A Comprehensive Exploration of Metabolism, Pathophysiology, and Genetics PKUGenetics and inheritance of PKUSymptoms, diagnosis and treatment of PKUSymptoms DiagnosisTreatmentExplanation of blood test resultsPregnancy and PKUBreastfeedingNeonatal testing for metabolic disordersConclusionREFERENCESThe scenario presents a 4-month-old pregnant woman with phenylketonuria (PKU). Due to the teratogenic effects of phenylalanine on the fetus, her GP advised her to follow a low protein diet. The distress this caused Nuria led her to radically change her eating habits to the point that after her monthly blood test her GP became concerned. The GP then decided to refer Nuria to a PKU treatment center for nutritional assessment and genetic counseling. Say no to plagiarism. Get a tailor-made essay on “Why Violent Video Games Should Not Be Banned”?Get an original essayIn the following paragraphs, I will explain the following learning objectives.Unknown TermsPhenylalanine MetabolismPathophysiology of PKUGenetics and Inheritance of PKUDiagnosis , symptoms and treatment of PKUExplanation of Nuria's blood test resultsPKU and pregnancyNeonatal test for metabolic diseasesUnknown termsTeratogen= term that describes a substance that can cause disruption or abnormal development of the fetus resulting from birth defects. The word is derived from the Greek word for monster “τέρας”. [Chanapa, T. (2014).]Microcephaly = condition in which the fetal head is smaller than normal, caused by substances that can cause brain damage in vivo, including alcohol, smoking and, in this case , phenylalanine. [MedicineNet. (2019).] Mental retardation = when an individual has an intellectual ability at or below an IQ of 70 as well as a reduced ability to function independently in daily life. [Webster, M. (2019)] Phenylalanine Metabolism What is Phenylalanine Phenylalanine is an essential aromatic amino acid and it is a precursor of tyrosine which in turn is a precursor of catecholamines like tyramine , dopamine, epinephrine and norepinephrine. Phenylalanine can be found in high concentrations in the brain and plasma. An average adult should digest 5 to 8 g of phenylalanine per day. [National Center for Biotechnology Information] Phenylalanine MetabolismPhenylalanine can be metabolized to tyrosine by phenylalanine hydroxylase in the presence of molecular oxygen and the coenzyme tetrahydrobiopterin (BH4), a molecular oxygen becoming the hydroxyl group of tyrosine and the other being reduced to water. While BH4 is oxidized to dihydrobiopterin (BH2) which is regenerated via dihydropteridine reductase requiring NAHD. [A. Harvey, R. and Ferrier, D. (2019).] Further metabolism of tyrosine As tyrosine is made from an essential amino acid, it is then a non-essential amino acid in the body. Tyrosine is the precursor of catecholamines; dopamine, norepinephrine and epinephrine. First, tyrosine is hydroxylated by tyrosine hydroxylase to form 3,4-dihydroxulphenylalalnine (DOPA). Next, DOPA is then decarboxylated to form dopamine via pyridoxal phosphate which is then hydroxylated by dopamine beta-hydroxylase to produce norepinephrine. Noradrenaline is then n-methylated via S-adenosylmethionine to produce epinephrine. DOPA could beconverted by tyrosinase into dopaquinone to then form melanin in the epidermis of the skin, particularly in the melanocytes. Thyroid hormones are another important metabolite of tyrosine. The final metabolites of phenylalanine metabolism are fumarate and acetoacetate which are used to produce energy. In PKU, side reactions to phenylalanine may occur, producing phenylpyruvate and phenylethylamine. These byproducts lead to aminoaciduria, which is an excess of amino acids in the urine. [A. Harvey, R. and Ferrier, D. (2019).]Figure 1: A diagram showing the different metabolites from phenylalanine as well as the catalyst and by-products of each reaction. [Fernanda Schuck, et al. (2015).] Pathophysiology of Phenylketonuria What is Phenylketonuria Phenylketonuria is an inherited protein metabolic disorder associated with an individual's inability to metabolize phenylalanine resulting from accumulation of the substance in the organism due to the lack of the enzyme phenylalanine hydroxylase or dihydrobiopterin reductase. [Al Hadif, N. and Christodoulou, J. (2015).], [Pietz, J., et al. (1999).] Pathophysiology of PKU Since phenylalanine cannot be metabolized in the body, this suggests that with a normal diet, an affected person would have an increased concentration of phenylalanine in their blood plasma, leading to its tour is toxic to the brain. The pathophysiology of PKU is not fully understood, but two models have been proposed [A. Dyer, C. (1999).]. One being that increased phenylalanine concentration in the brain causes neuroxicity. The other being the lack of neurotransmitters produced by the metabolism of phenylalanine to tyrosine, such as dopamine, could also cause the side effects of PKU. [Schuck, et al. (2015) tetrahydrobiopterin (BH4) giving rise to non-PKU HPA [Robin A Williams, J., et al. (2008).]. Inactive or less effective PAHs would discourage the metabolism of phenylalanine to tyrosine and its constituents. [Reference, G. (2019).] Autosomal would suggest that it only affects the 22 non-sex chromosomes and recessive would mean that for an individual to have the phenotype of this disease they must inherit one allele from each parent [Reference, G. . (2019).]. In this case, the mother is affected because the father is not and is also not a carrier, so the probability that the child is a carrier of the disease is 0%, but there is 50% of him who is a carrier. If the father was a carrier, the probability of the child being a carrier of the disease would be 50% and that he would also be a carrier 50%. Figure 2: Illustration showing the inheritance pattern of an autosomal recessive disease when both parents are carriers of the disease. carriers of the defective gene. [More, M. (2019).] PKU Symptoms, Diagnosis and Treatment Symptoms Symptoms are said to occur when the disease is not treated in the early stages of life. The effects of phenylalanine can include damage to the brain and nervous system leading to learning disabilities. Other symptoms may include: [NHS (2019).], [NIH. (2019).] Behavioral difficulties Lighter skin, hair, and eyes due to decreased melanin production Eczema Recurrent vomiting Jerky arm and leg movements Tremors Epilepsy Musky odor of breath, skin, and urine Growth retardation Microcephaly or small head size Diagnosis A blood spot screening in newborns would be done to show increased levels of phenylalanine in the blood by tandem mass spectroscopy. Genetic screening to show the presence of a PAH gene mutation. This could also be used to explain inheritancegenetics of their disease and the probability that the child will have the disease. [Cindie, S. (2017).]TreatmentThere is no cure for PKU, but symptoms can be controlled with a strict diet. This includes a low-protein diet avoiding foods high in protein. This would include: [NIH. (2019).]MeatEggsNutsSoybeansDairy Controlling intake of other foods like potatoes and grainsSpecial avoidance of aspartame as it can be metabolized in the body to phenylalanine. Protein should not be completely excluded from the diet because phenylalanine is an essential amino acid and therefore cannot be metabolized by the body. As tyrosine cannot be made in the body, supplementation would be necessary. Medications may also be prescribed such as sapropterin dihydrochloride, brand name Kuvan, is an approved treatment for PKU. Kuvan is a form of BH4 that helps the body break down phenylalanine. However, a person's failure to break down phenylalanine is due to a lack of BH4. Therefore, using Kuvan only helps some people reduce the amount of phenylalanine in their blood. Kuvan alone will not decrease the amount of phenylalanine to the required level and should therefore be used alongside the PKU diet. [Rohr, F., et al (2004).] Genetic counseling should be carried out in cases of genetic diseases, such as Nuria's. This usually contains: [NHS. (2016).] How parents should cope if their child is affected Provides information about the possibility that other family members are carriers Build a support group around the parents and the affected person The GP recommended this action due to Nuria's fear that her child could also be affected by PKU. This way, she will be able to learn how genetic traits are passed on and the likelihood of her child having the disease will also depend on her husband's genotype. Explanation of blood test resultsLow hemoglobin (Hb) and hematocrit (Hct), mean corpuscular volume (MCV) and ferritin could be linked to the drastic diet changes that Nuria implemented to s ensure that your child is not exposed to high levels of phenylalanine. Based on her test result, we can deduce that she suffers from an iron deficiency, which could be the cause of her microcytic anemia. Due to her protein-restricted diet, she might not be able to get enough iron in her diet, as iron is high in protein in foods like meat, fish, and nuts. [Eatright.org. (2019).]However, as folate is replaced by pregnant women, there is no decrease in folate in her blood sample. Pregnancy and PKUBefore and during conception, women with PKU must follow a strict PKU regimen in order to protect the fetus from the teratogenic effects of high levels of phenylalanine in the maternal blood which can be transferred to the fetus via the placenta. Dietary management as well as newborn screening have significantly reduced the morbidity of untreated PKU during infancy. So, phenylalanine levels should be measured 2-3 times a week along with amino acids, vitamins, minerals and trace elements. Tyrosine also needs to be supplemented with various vitamins and minerals. Ultrasound scans could be used to check for microcephaly, but the definition of microcephaly is controversial because there is no clear definition of the term. [R. Carol, M., et al. (2018)].BreastfeedingPhenylalanine levels in the breast milk of affected womenare higher than normal. However, their breastfed infants should have normal phenylalanine levels so that no adverse effects can be caused by breastfeeding if the child is not affected by the disease. [Acog.org. (2015).]Neonatal screening for metabolic disordersA complete examination should be performed within 72 hours of birth. This would involve checking the baby's eyes with a flashlight to assess their movements, their heart for any abnormal heart sounds like a murmur, and their hips to check their joints, which if left untreated could cause permanent joint problems in the future. A hearing test would also be performed by a healthcare professional before the baby is discharged or 4 to 5 weeks after birth. Hearing defects can affect a baby's development, so early diagnosis is necessary to increase the likelihood of developing language, speech and communication skills. As mentioned earlier, a blood sample would be required to test for PKU. This involves a healthcare professional pushing down on the baby's heel so that 4 drops of blood are placed on a special card. Next, the blood can be tested for 9 rare serious conditions, including: Keep in mind: This is just a sample. Get a personalized article from our expert writers now. Get a Personalized Test Sickle Cell Disease Cystic Fibrosis Congenital Hypothyroidism Phenylketonuria (PKU) Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)Maple Syrup Urinary Disease (MSUD)Isovaleric Acidemia (IVA)Glutaric Acid Type 1 (GA1)Homocystinuria (HCU) [NHS. (2018).]ConclusionIn conclusion, this scenario highlights the need for people with PKU to seriously monitor their diet in order to combat the adverse effects that an increase in phenylalanine would have on their body. Especially for pregnant women, like Nuria, because out of fear that her condition could affect her child, she exposed herself to anemia. In cases like this, special treatment centers would be needed for nutritional assessment and counseling. Genetic counseling helping families to understand the measures to take if their child were to be affected, or even to explain to them the probability of having an affected child.REFERENCESA. Dyer, C. (1999). PATHOPHYSIOLOGY OF PHENYLKETONURIA. [online] Wiley Online Library. Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1002/%28SICI%291098-2779%281999%295%3A2%3C104%3A%3AAID-MRDD2%3E3.0.CO%3B2-7 [ Accessed February 18, 2019].A. Harvey, R. and Ferrier, D. (2019). Biochemistry. 5th ed. Lippincott, Williams and Wilkins, pp.278-282.Acog.org. (2015). Management of women with phenylketonuria - ACOG. [online] Available at: https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Genetics/Management-of-Women-With-Phenylketonuria?IsMobileSet=false [Accessed February 18, 2019].Al Hadif, b. and Christodoulou, J. (2015). Phenylketonuria: a review of current and future treatments. [online] PubMed Central (PMC). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728993/ [Accessed February 18, 2019]. Chanapa, T. (2014). Teratogens | The Embryo Project Encyclopedia. [online] Embryo.asu.edu. Available at: https://embryo.asu.edu/pages/teratogens [Accessed February 18, 2019]. Cindie, S. (2017). Phenylketonuria: causes, symptoms and diagnosis. [online] Health Line. Available at: https://www.healthline.com/health/phenylketonuria#treatments [Accessed February 18, 2019].Eatright.org. (2019). Foods to combat iron deficiency. [online] Available at: https://www.eatright.org/health/wellness/preventing-illness/iron-deficiency [Accessed February 18, 2019].Fernanda Schuck, et al. (2015).. 2019].

Essay / A Comprehensive Exploration of Metabolism, Pathophysiology, and Genetics PKUGenetics and inheritance of PKUSymptoms, diagnosis and treatment of PKUSymptoms DiagnosisTreatmentExplanation of blood test resultsPregnancy and PKUBreastfeedingNeonatal testing for metabolic disordersConclusionREFERENCESThe scenario presents a 4-month-old pregnant woman with phenylketonuria (PKU). Due to the teratogenic effects of phenylalanine on the fetus, her GP advised her to follow a low protein diet. The distress this caused Nuria led her to radically change her eating habits to the point that after her monthly blood test her GP became concerned. The GP then decided to refer Nuria to a PKU treatment center for nutritional assessment and genetic counseling. Say no to plagiarism. Get a tailor-made essay on “Why Violent Video Games Should Not Be Banned”?Get an original essayIn the following paragraphs, I will explain the following learning objectives.Unknown TermsPhenylalanine MetabolismPathophysiology of PKUGenetics and Inheritance of PKUDiagnosis , symptoms and treatment of PKUExplanation of Nuria's blood test resultsPKU and pregnancyNeonatal test for metabolic diseasesUnknown termsTeratogen= term that describes a substance that can cause disruption or abnormal development of the fetus resulting from birth defects. The word is derived from the Greek word for monster “τέρας”. [Chanapa, T. (2014).]Microcephaly = condition in which the fetal head is smaller than normal, caused by substances that can cause brain damage in vivo, including alcohol, smoking and, in this case , phenylalanine. [MedicineNet. (2019).] Mental retardation = when an individual has an intellectual ability at or below an IQ of 70 as well as a reduced ability to function independently in daily life. [Webster, M. (2019)] Phenylalanine Metabolism What is Phenylalanine Phenylalanine is an essential aromatic amino acid and it is a precursor of tyrosine which in turn is a precursor of catecholamines like tyramine , dopamine, epinephrine and norepinephrine. Phenylalanine can be found in high concentrations in the brain and plasma. An average adult should digest 5 to 8 g of phenylalanine per day. [National Center for Biotechnology Information] Phenylalanine MetabolismPhenylalanine can be metabolized to tyrosine by phenylalanine hydroxylase in the presence of molecular oxygen and the coenzyme tetrahydrobiopterin (BH4), a molecular oxygen becoming the hydroxyl group of tyrosine and the other being reduced to water. While BH4 is oxidized to dihydrobiopterin (BH2) which is regenerated via dihydropteridine reductase requiring NAHD. [A. Harvey, R. and Ferrier, D. (2019).] Further metabolism of tyrosine As tyrosine is made from an essential amino acid, it is then a non-essential amino acid in the body. Tyrosine is the precursor of catecholamines; dopamine, norepinephrine and epinephrine. First, tyrosine is hydroxylated by tyrosine hydroxylase to form 3,4-dihydroxulphenylalalnine (DOPA). Next, DOPA is then decarboxylated to form dopamine via pyridoxal phosphate which is then hydroxylated by dopamine beta-hydroxylase to produce norepinephrine. Noradrenaline is then n-methylated via S-adenosylmethionine to produce epinephrine. DOPA could beconverted by tyrosinase into dopaquinone to then form melanin in the epidermis of the skin, particularly in the melanocytes. Thyroid hormones are another important metabolite of tyrosine. The final metabolites of phenylalanine metabolism are fumarate and acetoacetate which are used to produce energy. In PKU, side reactions to phenylalanine may occur, producing phenylpyruvate and phenylethylamine. These byproducts lead to aminoaciduria, which is an excess of amino acids in the urine. [A. Harvey, R. and Ferrier, D. (2019).]Figure 1: A diagram showing the different metabolites from phenylalanine as well as the catalyst and by-products of each reaction. [Fernanda Schuck, et al. (2015).] Pathophysiology of Phenylketonuria What is Phenylketonuria Phenylketonuria is an inherited protein metabolic disorder associated with an individual's inability to metabolize phenylalanine resulting from accumulation of the substance in the organism due to the lack of the enzyme phenylalanine hydroxylase or dihydrobiopterin reductase. [Al Hadif, N. and Christodoulou, J. (2015).], [Pietz, J., et al. (1999).] Pathophysiology of PKU Since phenylalanine cannot be metabolized in the body, this suggests that with a normal diet, an affected person would have an increased concentration of phenylalanine in their blood plasma, leading to its tour is toxic to the brain. The pathophysiology of PKU is not fully understood, but two models have been proposed [A. Dyer, C. (1999).]. One being that increased phenylalanine concentration in the brain causes neuroxicity. The other being the lack of neurotransmitters produced by the metabolism of phenylalanine to tyrosine, such as dopamine, could also cause the side effects of PKU. [Schuck, et al. (2015) tetrahydrobiopterin (BH4) giving rise to non-PKU HPA [Robin A Williams, J., et al. (2008).]. Inactive or less effective PAHs would discourage the metabolism of phenylalanine to tyrosine and its constituents. [Reference, G. (2019).] Autosomal would suggest that it only affects the 22 non-sex chromosomes and recessive would mean that for an individual to have the phenotype of this disease they must inherit one allele from each parent [Reference, G. . (2019).]. In this case, the mother is affected because the father is not and is also not a carrier, so the probability that the child is a carrier of the disease is 0%, but there is 50% of him who is a carrier. If the father was a carrier, the probability of the child being a carrier of the disease would be 50% and that he would also be a carrier 50%. Figure 2: Illustration showing the inheritance pattern of an autosomal recessive disease when both parents are carriers of the disease. carriers of the defective gene. [More, M. (2019).] PKU Symptoms, Diagnosis and Treatment Symptoms Symptoms are said to occur when the disease is not treated in the early stages of life. The effects of phenylalanine can include damage to the brain and nervous system leading to learning disabilities. Other symptoms may include: [NHS (2019).], [NIH. (2019).] Behavioral difficulties Lighter skin, hair, and eyes due to decreased melanin production Eczema Recurrent vomiting Jerky arm and leg movements Tremors Epilepsy Musky odor of breath, skin, and urine Growth retardation Microcephaly or small head size Diagnosis A blood spot screening in newborns would be done to show increased levels of phenylalanine in the blood by tandem mass spectroscopy. Genetic screening to show the presence of a PAH gene mutation. This could also be used to explain inheritancegenetics of their disease and the probability that the child will have the disease. [Cindie, S. (2017).]TreatmentThere is no cure for PKU, but symptoms can be controlled with a strict diet. This includes a low-protein diet avoiding foods high in protein. This would include: [NIH. (2019).]MeatEggsNutsSoybeansDairy Controlling intake of other foods like potatoes and grainsSpecial avoidance of aspartame as it can be metabolized in the body to phenylalanine. Protein should not be completely excluded from the diet because phenylalanine is an essential amino acid and therefore cannot be metabolized by the body. As tyrosine cannot be made in the body, supplementation would be necessary. Medications may also be prescribed such as sapropterin dihydrochloride, brand name Kuvan, is an approved treatment for PKU. Kuvan is a form of BH4 that helps the body break down phenylalanine. However, a person's failure to break down phenylalanine is due to a lack of BH4. Therefore, using Kuvan only helps some people reduce the amount of phenylalanine in their blood. Kuvan alone will not decrease the amount of phenylalanine to the required level and should therefore be used alongside the PKU diet. [Rohr, F., et al (2004).] Genetic counseling should be carried out in cases of genetic diseases, such as Nuria's. This usually contains: [NHS. (2016).] How parents should cope if their child is affected Provides information about the possibility that other family members are carriers Build a support group around the parents and the affected person The GP recommended this action due to Nuria's fear that her child could also be affected by PKU. This way, she will be able to learn how genetic traits are passed on and the likelihood of her child having the disease will also depend on her husband's genotype. Explanation of blood test resultsLow hemoglobin (Hb) and hematocrit (Hct), mean corpuscular volume (MCV) and ferritin could be linked to the drastic diet changes that Nuria implemented to s ensure that your child is not exposed to high levels of phenylalanine. Based on her test result, we can deduce that she suffers from an iron deficiency, which could be the cause of her microcytic anemia. Due to her protein-restricted diet, she might not be able to get enough iron in her diet, as iron is high in protein in foods like meat, fish, and nuts. [Eatright.org. (2019).]However, as folate is replaced by pregnant women, there is no decrease in folate in her blood sample. Pregnancy and PKUBefore and during conception, women with PKU must follow a strict PKU regimen in order to protect the fetus from the teratogenic effects of high levels of phenylalanine in the maternal blood which can be transferred to the fetus via the placenta. Dietary management as well as newborn screening have significantly reduced the morbidity of untreated PKU during infancy. So, phenylalanine levels should be measured 2-3 times a week along with amino acids, vitamins, minerals and trace elements. Tyrosine also needs to be supplemented with various vitamins and minerals. Ultrasound scans could be used to check for microcephaly, but the definition of microcephaly is controversial because there is no clear definition of the term. [R. Carol, M., et al. (2018)].BreastfeedingPhenylalanine levels in the breast milk of affected womenare higher than normal. However, their breastfed infants should have normal phenylalanine levels so that no adverse effects can be caused by breastfeeding if the child is not affected by the disease. [Acog.org. (2015).]Neonatal screening for metabolic disordersA complete examination should be performed within 72 hours of birth. This would involve checking the baby's eyes with a flashlight to assess their movements, their heart for any abnormal heart sounds like a murmur, and their hips to check their joints, which if left untreated could cause permanent joint problems in the future. A hearing test would also be performed by a healthcare professional before the baby is discharged or 4 to 5 weeks after birth. Hearing defects can affect a baby's development, so early diagnosis is necessary to increase the likelihood of developing language, speech and communication skills. As mentioned earlier, a blood sample would be required to test for PKU. This involves a healthcare professional pushing down on the baby's heel so that 4 drops of blood are placed on a special card. Next, the blood can be tested for 9 rare serious conditions, including: Keep in mind: This is just a sample. Get a personalized article from our expert writers now. Get a Personalized Test Sickle Cell Disease Cystic Fibrosis Congenital Hypothyroidism Phenylketonuria (PKU) Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)Maple Syrup Urinary Disease (MSUD)Isovaleric Acidemia (IVA)Glutaric Acid Type 1 (GA1)Homocystinuria (HCU) [NHS. (2018).]ConclusionIn conclusion, this scenario highlights the need for people with PKU to seriously monitor their diet in order to combat the adverse effects that an increase in phenylalanine would have on their body. Especially for pregnant women, like Nuria, because out of fear that her condition could affect her child, she exposed herself to anemia. In cases like this, special treatment centers would be needed for nutritional assessment and counseling. Genetic counseling helping families to understand the measures to take if their child were to be affected, or even to explain to them the probability of having an affected child.REFERENCESA. Dyer, C. (1999). PATHOPHYSIOLOGY OF PHENYLKETONURIA. [online] Wiley Online Library. Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1002/%28SICI%291098-2779%281999%295%3A2%3C104%3A%3AAID-MRDD2%3E3.0.CO%3B2-7 [ Accessed February 18, 2019].A. Harvey, R. and Ferrier, D. (2019). Biochemistry. 5th ed. Lippincott, Williams and Wilkins, pp.278-282.Acog.org. (2015). Management of women with phenylketonuria - ACOG. [online] Available at: https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Genetics/Management-of-Women-With-Phenylketonuria?IsMobileSet=false [Accessed February 18, 2019].Al Hadif, b. and Christodoulou, J. (2015). Phenylketonuria: a review of current and future treatments. [online] PubMed Central (PMC). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728993/ [Accessed February 18, 2019]. Chanapa, T. (2014). Teratogens | The Embryo Project Encyclopedia. [online] Embryo.asu.edu. Available at: https://embryo.asu.edu/pages/teratogens [Accessed February 18, 2019]. Cindie, S. (2017). Phenylketonuria: causes, symptoms and diagnosis. [online] Health Line. Available at: https://www.healthline.com/health/phenylketonuria#treatments [Accessed February 18, 2019].Eatright.org. (2019). Foods to combat iron deficiency. [online] Available at: https://www.eatright.org/health/wellness/preventing-illness/iron-deficiency [Accessed February 18, 2019].Fernanda Schuck, et al. (2015).. 2019].

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