene are the only known genetic cause of Aarskog-Scott syndrome. The FGD1 gene provides instructions for making a protein that turns on (activates) another protein called Cdc42, which transmits signals that are important for various aspects of development before and after birth.Mutations in the FGD1 gene lead to the production of an abnormally functioning protein. These mutations disrupt Cdc42 signaling, leading to the wide variety of abnormalities that occur in people with Aarskog-Scott syndrome.Only about 20 percent of people with this disorder have identifiable mutations in the FGD1 gene. The cause of Aarskog-Scott syndrome in other affected individuals is unknown.

Pathophysiology
The Aarskog–Scott syndrome is due to mutation in the FGD1 gene. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates Cdc42, a member of the Rho (Ras homology) family of the p21 GTPases. By activating Cdc42, FGD1 protein stimulates fibroblasts to form filopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 protein also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis, and cellular differentiation.Within the developing mouse skeleton, FGD1 protein is expressed in precartilaginous mesenchymal condensations, the perichondrium and periosteum, proliferating chondrocytes, and osteoblasts. These results suggest that FGD1 signaling may play a role in the biology of several different skeletal cell types including mesenchymal prechondrocytes, chondrocytes, and osteoblasts. The characterization of the spatiotemporal pattern of FGD1 expression in mouse embryos has provided important clues to the understanding of the pathogenesis of Aarskog–Scott syndrome.It appears likely that the primary defect in Aarskog–Scott syndrome is an abnormality of FGD1/Cdc42 signaling resulting in anomalous embryonic development and abnormal endochondral and intramembranous bone formation.

Diagnosis
Genetic testing may be available for mutations in the FGDY1 gene. Genetic counseling is indicated for individuals or families who may carry this condition, as there are overlapping features with fetal alcohol syndrome.Other examinations or tests can help with diagnosis. These can include:

detailed family history
conducting a detailed physical examination to document morphological features
testing for genetic defect in FGDY1
x-rays can identify skeletal abnormalities
echo cardiogram can screen for heart abnormalities
CT scan of the brain for cystic development
X-ray of the teeth
Ultrasound of abdomen to identify undescended testis

Treatment
Similar to all genetic diseases Aarskog–Scott syndrome cannot be cured, although numerous treatments exist to increase the quality of life.Surgery may be required to correct some of the anomalies, and orthodontic treatment may be used to correct some of the facial abnormalities. Trials of growth hormone have been effective to treat short stature in this disorder.

Prognosis
Some people may have some mental slowness, but children with this condition often have good social skills. Some males may have problems with fertility.

History
The syndrome is named for Dagfinn Aarskog, a Norwegian pediatrician and human geneticist who first described it in 1970, and for Charles I. Scott, Jr., an American medical geneticist who independently described the syndrome in 1971.

References
Jones, Kenneth Lyons (2005). Smiths Recognizable Patterns of Human Malformation (6th ed.). Philadelphia: WB Saunders </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Remitting seronegative symmetrical synovitis with pitting edema and explain in detail? [/INST] Remitting seronegative symmetrical synovitis with pitting edema (or sometimes RS3PE) is a rare syndrome identified by symmetric polyarthritis, synovitis, acute pitting edema (swelling) of the back of the hands and/or feet, and a negative serum rheumatoid factor. If no underlying disorder can be identified (idiopathic RS3PE), this entity has an excellent prognosis and responds well to treatment.RS3PE typically involves the joints of the extremities, specifically the metacarpophalangeal and proximal interphalangeal joints, wrists, shoulders, elbows, knees and ankles.
It is more common in older adults, with the mean age between 70 and 80 years in most studies.
It occurs more often in men than in women with a 2:1 ratio.
It is unknown how common this condition is.

Signs and symptoms
Individuals affected by RS3PE typically have repeated episodes of inflammation of the lining of their synovial joints and swelling of the end portion of the limbs. The arms and hands are more commonly affected than the legs and feet. Both sides are usually involved though RS3PE can affect only one side in certain cases.

Causes
RS3PE is a constellation of symptoms that can be caused by many other conditions </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Uveitic glaucoma and explain in detail? [/INST] Uveitic glaucoma (or uveitis glaucoma, or anterior uveitic glaucoma, or anterior noninfectious uveitic glaucoma, or uveitis associated with glaucoma, or iritic glaucoma) is most commonly a progression stage of noninfectious anterior uveitis or iritis.
Noninfectious anterior uveitis is an inflammation of the anterior (front) part of the eye and is instigated by autoimmune or other noninfectious causes (noninfectious uveitis can also affect the posterior segments of the eye, and then is called posterior, pan or intermediate uveitis). The onset of noninfectious uveitis occurs in patients in their thirties, with up to 10% of cases diagnosed in children under the age of 16. The condition may persist as a chronic disease.
Noninfectious uveitis is the most common form of uveitis in developed countries. Approximately 30% of uveitis patients develop glaucoma as a result of the inflammation that occurs in uveitis, as a complication of steroid treatment or a combination of both.Uveitis, as well as steroid treatment for uveitis, can cause an increased resistance to the flow of aqueous humour (the clear liquid suspended between the lens and the cornea) from the eye. This leads to an excess of fluid buildup, which exerts elevated pressure on the inside parts of the eye, or elevated intraocular pressure (IOP). Elevated intraocular pressure can in turn lead to optic nerve damage and glaucoma.
Based on epidemiological studies of uveitis, approximately 34-94/100,000 people will develop uveitic glaucoma (see Epidemiology section). Uveitic glaucoma patients are at significantly higher risk for visual field loss in the long term compared to patients who only have uveitis. Patients with uveitic glaucoma also experience a particularly high burden of care.

Signs and symptoms
Because uveitic glaucoma is a progressive stage of anterior non infectious uveitis, uveitic glaucoma involves signs and symptoms of both glaucoma and uveitis.
Patients with acute non infectious anterior uveitis may experience the following symptoms: pain, blurry vision, headache, photophobia (discomfort or pain due to light exposure), or the observance of haloes around lights.
An ophthalmologist may be able to observe the main sign of active noninfectious anterior uveitis, which is the presence of immune cells (anterior chamber cells, or ACCs) floating within the anterior segment of the eye (see "Noninfectious anterior uveitis" in Diagnosis section). The ophthalmologist also may observe peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork, the tissue responsible for draining aqueous humour from the eye.Patients with uveitis who also experience symptoms of glaucoma may have uveitic glaucoma.
In an eye with uveitic glaucoma, the following glaucoma signs may be observed: elevated intraocular pressure, scotomas in the field of vision, defects in the fiber layer of the retinal nerve, and/or excavation (a regional deformation or depression of the optic nerve). Pupillary blocks, or the obstruction of "the flow of aqueous humor from the posterior chamber to the anterior chamber" due to a "functional block between the pupillary portion of the iris and the lens" may also be detected. Finally, the ophthalmologist may observe peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork.The dual presence of glaucoma and uveitis symptoms points to a diagnosis of uveitic glaucoma.

Causes
Uveitic glaucoma is a progressive stage of anterior noninfectious uveitis. Patients diagnosed with anterior noninfectious uveitis may also develop glaucoma; in this case the condition is termed uveitic glaucoma. Uveitic glaucoma can arise from the inflammation that occurs in uveitis; from steroid treatment for uveitis; or a combination of both.

Uveitis inflammation
The inflammatory response associated with uveitis may lead to glaucoma. Active anterior uveitis flare-ups may develop quickly; in these cases, the inflammation can damage the tissues in the front part of the eye. Anterior uveitis may also be chronic; in these cases, repeated inflammation can cause progressive, accumulating damage to the eye tissues.
In all cases — acute one-time episodes, recurrent chronic inflammation or acute-on-chronic inflammation — damage to the eye tissues can cause increased resistance to the outflow of aqueous humour from the eye, which then increases the pressure inside the eye. In some chronic uveitis cases, the pressure inside the eye waxes and wanes due to the uveitis flare-ups.Elevated pressure inside the eye can lead to irreversible optic nerve damage and glaucoma.

Steroid treatment for uveitis
Topical corticosteroids are the first-line treatment for an active flare-up of noninfectious anterior uveitis, and the only effective treatment available for active inflammation. However, steroid treatment for uveitis can lead to uveitic glaucoma. Corticosteroids increase the fluid pressure inside the eye by increasing resistance to the outflow of aqueous humour, which can cause optic nerve damage and glaucoma. Steroid treatment can therefore cause or worsen uveitic glaucoma.Elevated pressure inside the eye typically develops 2 to 6 weeks after starting corticosteroid therapy, but can occur at any time during corticosteroid therapy and may continue for weeks after steroid use has been stopped. According to the Glaucoma Research Foundation, the risk of developing chronic steroid-induced glaucoma increases with every week of steroid use.Around 90% of patients with open angle glaucoma experience a steroid response of elevated intraocular pressure following steroid treatment. Therefore, once uveitis patients have developed uveitic glaucoma, they should ideally avoid steroids wherever possible.

Combination of uveitis inflammation and steroid treatment
In some cases, uveitis inflammation and steroid treatment both contribute to elevated pressure inside the eye, which leads to optic nerve damage and glaucoma.

Pathogenesis
Uveitic glaucoma as a result of recurring uveitic inflammation
Uveitic glaucoma can develop as a complication of anterior uveitis resulting from the inflammatory response associated with the disease. The inflammatory response can be characterized by occlusion of the trabecular meshwork, or blocking of the tissue that is responsible for draining aqueous humour from the eye. Another characteristic that presents in some patients is peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork. These two characteristics of the inflammatory uveitic response can lead to an increase in intraocular pressure, and consequently to irreversible optic nerve damage and glaucoma.
Noninfectious uveitis is characterized by an inflammatory process that may be acute, recurrent, chronic or acute-on-chronic. Uveitic glaucoma is associated with an aggressive disease course caused by very high levels of intraocular pressure that wax and wane. When uveitis is acute, the onset of inflammation is rapid, with obstruction of intertrabecular spaces. When uveitis is chronic, recurrent bouts lead to tissue destruction from direct inflammation. Obstruction of the intertrabecular spaces characteristic of acute onset uveitis, as well as the repeated inflammation characteristic to chronic uveitis, can lead to elevated intraocular pressure. This can consequently cause optic nerve damage and glaucoma.

Uveitic glaucoma as a response to steroid treatment of uveitis
Uveitic glaucoma can also develop as a response to steroid treatment of uveitis. Corticosteroids cause a rise in the fluid pressure inside the eye. While the pathogenesis of corticosteroid-induced ocular hypertension is not fully understood, it likely involves swelling and remodeling (alterations to the extracellular matrix) of the trabecular meshwork, which leads to increased resistance to aqueous humour outflow and an increase in intraocular pressure. Another possible mechanism by which corticosteroids increase fluid pressure inside the eye is as follows:

Corticosteroids inhibit (partly prevent and slow) the breakdown of glycosaminoglycans (GAGs) in the trabecular meshwork.
GAGs accumulate in the meshwork.
Fluid drainage is decreased.
Fluid pressure in the eye is increased.It has also been suggested that corticosteroids may be capable of modifying the trabecular meshwork cells, modulating their size as well as their cytoskeletal arrangement, which in turn could limit fluid drainage.

Diagnosis
Uveitic glaucoma is a progression stage of noninfectious acute anterior uveitis. In order to diagnose uveitic glaucoma, a dual diagnosis of non-infectious anterior uveitis and glaucoma is required. A thorough examination of the eye by an ophthalmologist is performed in order to diagnose uveitic glaucoma.

Noninfectious anterior uveitis
[Main article: Uveitis]

The main diagnostic sign of noninfectious acute anterior uveitis is the presence of anterior chamber cells (ACCs), or immune cells, in the anterior, or front, chamber of the eye. The anterior chamber of healthy eyes does not contain any immune cells, hence the main indicator of noninfectious anterior uveitis is the presence of immune blood cells inside the anterior chamber of the eye. The more cells found floating in the anterior chamber, the more severe the uveitis.The quantity of immune cells present in the anterior chamber can be determined via a slit lamp examination.In 2005, an International Working Group on SUN (Standardization of Uveitis Nomenclature) took steps towards standardizing the methods for reporting clinical data in the field of uveitis. One of their products was a grading scheme for anterior chamber cells.
In 2021, a new slit lamp–based ACC assessment method, TGIS (Tarsier Grading Image Scale), was developed. TGIS uses a visual analog scale to enable pattern recognition-based evaluation of ACC density during a uveitic flare-up. This is achieved by graphically representing a high-power field slit beam through the anterior chamber, from the cornea to the lens surface.
Another important clinical measurement of ocular inflammation is flare. Flare is the leakage of various proteins (such as fibrin and cytokines) into the ocular anterior chamber, as a manifestation of inflammation. It will usually have a "milky" appearance. Flare can also be observed via slit lamp examination.

Glaucoma
[Main article: Glaucoma]
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss.Glaucoma is challenging to diagnose and relies on several different methods of assessment to determine the level of optic nerve damage. These may include tonometry, a procedure to determine pressure inside the eye; a visual field test, which assesses peripheral vision; and imaging tests of the optic nerve.

Treatment
Treatment for uveitic glaucoma requires addressing the noninfectious anterior uveitis as well as the glaucoma present in uveitic glaucoma patients. Most urgently, the inflammation associated with uveitis must be identified and treated, to ensure as little damage to the eye as possible. Secondly, the elevated intraocular pressure associated with glaucoma must be treated. Steroid treatment may be discouraged because of the associated side effects.

Treatment of noninfectious anterior uveitis
Topical corticosteroid eyedrops are first-line treatment for uveitis and represent the only approved topical treatment for active non-infectious anterior uveitis. They are the only effective treatment for the short term available today. Corticosteroids can also be administered via periocular injection or intravitreal (IVT) injection. In more severe cases, treatment may be administered systemically via oral or intravenous corticosteroids.
Other treatments, including systemic immunosuppressive agents — which require close monitoring — may be considered where corticosteroids are ineffective or if there are concerns regarding side effects. Immunosuppressive agents include T-cell inhibitors such as cyclosporine and tacrolimus; antimetabolites such as azathioprine, methotrexate, mycophenolate mofetil, and leflunomide; alkylating agents such as cyclophosphamides and chlorambucil; and biological drugs such as adalimumab.
Most uveitis patients are treated with local steroids in the acute phase but may also need long-term treatment with lower-dose steroids as a preventive measure between flare-ups. This precaution is employed in order to minimize the use of topical corticosteroids, due to their severe ocular side effects.
Despite significant advances in therapeutics, the prevalence of blindness secondary to uveitis has not been reduced in the U.S. for the past 30 years.

Challenges related to steroid treatment of noninfectious anterior uveitis
Steroid treatment for uveitis can lead to uveitic glaucoma. Corticosteroids increase the fluid pressure inside the eye (by increasing the resistance to the outflow of aqueous humour), which can cause optic nerve damage and glaucoma. Steroid treatment can therefore cause or worsen uveitic glaucoma.Studies show that 40% to 50% of patients treated with the corticosteroid triamcinolone via intravitreal injection developed clinically significant ocular hypertension. Corticosteroid-induced ocular hypertension typically develops 2 to 6 weeks after starting therapy but can occur at any time during corticosteroid therapy and may persist for weeks after corticosteroids have been discontinued. According to the Glaucoma Research Foundation, "every week of steroid use averaged over a lifetime leads to a 4% increased risk of chronic steroid[-induced] glaucoma".In addition, around 90% of patients with pre-existing open angle glaucoma develop an additional adverse response to steroid treatment.

Treatment of uveitic glaucoma
Glaucoma medications, glaucoma surgery and steroids are the primary options for addressing uveitic glaucoma. Approximately 30% of uveitic glaucoma patients require surgical intervention due to insufficient intraocular pressure control while on maximum medicinal therapy.Available surgical interventions to treat the glaucoma in uveitic glaucoma patients pose a high risk to the eye, with a lower success rate compared to glaucoma surgeries in non-uveitic eyes. Steroids for treating uveitic glaucoma patients also carry high risks.
Because of the risks inherent in steroid treatment and the ineffectiveness of surgical interventions for uveitic glaucoma, there is currently no approved treatment for uveitic patients who also have glaucoma.
A steroid-free medication for uveitis in uveitic glaucoma patients, formulated by Tarsier Pharma, is currently undergoing clinical trials [see Research section].

Challenges related to surgical treatment of uveitic glaucoma
Uveitic glaucoma patients respond poorly to glaucoma surgery; surgery in uveitic glaucoma patients commonly has complications. These complications are caused by either the surgical wound healing improperly or unhealthy levels of pressure inside the eye.Glaucoma surgery usually leads to increased levels of inflammation in the eyes. This is an undesirable consequence, especially in uveitis patients, who already have a high tendency to develop inflammation. Because of this, 80% of uveitis experts report that glaucoma surgeries for uveitic glaucoma patients are likely to fail. Surgery in an eye with uveitis is associated with a higher complication rate, and in some cases surgeries such as valve implantation are too complicated to perform.

Prognosis for  uveitic glaucoma patients
About 30% of uveitis patients also develop uveitic glaucoma. Uveitic glaucoma patients are at significantly higher risk for visual field loss in the long term (>5 years) compared to patients who only have uveitis. A patient who only has glaucoma (without uveitis) will, on average, become blind in one eye within 20 years of glaucoma onset </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Generalized epilepsy with febrile seizures plus and explain in detail? [/INST] Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood (i.e., 6 years of age). GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravets syndrome, borderline SMEI (SMEB), and intractable  epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative gene mutations are in the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and in a GABAA receptor γ subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. Penetrance for this disorder is estimated at 60%.

Signs and symptoms
Individuals with GEFS+ present with a range of epilepsy phenotypes. These include febrile seizures that end by age 6 (FS), such seizures extending beyond age 6 that may include afebrile tonic-clonic, myoclonic, absence, atonic seizures and myoclonic-astatic epilepsy. Individuals may also present with SMEI, characterized by generally tonic-clonic seizures, impaired psychomotor development, myoclonic seizures, ataxia, and poor response to many anticonvulsants.

Pathophysiology
Type 1
GEFS+ type 1 is a subtype of GEFS+ in which there are mutations in SCN1B, a gene encoding a sodium channel β subunit. The β subunit is required for proper channel inactivation. There are two known mutations in SCN1B that lead to GEFS+ (Figure 1). The first and best characterized of these mutations is C121W. This mutation alters a cysteine involved in a disulfide bond in the extracellular N-terminus of the protein. This extracellular region is similar to the cell adhesion molecule contactin and other cell adhesion molecules. It is believed that the disulfide bond disrupted by the C121W mutation is required for the proper folding of this N-terminus motif. Coexpression of SCN1B with sodium channel α subunits in oocytes and other cells results in channels that inactivate more slowly. Expression of C121W mutant along with wild-type α subunits produces current indistinguishable from that through α subunits alone. Further investigation of this mutation has indicated that it results in decreased frequency dependent rundown and, thus, likely hyperexcitability when compared to cells expressing the wild-type subunit. This mutation also disrupts the subunits ability to induce cellular aggregation. The importance of this last fact is unclear, though it is presumed that proper channel aggregation within cells and cell-cell contact are required for normal neuronal function.A second mutation has been found in one kindred with GEFS+ type 1. This mutation is in a splice acceptor site of exon 3. The loss of this acceptor site reveals a downstream cryptic acceptor site and a protein missing 5 amino acids in the N-terminus (I70_E74del). This mutation has not been further characterized.

Type 2
A second subtype of GEFS+, type 2, is the result of mutations in SCN1A, a gene encoding a sodium channel α subunit. There are currently almost 90 known mutations in the SCN1A gene throughout the entirety of the channel (see table 1). These mutations result in almost any imaginable mutation type in the gene, short of duplications. The results of these mutations are highly variable, some producing functional channels while others result in non-functional channels. Some functional channels result in membrane hyperexcitability while others result in hypoexcitability. Most of the functional mutant channels result in hyperexcitability due to decreased frequency dependent rundown. An example of this is the D188V mutation. A 10 Hz stimulation of wild-type channels causes current to decrease to approximately 70% of maximum whereas the same stimulation of mutant channels results in rundown to 90% of maximum. This is caused by an expedited recovery from inactivation for mutant channels versus wild-type. The D188V mutant, for example, recovers to 90% maximal current in 200ms while wild-type channels are unable to recover to this degree in >1000ms. Some other functional mutations that lead to hyperexcitability do so by other means, such as decreasing the rate of entrance into the slow inactivated state.Some of the other functional mutations are believed to result in hypoexcitability. The R859C mutation, for example, has a more depolarized voltage dependence of activation, meaning that the membrane must be more depolarized for the channel to open. This mutant also recovers more slowly from inactivation. The nonfunctional channels are believed to produce similar changes in cell excitability. Likewise, many of the nonsense mutations likely result in nonfunctional channels and hypoexcitability, though this has yet to be tested. It is also unclear how this membrane hypoexcitability leads to the GEFS+ phenotype.

Type 3
Patients with GEFS+ type 3 have mutations in the GABRG2 gene, which encodes the GABAA γ2 subunit (figure 2). The first mutation discovered in GABRG2 was K289M, in the extracellular region linking membrane-spanning domains M2 and M3. Oocytes injected with α1, β2, and γ2 subunits produce large GABA inducible currents whereas those injected with K289M mutant instead of wild-type subunits produce currents much smaller (about 10% of wild-type). This abnormal current is not the result of non-incorporation of mutant subunits since mutant containing receptors are still sensitive to benzodiazepines, a property for which functional γ subunits are required. Because of these results, it is believed that the GEFS+ phenotype in these individuals is a result of hyperexcitability.Concurrent with the previous mutation, a second group found a second mutation in GABRG2 associated with GEFS+. This mutation, R43Q, is located in the one of two benzodiazepine binding-sites located in the extracellular N-terminus. Benzodiazepines, such as Diazepam, potentiate GABA induced current. This potentiation is abolished in cells expressing the R43Q mutant subunit instead of the wild-type γ subunit. This mutation does not affect the subunits ability to coassemble into function receptors as it still confers resistance to GABA current blockade by zinc. As with the previous mutation, this mutation is expected to result in neuronal hyperexcitability.The final known GEFS+ type 3 mutation is a nonsense mutation, Q351X, located in the intracellular  region linking the third and fourth membrane spanning segments. When this mutant subunit is expressed in cells with wild-type α and β subunits it produces non-functional receptors. Since wild-type α and β subunits expressed alone are able to produce GABA inducible current this indicates that the mutation either prevents both coassembly of the mutant and wild-type subunits but also coassembly of the wild-type α and β subunits or prevents proper trafficking of the formed receptor to the membrane. Fusion of GFP onto this mutated subunit has indicated that it is localized to the endoplasmic reticulum instead of the cell membrane </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Anterior cerebral artery syndrome and explain in detail? [/INST] Anterior cerebral artery syndrome is a condition whereby the blood supply from the anterior cerebral artery (ACA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the medial aspects of the frontal and parietal lobes, basal ganglia, anterior fornix and anterior corpus callosum.Depending upon the area and severity of the occlusion, signs and symptoms may vary within the population affected with ACA syndrome. Blockages to the proximal (A1) segment of the vessel produce only minor deficits due to the collateral blood flow from the opposite hemisphere via the anterior communicating artery. Occlusions distal to this segment will result in more severe presentation of ACA syndrome. Contralateral hemiparesis and hemisensory loss of the lower extremity is the most common symptom associated with ACA syndrome.

Signs and symptoms
Hemiparesis or hemiplegia contralaterally, involving primarily the lower limbs and pelvic floor musculature
Sensory deficits contralaterally, involving primarily the leg and perineum
Apraxia (due to branches to the supplementary motor area and corpus callosum)
Disconnection syndrome (due to callosal branches)
Anosmia (due to branches of the olfactory bulb and olfactory tract)
Urinary incontinence
Grasp reflex and or sucking reflex contralaterally (if circle of Willis compromised)

Diagnosis
Once an acute ischemic stroke is suspected, the standard evaluation includes performing routine airway, breathing and circulation assessment, checking blood glucose, performing a validated stroke severity scale assessment and accurate, focused history regarding the time of symptom onset or last known well or at baseline. The National Institutes of Health Stroke Scale (NIHSS) is a standardized method for quantifiable assessment of stroke symptoms. It is the preferred scoring system, and scores range from 0 to 42. A patient with a higher score on this scale is more likely to be considered disabled; however, the definition of "disabling" depends on age, occupation, underlying life-limiting comorbidities, advance directives.
The crucial step in the evaluation of stroke patients is to obtain brain imaging to ascertain the type and characteristics of the stroke. In this regard, non-contrast CT of the head is the imaging modality of choice. Ischemic changes may classify as acute, subacute, and chronic, depending on the time in which they present after the onset of stroke. CT scan can also rule out intracranial hemorrhage.[18] If an intracranial hemorrhage is present, aneurysmal rupture should be investigated given its association with arterial vasospasm resulting in stroke.[3] Anterior cerebral artery strokes could be missed on imaging studies depending on their location or size. One case series found that 37.5% (6 of 16) of ACA infarcts evaluated by CT were identifiable only after using contrast injection or angiography. If the area of hypodensity is small and localized over a sulcus, the infarct could be overlooked.[1] [13]  Noncontrast head CT should be quickly followed by CT angiography of the head and neck to expedite identification of intracranial large vessel occlusion.
The finding of a hyperdense lesion in the ACA on CT scan aid in the diagnosis of stroke in its acute phase, particularly when it may be otherwise difficult to establish. The frequency of this sign in ACA infarcts is similar to that in the territories of the middle cerebral artery and the posterior circulation.[19]
As in strokes involving other areas of the brain, magnetic resonance imaging is also of critical value in the diagnosis of ACA strokes. MRI with diffusion-weight imaging is a highly useful modality, which facilitates the demarcation of ischemic boundaries in the territory of the ACA.[3] [18] MR angiography can be a helpful adjunct in the evaluation of stroke mechanisms.[7] The goal of completing head CT or MRI should be 25 min or less within patient arrival.
The National Institutes of Neurological Disorders and Stroke (NINDS) established time frame goals in the evaluation of stroke patients: door to physician less than 10 min, door to stroke team less than 15 min, door to CT scan less than 25 min, door to drug less than 60 min.[20]
Along with accurate history and early imaging, laboratory studies including capillary blood glucose, complete blood count with platelets, chemistries, coagulation studies, hemoglobin A1c, lipid panel, and markers of hypercoagulability or inflammation can be useful in identifying the risk factors or establishing the etiology of stroke. The medication checklist is an integral part of the evaluation, specifically recent use of anticoagulants, as contraindications to thrombolytic therapy should undergo rapid assessment. Cardiac sources of embolism can be evaluated as part of the work up with EKG monitoring and echocardiogram.

Management
Pulse oximetry can guide the use of supplemental oxygen to maintain oxygen saturation greater than 94%. Hyperoxia should be avoided as may be detrimental in stroke. Hypertension is common in an acute ischemic stroke. A low BP is uncommon and may indicate symptoms exacerbation of a previous stroke due to poor perfusion. Blood pressure of 220/120 mmHg should receive treatment. There is a consensus approach of allowing permissive hypertension up to 220/120 mmHg for patients that are not candidates for thrombolysis.[21]
However, for a patient that is a potential candidate for alteplase, attempt to control BP should be made immediately as goal BP for initiation of IV alteplase is 185/110 mmHg. Usually, titratable short-acting intravenous hypotensive agents are recommended to avoid dropping the BP too much once the patient is at goal. Hypotensive agents that can be options include labetalol, nicardipine, clevidipine, hydralazine, enalaprilat.[21]
For the patients that present within the therapeutic window, the decision to treat with intravenous recombinant tissue plasminogen (less than 4.5 hours from symptom onset) or endovascular treatment with mechanical thrombectomy should be made. Initiation of IV alteplase treatment in the 3 to 4.5-hour window is the current recommendation for patients less than 80 years of age, no history of both diabetes mellitus and prior stroke, use of anticoagulants, and NIHSS score of less than 25.  Only patients with disabling symptoms are considered eligible for thrombolytic treatment. Eligibility and absolute and relative contraindications should undergo rapid assessment. Randomized controlled trials have shown that intravenous administration of recombinant tissue plasminogen activator (alteplase) decrease functional disability with an absolute reduction risk of 7%-13% relative to placebo.[21]
Unfortunately, over half of patients arrive after this time window has closed and are not eligible for thrombolysis. Treatment delays may result from failure to ascribe a patients symptoms to stroke, and furthermore, the risk of harm increases with time elapsed from symptom onset.[21] This situation could be of particular concern in ACA strokes, given their sometimes atypical presentation.
Endovascular treatment with mechanical thrombectomy (MT) is another proven treatment modality in the management of patients with acute stroke suffering a large vessel occlusion, although treatment efficacy is highly time-dependent.  The procedure is available in tertiary hospitals as requires stroke team with the expertise to use timely imaging and intervention. One study evaluating MT in ACA stroke patients found that while recanalization rates were high, the outcomes were otherwise unsatisfactory. The latter was attributed to larger infarct volumes and longer times to recanalization.[22] [23].
New guidelines recommend that in patients with acute ischemic stroke within 6 to 24 hours from last known well and who have large vessel occlusion in anterior circulation, obtaining CTP, DW-MRI, or MRI perfusion is recommended to aid in selection for mechanical thrombectomy. However, this is only with the strict application of imaging or other eligibility criteria from RCTs showing benefit are in selecting patients for MT. The DAWN trial used clinical imaging mismatch (imaging from CTP or DW-MRI and NIHSS scoring) as criteria to select patients with anterior circulation LVO for MT between 6 and 24 hours from last known well. The trial demonstrated an overall functional benefit at 90 days in the treatment group (mRS score 0 to 2, 49% versus 13%, adjusted difference 33%, 95% CI, 21 to 44; a probability of superiority greater than 0.999). The DEFUSE 3 trial used perfusion core mismatch and maximum core size as criteria in selecting the patient for MT with LVO in anterior circulation 6 to 16 hours from last time seen normal. This trial also showed outcome benefit at 90 days in the treated group (mRS score 0 to 2, 44.6% vs. 16.7%, RR 2.67, 95% CI, 1.60 to 4.48, p greater than 0.0001). DAWN and DEFUSE 3 are the only trials showing a benefit of mechanical thrombectomy greater than 6 hours from symptoms onset. Only criteria from these trials should be viable for patient selection who might benefit from MT.[21] One should be aware that most of the patients involved in DAWN and DEFUSE 3 trials had middle cerebral artery occlusions.
Beyond the acute management of stroke, the use of antihypertensives, dual antiplatelet therapy, anticoagulants, carotid endarterectomy should be used to prevent recurrent events. Antiplatelet therapy or anticoagulants are not recommended within 24h after alteplase administration. Aspirin is not a recommendation as a substitute for other interventions for acute stroke. Administration of glycoprotein IIb/IIIa receptor inhibitor is not recommended, and a recent Cochrane review showed that these agents correlated with a high risk of intracranial hemorrhage. Dual antiplatelet therapy (aspirin and clopidogrel) are recommended to start within 24 hours for 21 days in patients with minor stroke for early secondary stroke prevention. The CHANCE trial showed that the primary outcome of recurrent stroke at 90 days favored dual antiplatelet therapy over Aspirin alone (HR 0.68; 95% CI, 0.57 to 0.81, p<0.0001). Ticagrelor over aspirin in acute stroke treatment is not recommended. According to SOCRATES trial with the primary outcome of time to the composite endpoint of stroke, MI or death up to 90 days, ticagrelor was not found to be superior to aspirin (HR 0.89, 95% CI, 0.78-1.01; p=0.07). However, ticagrelor is a reasonable alternative in patients with contraindication to aspirin. The efficacy of tirofiban and eptifibatide is currently unknown.[21] [20]
Optimization of risk factors is essential for secondary prevention of stroke in order to improve outcomes from the principal event.[21]

References
Kubis N, Guichard JP, Woimant F. Isolated anterior cerebral artery infarcts: A series of 16 patients. Cerebrovasc. Dis. 1999 May-Jun;9(3):185-7. [PubMed]
Chandra A, Li WA, Stone CR, Geng X, Ding Y. The cerebral circulation and cerebrovascular disease I: Anatomy. Brain Circ. 2017 Apr-Jun;3(2):45-56. [PMC free article] [PubMed]
Kumral E, Bayulkem G, Evyapan D, Yunten N. Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings. Eur. J. Neurol. 2002 Nov;9(6):615-24. [PubMed]
Toyoda K. Anterior cerebral artery and Heubners artery territory infarction. Front Neurol Neurosci. 2012;30:120-2. [PubMed]
Krishnan M, Kumar S, Ali S, Iyer RS. Sudden bilateral anterior cerebral infarction: unusual stroke associated with unusual vascular anomalies. Postgrad Med J. 2013 Feb;89(1048):120-1. [PubMed]
Arboix A, García-Eroles L, Sellarés N, Raga A, Oliveres M, Massons J. Infarction in the territory of the anterior cerebral artery: clinical study of 51 patients. BMC Neurol. 2009 Jul 09;9:30. [PMC free article] [PubMed]
Kang SY, Kim JS. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology. 2008 Jun 10;70(24 Pt 2):2386-93. [PubMed]
Hensler J, Jensen-Kondering U, Ulmer S, Jansen O. Spontaneous dissections of the anterior cerebral artery: a meta-analysis of the literature and three recent cases. Neuroradiology. 2016 Oct;58(10):997-1004. [PubMed]
Mohindra S, Kovai P, Chhabra R. Fatal Bilateral ACA Territory Infarcts after Pituitary Apoplexy: A Case Report and Literature Review. Skull Base. 2010 Jul;20(4):285-8. [PMC free article] [PubMed]
Kurre W, Vorlaender K, Aguilar-Pérez M, Schmid E, Bäzner H, Henkes H. Frequency and relevance of anterior cerebral artery embolism caused by mechanical thrombectomy of middle cerebral artery occlusion. AJNR Am J Neuroradiol. 2013 Aug;34(8):1606-11. [PubMed]
Nagaratnam N, Davies D, Chen E. Clinical effects of anterior cerebral artery infarction. J Stroke Cerebrovasc Dis. 1998 Nov-Dec;7(6):391-7. [PubMed]
Bogousslavsky J, Martin R, Moulin T. Homolateral ataxia and crural paresis: a syndrome of anterior cerebral artery territory infarction. J. Neurol. Neurosurg. Psychiatry. 1992 Dec;55(12):1146-9. [PMC free article] [PubMed]
Honig A, Eliahou R, Auriel E. Confined anterior cerebral artery infarction manifesting as isolated unilateral axial weakness. J. Neurol. Sci. 2017 Feb 15;373:18-20. [PubMed]
Kobayashi S, Maki T, Kunimoto M. Clinical symptoms of bilateral anterior cerebral artery territory infarction. J Clin Neurosci. 2011 Feb;18(2):218-22. [PubMed]
Edlow JA, Selim MH. Atypical presentations of acute cerebrovascular syndromes. Lancet Neurol. 2011 Jun;10(6):550-60. [PubMed]
Nishida Y, Irioka T, Sekiguchi T, Mizusawa H. Pure sensory infarct in the territories of anterior cerebral artery. Neurology. 2010 Jul 20;75(3):287. [PubMed]
Bejot Y, Caillier M, Osseby GV, Didi R, Ben Salem D, Moreau T, Giroud M. Involuntary masturbation and hemiballismus after bilateral anterior cerebral artery infarction. Clin Neurol Neurosurg. 2008 Feb;110(2):190-3. [PubMed]
Birenbaum D, Bancroft LW, Felsberg GJ. Imaging in acute stroke. West J Emerg Med. 2011 Feb;12(1):67-76. [PMC free article] [PubMed]
Jensen UR, Weiss M, Zimmermann P, Jansen O, Riedel C. The hyperdense anterior cerebral artery sign (HACAS) as a computed tomography marker for acute ischemia in the anterior cerebral artery territory. Cerebrovasc. Dis. 2010;29(1):62-7. [PubMed]
Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H., American Heart Association Stroke Council. Council on Cardiovascular Nursing. Council on Peripheral Vascular Disease. Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013 Mar;44(3):870-947. [PubMed]
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL., American Heart Association Stroke Council. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Mar;49(3):e46-e110. [PubMed]
Musuka TD, Wilton SB, Traboulsi M, Hill MD. Diagnosis and management of acute ischemic stroke: speed is critical. CMAJ. 2015 Sep 08;187(12):887-93. [PMC free article] [PubMed]
Uno J, Kameda K, Otsuji R, Ren N, Nagaoka S, Kazushi M, Ikai Y, Gi H. Mechanical Thrombectomy for Acute Anterior Cerebral Artery Occlusion. World Neurosurg </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Chronic periodontitis and explain in detail? [/INST] Chronic periodontitis is one of the seven categories of periodontitis as defined by the American Academy of Periodontology 1999 classification system. Chronic periodontitis is a common disease of the oral cavity consisting of chronic inflammation of the periodontal tissues that is caused by the accumulation of profuse amounts of dental plaque. Periodontitis initially begins as gingivitis and can progress onto chronic and subsequent aggressive periodontitis according to the 1999 classification.
Diagnosing chronic periodontitis is important in its early stages to prevent severe and irreversible damage to the protective and supportive structures of the tooth. However, due to chronic periodontitis being a painless progressing disease, few patients will seek dental care in the early stages. Mild to moderate chronic periodontitis can be managed by proper mechanical removal of the biofilm and calculus subgingivally. Full and effective oral hygiene and regular 3 monthly periodontal checkups are important for maintaining the stability of the disease.
Chronic periodontitis is prevalent in adults and seniors worldwide. In the US around 35% of adults (30–90 years) are affected. The cumulative effects of alveolar bone loss, attachment loss and pocket formation is more apparent with an increase in age. Age is related to the incidence of periodontal destruction: "...in a well-maintained population who practises oral home care and has regular check-ups, the incidence of incipient periodontal destruction increases with age, the highest rate occurs between 50 and 60 years, and gingival recession is the predominant lesion before 40 years, while periodontal pocketing is the principal mode of destruction between 50 and 60 years of age."There are a variety of periodontal risk factors which can affect the prevalence, rate, extent and severity of the disease progression. Major risk factors include smoking, lack of oral hygiene with inadequate plaque biofilm control.
There is a slow to moderate rate of disease progression but the patient may have periods of rapid progression ("bursts of destruction"). Chronic periodontitis can be associated with local predisposing factors (e.g. tooth-related or iatrogenic factors). The disease may be modified by and be associated with systemic diseases (e.g. diabetes mellitus, HIV infection) It can also be modified by factors other than systemic disease such as smoking and emotional stress, anxiety and depression. Care should be taken however, when diagnosing a patient who smokes as smoking can alter some of the results of an examination. In smokers, the gingiva are pale and fibrous and tend to bleed less while being probed due to the effect of nicotine on the vasculature by vasoconstricting them. Thus, a lowered response is produced and this explains why incorrect data can be gained. There is also an increase in supragingival calculus alongside visible nicotine staining. The anterior dentition occasionally have recession and maxillary anterior and palatal surfaces are more adversely affected.

Pathophysiology
Chronic periodontitis is initiated by Gram-negative tooth-associated microbial biofilms that elicit a host response, which results in bone and soft tissue destruction. In response to endotoxin derived from periodontal pathogens, several osteoclast-related mediators target the destruction of alveolar bone and supporting connective tissue such as the periodontal ligament. Major drivers of this aggressive tissue destruction are matrix metalloproteinases (MMPs), cathepsins, and other osteoclast-derived enzymes.

Plaque hypothesis
At least two mechanisms of the microbiology of periodontitis have been described: the specific plaque hypothesis and the non-specific plaque hypothesis.
Consensus is that neither view is entirely correct, but via a middle path, that damage is due to a shift in the relative populations of more and less dangerous bacteria in the plaque. This is called the ecological plaque hypothesis.
The disease is associated with a variable microbial pattern.Anaerobic species of bacteria Porphyromonas gingivalis, Bacteroides forsythus, Treponema denticola, Prevotella intermedia, Fusobacterium nucleatum, Eubacterium sp. have all been implicated in chronic periodontitis.Microaerophile bacteria Actinomyces actinomycetemcomitans, Campylobacter rectus, and Eikenella corrodens also may play a role in chronic periodontitis.

Signs and symptoms
In the early stages, chronic periodontitis has few symptoms and in many individuals the disease has progressed significantly before they seek treatment.
Symptoms may include the following:

Redness or bleeding of gums while brushing teeth, using dental floss or biting into hard food (e.g. apples) (though this may occur even in gingivitis, where there is no attachment loss)
Gum swelling that reoccurs
Halitosis, or bad breath, and a persistent metallic taste in the mouth
Gingival recession, resulting in apparent lengthening of teeth. (This may also be caused by heavy-handed brushing or with a stiff tooth brush.)
Deep pockets between the teeth and the gums (pockets are sites where the attachment has been gradually destroyed by collagen-destroying enzymes, known as collagenases)
Loose teeth, in the later stages (though this may occur for other reasons as well)
Drifting of incisorsGingival inflammation and bone destruction are often painless. Patients sometimes assume that painless bleeding after teeth cleaning is insignificant, although this may be a symptom of progressing chronic periodontitis in that patient.
Subgingival calculus is a frequent finding as well as supragingival calculus due to the bacteria migrating apically and the combined effect of the host response system of the body.

Diagnosis
1999 classification
Chronic periodontitis is one of the seven destructive periodontal diseases as listed in the 1999 classification. Not every case of gingivitis will progress onto chronic periodontitis, but all chronic perodontitis results from gingivitis. Therefore it is important to control the first step; gingival inflammation.
A difficulty which arises with diagnosing chronic periodontitis patients is due to the slow and painless progression of the disease. The most effective and timely diagnosis would be during the mild to moderate stage. However, usually when presenting complaints do arise the effects of mobility and alveolar bone loss have become severe.
A full mouth examination and recording is required to document and track periodontal disease including:

Pocket Depth (PD)
Clinical Attachment Loss (CAL)
Bleeding On Probing (BOP)
Plaque index/score
Furcation involvement
Suppuration
Mobility
RadiographsMeasuring disease progression is carried out by measuring probing pocket depth (PPD) and bleeding indices using a periodontal probe. Pockets greater than 3mm in depth are considered to be unhealthy. True pocket formation of 4 mm or more are specifically related to chronic periodontitis. Bleeding on probing is considered to be a sign of active disease. Discharge of pus, involvement of the root furcation area and deeper pocketing may all indicate reduced prognosis for an individual tooth.
Evidence of alveolar bone loss is also required to differentiate between true bone loss and not attributions of gingival oedema. Usually, a horizontal pattern of bone loss would be found however, vertical (infrabony) bone loss may also be present on specific sites. A Basic Periodontal Examination (BPE) or Periodontal Screening and Recording (PSR) should give a score of 3 or 4. A correct diagnosis is vital to allow the formation of a specific treatment plan for the patient and to arrest the disease progression.
Chronic periodontitis can be further classified into:

Extent (can be either localised affecting < 30% of sites; or generalised if > 30% of sites are affected)
Severity (slight = 1–2 mm CAL; moderate = 3–4 mm CAL; severe ≥5 mm CAL)

2017 classification
Chronic periodontitis is not included within the newer 2017 World Workshop classification. The 2017 classification of Periodontal Diseases and Conditions includes:Periodontitis:

Necrotizing periodontal diseases
Periodontitis
Periodontitis as a manifestation of systemic diseaseTherefore, in accordance to the 2017 classification, a diagnosis would be achieved through the patient assessment individually on the basis of:

Type
Distribution: localised (up to 30% of teeth) or generalised (more than 30% of teeth) and the molar/incisor pattern
Stage and grading
Stages: I (early/mild) with <15% or <2mm interproximal bone loss, II (moderate) with coronal third of root bone loss, III (severe) with mid third of root bone loss, IV (very severe) with apical third of root bone loss
Grading: A (slow) with <0.5% bone loss/age, B (moderate) with 0.5-1.0% bone loss/age, C (rapid) with >1.0% bone loss/age
Status: stable, remission or unstable (see Table 1)
Risk factors, which include systemic diseases such as diabetes or extrinsic factors such as smoking.

Treatment
There is professional agreement among dentists that smoking cessation and good oral hygiene are key to effective treatment and positive outcomes for patients. Similarly, any plaque retentive factors which exist and are modifiable should be corrected, such as overhangs on restorations.
Treatment can involve both non-surgical and surgical therapies. The typical initial treatment known to be effective is scaling and root planing (SRP) to mechanically debride the depths of the periodontal pocket and disrupt the biofilm present. This is done using a powered ultrasonic or sonic scaler and/or unpowered hand instruments.
"In patients with chronic periodontitis, subgingival debridement (in conjunction with supragingival plaque control) is an effective treatment in reducing probing pocket depth and improving the clinical attachment level. In fact it is more effective than supragingival plaque control alone". It is important for patients to be reviewed within 8–12 weeks to assess the treatment response.
Full mouth disinfection protocols are favoured by some clinicians. There is no evidence that full mouth disinfection or full mouth scaling protocols improve the outcome when compared to standard mechanical scaling and root planing.

Open flap debridement
Open flap debridement is used by some practitioners particularly in deeper pocket areas. The advantages of this approach is better visualization of the root surface to be cleaned. This must be weighed against the risks of surgery. Open flap surgery is more effective than non-surgical periodontal therapy in deep pocketing : "Both scaling and root planing alone and scaling and root planing combined with flap procedure are effective methods for the treatment of chronic periodontitis in terms of attachment level gain and reduction in gingival inflammation. In the treatment of deep pockets open flap debridement results in greater PPD reduction and clinical attachment gain."

Guided tissue regeneration
Guided tissue regeneration (GTR) using PTFE membranes is favoured by some practitioners, despite its cost and complexity: "GTR has a greater effect on probing measures of periodontal treatment than open flap debridement, including improved attachment gain, reduced pocket depth, less increase in gingival recession and more gain in hard tissue probing at re-entry surgery. However there is marked variability between studies and the clinical relevance of these changes is unknown. As a result, it is difficult to draw general conclusions about the clinical benefit of GTR. Whilst there is evidence that GTR can demonstrate a significant improvement over conventional open flap surgery, the factors affecting outcomes are unclear from the literature and these might include study conduct issues such as bias. Therefore, patients and health professionals need to consider the predictability of the technique compared with other methods of treatment before making final decisions on use."

Enamel matrix derivative
Enamel matrix derivative (EMD) is favoured by some practitioners despite its high cost:  "One year after its application, EMD significantly improved probing attachment levels (1.1 mm) and probing pocket depth reduction (0.9 mm) when compared to a placebo or control, however, the high degree of heterogeneity observed among trials suggests that results have to be interpreted with great caution. In addition, a sensitivity analysis indicated that the overall treatment effect might be overestimated. The actual clinical advantages of using EMD are unknown. With the exception of significantly more postoperative complications in the GTR group, there was no evidence of clinically important differences between GTR and EMD. Bone substitutes may be associated with less gingival recession than EMD."However, studies have shown that regardless of the conventional periodontal treatments, 20-30% of chronic periodontitis patients do not respond favorably to their treatment. There are many factors which account for these including: ineffective removal of calculus, defective restorations, impaired immune response as a result of a systemic condition, poor plaque control, smoking, etc.

Adjunctive systemic antibiotic treatment
Systemic antibiotics such as amoxicillin or metronidazole are sometimes used in addition to debridement based treatments.
"Systemic antimicrobials in conjunction with scaling and root planing (SRP), can offer an additional benefit over SRP alone in the treatment of periodontitis, in terms of clinical attachment loss (CAL) and probing pocket depth (PPD) change, and reduced risk of additional CAL loss. However, differences in study methodology and lack of data precluded an adequate and complete pooling of data for a more comprehensive analyses. It was difficult to establish definitive conclusions, although patients with deep pockets, progressive or active disease, or specific microbiological profile, can benefit more from this adjunctive therapy."There is currently low-quality evidence suggesting if adjunctive systemic antimicrobials are beneficial for the non-surgical treatment of periodontitis. It is not sure whether some antibiotics are better than others when used alongside scaling and root planning).

Locally delivered adjunctive antimicrobial treatment
Chemical antimicrobials may be used by the clinician to help reduce the bacterial load in the diseased pocket.
"Among the locally administered adjunctive antimicrobials, the most positive results occurred for tetracycline, minocycline, metronidazole, and chlorhexidine. Adjunctive local therapy generally reduced PD levels....Whether such improvements, even if statistically significant, are clinically meaningful remains a question."Minocycline is typically delivered via slim syringe applicators.
Chlorhexidine impregnated chips are also available.
Hydrogen peroxide is a naturally occurring antimicrobial that can be delivered directly to the gingival sulcus or periodontal pocket using a custom formed medical device called a Perio Tray.  [Title = Custom Tray Application of Peroxide Gel as an Adjunct to Scaling and Root Planing in the Treatment of Periodontitis:
A Randomized, Controlled Three-Month Clinical Trial  J Clin Dent 2012;23:48–56.]
Hydrogen peroxide gel was demonstrated to be effective in controlling the bacteria biofilm [Subgingival Delivery of Oral Debriding Agents: A Proof of Concept J Clin Dent 2011;22:149–158] The research shows that a direct application of hydrogen peroxide gel killed virtually all of the bacterial biofilm, was directly and mathematically delivered up to 9mm into periodontal pockets.

Modulating the host response
Sub-antimicrobial doses of doxycycline (SDD) have been used to alter host response to the periodontal pathogens. This is believed to disrupt the action of matrix metalloproteinases and thus minimise host mediated tissue destruction.
"The adjunctive use of SDD with SRP is statistically more effective than SRP alone in reducing PD and in achieving CAL gain."

Systemic Factors
Chronic periodontitis is an inflammatory immune response against the presence of bacteria present. Recent research has suggested that epithelial lining ulceration in chronic periodontal pockets are due to systemic bacterial dissemination and widespread bacterial inflammatory markers present in the host. Two of the most widely investigated systemic diseases associated with chronic periodontitis is diabetes mellitus and cardiovascular disease.

Diabetes Mellitus
Both type 1 and type 2 diabetes have shown a link with the treatment and progression of chronic periodontitis. Chronic periodontitis is more serve in patients that have diabetes than those without, confirming a significant association. With type 2 diabetes patients being shown to have 3.8 times more bone loss and 2.8 times more clinical attachment loss than non-diabetic individuals. With patients with poorly controlled diabetes having a higher risk of alveolar bone loss </s>