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By T. Kadok. Rutgers University. 2018.

The increase in PTH Calcitonin is a single-chain polypeptide composed of 32 synthesis and secretion induced by hypocalcemia is be- amino acid residues having a molecular weight of ap- lieved to be mediated through activation of parathyroid proximately 3600 lipitor 40 mg low price cholesterol readings chart australia. A cysteine disulfide bridge at the 1-7 gland adenylyl cyclase and a subsequent increase in in- position of the amino terminal end of the peptide is es- tracellular cyclic adenosine monophosphate (cAMP) buy lipitor 5mg low price cholesterol test ldl size. PreproPTH is the initial pep- tide that is synthesized within the parathyroid gland, and it serves as a precursor to both proPTH and PTH. Synthesis and Secretion PreproPTH is formed within the rough endoplasmic reticulum, transported into the cisternal space, and then The regulation of calcitonin synthesis and release from cleaved to form proPTH. The proPTH polypeptide is the parafollicular C cells of the thyroid gland is cal- transported into the cisternal space, where another pro- cium dependent. Calcitonin PTH in Target Tissues has been isolated in tissues other than the parafollicu- PTH has two levels of action in bone. First, in response lar C cells (parathyroid, pancreas, thymus, adrenal), to acute decreases in serum calcium, PTH stimulates but it is not known whether this material is biologically surface osteocytes to increase the outward flux of cal- active. Secretagogues, such as gastrin and pancreozymin, Thus, during brief periods of hypocalcemia, PTH re- may contribute significantly to the regulation of en- lease results in mobilization of calcium from labile areas dogenous calcitonin. This effect is not gastrin-induced calcitonin release following meals may associated with any significant increase in plasma phos- help regulate the postprandial calcium deposition in phate or bone resorption. It is thought to function in action on bone formation at physiological levels, and it a manner analogous to that of proPTH to facilitate in- is this action that allows it to be used pharmacologically tracellular transport and secretion of the hormone. However, in conditions that result metabolic degradation of calcitonin appears to occur in in chronic calcium deficiency or prolonged hypocal- both the liver and kidney. Serum to maintain normal concentrations of ionic or free calcitonin levels are used to screen and monitor patients plasma calcium. Intrarenal 1,25-(OH)2 D3 causes an amplification of the PTH-induced calcium re- Mechanism of Action absorption and phosphate diuresis. Once again, PTH does Calcitonin interacts with specific plasma membrane re- not directly affect intestinal calcium absorption, but it ceptors within target organs to initiate biological ef- does so indirectly through induction of 1,25-(OH)2 D3 fects. Circulating 25-(OH)D3 is then converted by the Vitamin D3, through its active metabolite, 1,25- kidney to the most active form of D3, 1,25-(OH)2D3,by (OH)2D3, also plays an important role in maintaining the 1-(OH)-D3-hydroxylase enzyme. Blood concentra- calcium homeostasis by enhancing intestinal calcium tions of 1,25-(OH)2D3 are approximately one five- absorption, PTH-induced mobilization of calcium from hundredth of those of 25-(OH)D3. In addition to the endogenous metabolites, some ex- Synthesis and Activation ogenous sterols possess biological activity similar to The primary supply of vitamin D3 in humans is not ob- that of D3. Ergocalciferol (vitamin D2) is derived from tained from the diet but rather is derived from the ultravi- the plant sterol ergosterol and may act as a substrate for olet photoconversion of 7-dehydrocholesterol to vitamin both the 25-hydroxylase and the 1-hydroxylase enzyme D3in skin. Thus, vitamin D3synthesis varies with the sea- systems of the liver and kidney to form 25-(OH)D2and sons. Ergocalciferol (vitamin D2) conversion to exert biological activity in its target organs is the form used in commercial vitamins and supple- (Fig. Dihydrotachysterol, another of metabolic activation of this endogenous sterol hor- sterol that is used as a therapeutic agent, also functions mone. The initial transformation of D3occurs in the liver as a substrate for the hydroxylase enzymes in the liver and is catalyzed by the enzyme 25-OH-D3-hydroxylase and kidney. The D3 receptor, similar to steroid receptor When osteoclasts first attach to bone in the active resorp- systems, translocates the hormone from the cell cyto- tive sites, the bisphosphonates are released from that plasm to the nucleus, where biological response is initi- bone. The bisphosphonates also may inhibit resorption by inducing apoptosis of osteoclasts and by inhibiting release BISPHOSPHONATES of interleukins and other compounds involved in bone re- sorption. The net result of actions of these compounds is The bisphosphonates are synthetic organic compounds inhibition of bone osteoclastic resorption. This action al- that are incorporated directly into the hydroxyapatite lows new bone formation to catch up in the remodeling of bone and then inhibit osteoclastic bone resorption. CLINICAL USES OF PARATHYROID HORMONE, CALCITONIN, VITAMIN D, Chemistry AND BISPHOSPHONATES The bisphosphonates have a common structure, P-C-P, These hormones and drugs are used most commonly for which is similar to the structure of the native pyrophos- disorders of calcium and bone metabolism rather than phate P-O-P found in bone hydroxyapatite. For example, ent compounds in clinical use vary by the attachments the use of PTH replacement in hypoparathyroidism in to the R component of the native molecule. Other compounds are avail- quantities of recombinant PTH (rPTH), its use will be able for the prevention of osteoporosis. For example, the bisphosphonates are now Hypercalcemia of Malignancy indicated for prophylaxis of osteoporosis when individ- Hypercalcemia is a common clinical condition that can uals are going to be treated with glucocorticoids or the accompany a variety of other medical conditions, such gonadotropin antagonists. Whatever compound is used The bisphosphonates are the most effective com- for prophylaxis or treatment of osteoporosis, calcium and pounds available to treat hypercalcemia of malignancy. Pamidronate (Aredia) and zoledronic acid (Zometa) can be infused intravenously and are the most effective Drug-Induced Osteopenia compounds available for rapid reduction of serum cal- cium levels.

It is interesting to note that the incidence of asthma (Custom Medical Stock Photo buy lipitor 5mg with mastercard cholesterol levels hdl, Inc discount 20 mg lipitor with mastercard cholesterol test kit cvs. While about 2% of children in China display symptoms of asthma, approxi- Other studies have documented higher rates of child- mately 30% of young people in Britain have indications hood asthma in some less advantaged, minority inner city of this disease. In Australia, the incidence of asthma is populations in the United States than in wealthier subur- very high in Caucasian children, but much lower in ban communities. Why such variations exist in the prevalence of Personalities with asthma asthma in different populations remains an unsolved mystery. Some scientists speculate that lifestyle factors, The symptoms of asthma have been observed and recorded in the medical literature since the time of such as a lack of physical activity, increased obesity, and Hippocrates, a famous doctor living in ancient Grecian more time spent indoors may contribute to higher rates times. The National Library of Medicine-Breath of Life of asthma in more highly developed countries. It is also Exhibit identifies many well known personalities who possible that environmental irritants such as poor indoor had a medical history of asthma. Despite their illness, and outdoor air quality, along with the presence of they pursued their chosen professions with great vigor potent irritants such as cockroach allergens, may con- and energy. The prolific American musician, Leonard tribute to higher rates of childhood asthma in poorer Bernstein, who composed West Side Story as well as communities. Other factors that may prompt the onset of many other celebrated scores, struggled with asthma asthma are viral respiratory infections, low birth weight, throughout his life. Another classical composer from a and smaller than average air passageways in asthmatic much earlier era, Ludwig von Beethoven, wrote some of patients. Robert Joffrey, founder of the avant-garde Many studies have shown that children who are exposed Joffrey Ballet, pursued an active dancing career in spite to viruses that cause the common cold and other respira- of his asthma. Contemporary individuals with asthma include the folk singer Judy Collins, track and field tory infections at a very young age are less likely to champion Jackie Joyner-Kersee, and professional basket- develop asthma than their peers living in a more ball star Dennis Rodman. So children living at home with older siblings and those who spend part of their week in John Kennedy, 35th president of the United States, daycare centers may be less likely to develop asthma than developed asthma from allergies to dogs, horses, and children who do not interact with others of their own age other animals. Asthma patients are encouraged to learn to the occurrence of symptoms (such as seasonal varia- recognize their own special pattern of early warning tions), when asthma symptoms first appeared, any con- signs that signal the start of an asthma episode. Asthma nection between symptoms and exposure to possible symptoms can be quite variable and are usually allergens, any disturbances in sleep patterns, and the reversible. Classification is include x rays to eliminate other possible causes of air- based on the severity and frequency at which symptoms way obstruction (blockage) and allergy tests. Asthmatic patients are also Moderate asthma more likely to develop other respiratory diseases such as pneumonia. Symptoms may persist for Asthma triggers many days and may interfere with normal physical activity. Many indoor and outdoor factors can Severe asthma trigger or initiate typical symptoms of asthma, including Patients with severe asthma have ongoing, persistent allergies, viral respiratory infections, weather changes, symptoms of this disease. Medications containing aspirin also act as much more serious, and can be life threatening. Allergens, such as inhaled dust particles and Asthma episodes can vary from mild to severe plant pollen, are substances that can stimulate an allergic attacks. The patient may start wheezing as a result Asthma and allergies of trying to inhale and exhale through constricted air pas- sageways. Many studies have confirmed that allergies cause the greatest majority of childhood asthma cases. Doctors Severe attacks can bring on a feeling of extreme refer to cases of asthma that are caused by allergies as tightening of the neck and chest, making breathing atopic asthma. In advanced stages of severe attacks, lips and over reaction—hypersensitivity—to allergens in the envi- fingernails may take on a grayish or bluish tinge indicat- ronment and the related overproduction of IgE antibodies ing declining oxygen levels in the blood. This action stimulates an asthma attack, in which the immune system Diagnosis releases substances that bring on the constriction and Medical diagnosis for asthma involves a complete inflammation of the airways of the lungs. One of the most important tests is the More than 80% of asthmatic patients also suffer measurement of pulmonary (lung) function—the volume from allergies such as hay fever. The medical term for of air a patient can inhale (breathe in) and exhale (breathe hay fever is allergic rhinitis. Many types of allergens are used to measure breathing efficiency and lung can trigger the immune system to produce the typical hay capacity.

In addi- tion cheap lipitor 40 mg free shipping cholesterol mayo clinic, for reasons not well understood buy lipitor 40mg on-line cholesterol levels nzgg, there is also active Adrenoleukodystrophy is a progressive condition breakdown of myelin, also known as demyelination. Genes contain the instructions for how the Description body grows and develops before and after a person is born. The ALD gene makes a protein called ALDP (ALD Adrenoleukodystrophy (ALD) was first described in protein). Different proteins put together make the tissues the early 1900s and was originally called Schilder- and organs in the body such as myelin. It is named for the different parts of the tant because it helps VLCFA get into the peroxisomes. As a result, the VCLFA often called the white matter in the brain and spinal cannot get into the peroxisomes and the VLCFA accu- cord), and “dystrophy” meaning impaired growth. Therefore, this disease affects the adrenal glands and the Genes are organized on structures called chromo- growth of the myelin in the brain and spinal cord. Hundreds to thousands of genes are found on is a wide range in the severity of symptoms. There are 46 chromosomes in each affects males, but occasionally females have mild or cell of the body. The 23rd pair is called the sex chromosomes; having one X Causes and effects chromosome and one Y chromosome causes a person to ALD is caused by problems in the peroxisomes. The be male; having two X chromosomes causes a person to peroxisomes are tiny structures in cells that help break be female. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 35 The ALD gene is located on the X chromosome. Thus, when a male has a muta- aspect of ALD is readily treatable, it is important to iden- tion in his ALD gene, he will have ALD. If they have a mutation in one Types of ALD copy of their ALD genes, they may only have mild symp- There is a wide range in the severity of symptoms toms of ALD or no symptoms at all. All different severities have normal copy of the ALD gene does make normal ALD been seen within the same family. Females who have one copy of the ALD gene who has many mildly affected members could still have with a mutation and one normal copy are called carriers. ALD is roughly divided into three different types according to severity Inheritance and age of onset. However, some patients do not fall ALD is passed on through families by X-linked neatly into one of these categories and instead fall some- recessive inheritance. Each type is given a different name, related through females in the family and there are no although all have mutations (changes in the genetic code) males in the family that have passed ALD onto their sons. Females pass on one of their X chromosomes to their The most severe form of ALD is called childhood children—sons or daughters. Very rarely is the onset before tion is passed on, a daughter will be a carrier and the son the age of three or after the age of 15. In other children, they or one in two chance of having an unaffected child (son become hyperactive and have behavioral problems that or daughter), a 25%, or one in four, chance of having a may initially be diagnosed as attention deficit disorder. When they pass on a Y chromosome, they have months, other more severe problems develop. Since the ALD mutation is on the X chromosome, include increasing problems with schoolwork and deteri- an affected male will always pass the ALD mutation on to oration in handwriting and speech. However, when he has a son, he passes on clumsiness, difficulty in reading and comprehension of the Y chromosome, and the son is not affected. Therefore, written material, aggressive or uninhibited behavior, and an affected male passes the ALD gene mutation on to all various personality and behavioral changes. Demographics A milder form of ALD called adrenomyeloneuro- pathy (AMN) usually has a symptom onset at the age of ALD has been described in people from all different 20 or later. Less than 20% of men with AMN will develop significant brain involvement Adrenal insufficiency that leads to cognitive and behavioral problems that are Almost all individuals affected with ALD have prob- severe and may cause a shortened life span. This of men with AMN will have problems with their adrenal is called adrenal insufficiency.

However cheap lipitor 10mg amex cholesterol juice fasting, if the X chromosome with the PLP mutation is passed on buy lipitor 20 mg line cholesterol lowering foods wikipedia, a daughter will be a carrier while the son Description would have PMD. Merzbacher, who first described the child (son or daughter), a 25%, or one in four chance of condition in the late 1800s. The severity of characteristics having a carrier daughter, and a 25%, or one in four in PMD can range from mild to severe. The brain Mutations and the spinal cord together are called the central nervous system. Everyone in a family who has the con- dition or is a carrier has the exact same PLP mutation. Genetic profile The most common type of mutation is a duplication (dou- PMD is caused by a mutation or change in the prote- bling) of the PLP gene. Having this tions to make proteolipid protein, one of the proteins that extra copy causes the myelin to be abnormal and leads to make up myelin in the central nervous system. About 50–75% of people with PMD have a PLP GALE ENCYCLOPEDIA OF GENETIC DISORDERS 899 duplication. A point mutation peripheral neuropathy, which is a problem with the is like a typo in the gene. This typo changes the message nerves that run from the spinal cord through the body. A This can cause weakness and problems with sensation few patients with PMD have a deletion of the PLP gene (telling if something is hot or cold, for example). They may have mild to copies of the PLP gene if they are male or one copy if moderate mental retardation. Another 5–20% of patients have charac- There are some people who have PLP mutations who teristics of PMD, but no mutation has been found in their are very mildly affected. Scientists are working to determine the cause times have other problems such as a spastic bladder. Although these individuals have mutations in the PLP gene, their condi- Demographics tion is given a different name, spastic paraplegia 2 PMD has been described in people from all over the (SPG2). The condition is rare and estimated to affect approximately Diagnosis one in 300,000 individuals in the United States. When problems are first noticed in an infant or a child, they will usually be referred to a pediatric neurol- Signs and symptoms ogist who is specially trained in diseases of the nerves There is a range in the severity of symptoms of and muscles in children. Rough categories have been set up based on the rologist will perform a clinical examination to evaluate age of onset and severity of symptoms. Patients with differ- should be taken to determine if there are others in the ent severities have been seen in the same family. In the most severe form of PMD, symptoms are first One of the initial tests that may be ordered is mag- noticed shortly after birth or in infancy. One of the first signs usually noticed is the brain are taken and the amount of white matter in the nystagmus, a side-to-side jerking of the eyes. Patients can have white matter is usually significantly reduced compared to significant mental retardation and never learn to walk, normal. They may have noisy breath- other neurological conditions and is not specific to PMD. Seizures may be Therefore, an MRI can be helpful in making the diagno- present in these children. They are often small for their sis of PMD, but if changes are seen on MRI, it does not age and have trouble gaining weight. Changes in the white floppy muscles called hypotonia, but later develop spas- matter may only be seen after one to two years of age ticity, which is stiffness or tightness in the muscles and when the brain has matured. If no one else in the family is known to be affected, Those patients who have classical PMD, which is testing may be performed to rule out conditions other less severe than the connatal type, usually have nystag- than PMD. Nystagmus develops within the first few months of when no one else is affected in the family. Other symptoms typically develop within the first uncommon for people to be misdiagnosed initially. These children also have hypotonia that turns Sometimes the diagnosis of PMD is made only after a into spasticity.