By I. Arakos. Voorhees College.

Blood samples for glucose and electrolytes were drawn repeatedly during the first 24 hours cheap prednisolone 40 mg mastercard. The hospital laboratory reported that the serum in each of these specimens appeared opalescent rather than having its normal clear or transparent appearance prednisolone 5 mg sale. This opalescence results from light scattering caused by the presence of elevated levels of triacylglycerol-rich lipoproteins in the blood When Ann Sulin initially presented with type 2 diabetes mellitus at age 39 generic prednisolone 5 mg with amex, she was approximately 30 lb above her ideal weight cheap prednisolone 20 mg without prescription. Her high serum glucose levels were accompanied by abnormalities in her 14-hour fasting lipid profile discount prednisolone 20 mg without prescription. Her serum total cholesterol, low-density lipoprotein (LDL) choles- terol, and triacylglycerol levels were elevated, and her serum high-density lipopro- tein (HDL) cholesterol level was below the normal range. REGULATION OF CARBOHYDRATE AND LIPID Glucose METABOLISM IN THE FED STATE ATP glucokinase A. Mechanisms That Affect Glycogen and Triacylglyc- high K m erol Synthesis in Liver ADP After a meal, the liver synthesizes glycogen and triacylglycerol. The level of glyco- Glucose-6-P gen stored in the liver can increase from approximately 80 g after an overnight fast to a limit of approximately 200–300 g. Although the liver synthesizes triacylglycerol, it does not store this fuel but rather packages it in very-low-density lipoprotein Fructose-6-P (VLDL) and secretes it into the blood. The fatty acids of the VLDL triacylglycerols phosphofructokinase-1 secreted from the liver are stored as adipose triacylglycerols. Adipose tissue has an AMP , F-2,6-BP ,+ + almost infinite capacity to store fat, limited mainly by the ability of the heart to pump ATP , Citrate– – blood through the capillaries of the expanding adipose mass. Although we store fat throughout our bodies, it tends to accumulate in places where it does not interfere too Fructose-1, 6-P much with our mobility: in the abdomen, hips, thighs, and buttocks. Both the synthesis of liver glycogen and the conversion by the liver of dietary glucose to triacylglycerol (lipogenesis) are regulated by mechanisms involving key enzymes in these pathways. GLUCOKINASE pyruvate (cAMP-dependent) kinase – Alanine After a meal, glucose can be converted to glycogen or to triacylglycerol in the liver. Because of the enzyme’s low affinity for glucose, this enzyme is most active in the fed state, when Fig. Regulation of glucokinase, PFK-1, the concentration of glucose is particularly high because the hepatic portal vein and pyruvate kinase in the liver. Synthesis of synthase– P glucokinase is also induced by insulin (which is elevated after a meal) and (inactive) repressed by glucagon (which is elevated during fasting). In keeping with the protein ADP protein liver’s function in maintaining blood glucose levels, this system is set up such that kinase A phosphatase the liver can only metabolize glucose when sugar levels are high, and not when + Glucagon + Insulin ATP sugar levels are low. GLYCOGEN SYNTHASE (active) In the conversion of glucose 6-phosphate to glycogen, the key regulatory enzyme is Glycogen UDP–Glucose glycogen synthase. This enzyme is activated by the dephosphorylation that occurs when insulin is elevated and glucagon is decreased (Fig. PHOSPHOFRUCTOKINASE-1 AND PYRUVATE KINASE For lipogenesis, glucose 6-phosphate is converted through glycolysis to pyruvate. Glucose–6–P Key enzymes that regulate this pathway in the liver are phosphofructokinase-1 (PFK-1) and pyruvate kinase. PFK-1 is allosterically activated in the fed state by Glucose fructose 2,6-bisphosphate and adenosine monophosphate (AMP) (see Fig. Phosphofructokinase-2, the enzyme that produces the activator fructose 2,6- This enzyme is phosphorylated by a series of bisphosphate, is dephosphorylated and active after a meal (see Chapter 22). Pyru- kinases, which are initiated by the cAMP- vate kinase is also activated by dephosphorylation, which is stimulated by the dependent protein kinase, under fasting condi- increase of the insulin/glucagon ratio in the fed state (see Fig. It is dephosphorylated and active after a meal, and glycogen is stored. Circled P phosphate; a circled sign activated by; a 4. PYRUVATE DEHYDROGENASE AND PYRUVATE CARBOXYLASE circled sign inhibited by. The conversion of pyruvate to fatty acids requires a source of acetyl CoA in the cytosol. Pyruvate can only be converted to acetyl CoA in mitochondria, so it enters mitochondria and forms acetyl CoA through the pyruvate dehydrogenase (PDH) reaction. This enzyme is dephosphorylated and most active when its supply of sub- P strates and adenosine diphosphate (ADP) is high, its products are used, and insulin pyruvate is present (Fig. The enzyme that catalyzes this reac- inactive tion, pyruvate carboxylase, is activated by acetyl CoA. Because acetyl CoA cannot directly cross the mitochondrial membrane to form fatty acids in the cytosol, it con- ADP denses with oxaloacetate, producing citrate.

The side chains H O 2 O interact with the peptide backbone of other regions of the chain or with the side + – chains of other amino acids in the protein to form hydrophobic regions order prednisolone 20mg otc, electrostatic H3N N bonds discount 5 mg prednisolone fast delivery, hydrogen bonds discount prednisolone 20 mg line, or disulfide bonds quality 20mg prednisolone. These interactions dictate the folding pat- R1 H H tern of the molecule buy prednisolone 40 mg without prescription. The three-dimensional folding of the protein forms distinct regions called binding sites that are lined with amino acid side chains that interact Fig. Amino acids in a specifically with another molecule termed a ligand (such as the heme in hemoglo- polypeptide chain are joined through peptide bin). Thus, the chemical properties of the side chains determine how the protein bonds between the carboxyl group of one folds, how it binds specific ligands, and how it interacts with its environment (such amino acid and the amino group of the next as the aqueous medium of the cytoplasm). The names of the different amino acids have been given three-letter and one-let- ter abbreviations (Table 6. The three-letter abbreviations use the first two letters in the name plus the third letter of the name or the letter of a characteristic sound, such as trp for tryptophan. The one-letter abbreviations use the first letter of the name of the most frequent amino acid in proteins (such as an “A” for alanine). If the first letter has already been assigned, the letter of a characteristic sound is used According to some biochemists, (such as an “R” for arginine). Single-letter abbreviations are usually used to denote “W” stands for the characteristic the amino acids in a polypeptide sequence. These groupings can be helpful in describing common functional roles or Three-Letter One-Letter metabolic pathways of the amino acids. However, some amino acid side chains Alanine Ala A Arginine Arg R fit into a number of different classifications and are therefore grouped differently Asparagine Asn N in different textbooks. Two of the characteristics of the side chain that are useful Aspartate Asp D for classification are its pKa and its hydropathic index, shown in Table 6. The more Histidine His H Isoleucine Ile I negative the hydropathic index of an amino acid, the more hydrophilic is its side Leucine Leu L chain. Lysine Lys K Methionine Met M Phenylalanine Phe F A. Nonpolar, Aliphatic Amino Acids Proline Pro P Serine Ser S Glycine is the simplest amino acid, and it really does not fit well into any classifi- Threonine Thr T cation because its side chain is only a hydrogen atom. Alanine and the branched Tryptophan Trp W chain amino acids (valine, leucine, and isoleucine) have bulky, nonpolar, aliphatic Tyrosine Tyr Y Valine Val V side chains. The high degree of hydrophobicitiy of the branched chain amino acid side chains is denoted by their high hydropathic index (see Table 6. Electrons are *Three-letter abbreviations are generally used. One- letter abbreviations are used mainly to list the amino shared equally between the carbon and hydrogen atoms in these side chains, so that acid sequences of long protein chains. Within proteins, these amino acid side chains will cluster together to form hydrophobic cores. Their association is also promoted by van der Waals forces between the positively charged nucleus of one The proteolytic digestive enzyme atom and the electron cloud of another. This force is effective over short distances chymotrypsin cleaves the peptide when many atoms pack closely together. The amino acid proline contains a ring involving its -car- acids. Which amino acids fall into this cate- bon and its -amino group, which are part of the peptide backbone. The amino acids are grouped by the polarity and structural fea- tures of their side chains. Tyrosine and tryptophan, often listed with the nonpolar amino acids, are more polar than other aromatic amino acids because of their phenolic and indole rings, respectively. Properties of the Common Amino Acids Chymotrypsin’s highest activity is pKa1 Ka2 pKaR Hydropathy toward peptide bonds formed by Amino Acid (Carboxyl) (Amino) (R Group) Index** the carboxyl groups of aromatic Nonpolar aliphatic amino acids (phenylalanine, tyrosine, trypto- Glycine 2. Because the side chain of glycine is so small compared with that of other amino acids, it causes the least amount of steric hindrance in a protein (i.

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This apparent reduction in arteriosclerosis as a cause of PS is due to increased diagnostic accuracy of PS 40mg prednisolone with mastercard, rather than a dramatic decline in arteriosclerosis in the general population cheap 20mg prednisolone free shipping. Neuroleptic-induced parkinsonism (DIP) was first recognized in the late 1950s and is now a common PS variant (28 order 5 mg prednisolone visa,29 5 mg prednisolone amex,38) accounting for between 7% (28) and 20% of all PS cases (29) 10mg prednisolone overnight delivery. DIP is now the second most common PS variant and is more common in women than men (29). Large clinicopathological studies of Shy-Drager syndrome (SDS) (46), striatonigral degeneration (SND) (47), and progressive supranuclear palsy (PSP) (48) were first reported in the 1960s, though clinical description of PSP was documented in the nineteenth century (49). Olivopontocerebellar atrophy (OPCA), which often includes some features of PS, has been known since 1900. The current classification includes SND, SDS, and OPCA under the common heading of multiple system atrophy (MSA). Prominent dysautonomia in SDS and akinetic rigid PS features in SND were not fully recognized until 1960 and 1964, respectively, and in all likelihood such cases prior to that were classified as PEP or atypical parkinsonism because they occurred at a relatively young age and had widespread nervous system involvement. In spite of the improved understanding of these uncommon PS variants, the diagnosis is not always possible clinically (7,21,22,50). Autopsy series may be biased because the families of those suffering from the unusual Copyright 2003 by Marcel Dekker, Inc. PS variants may have heightened interest in finding out the nature of the disease and, therefore, be more likely to consent to an autopsy. The true frequency of these variants in the general population is, therefore, not possible to determine. A previous study from the same community reported PSP diagnosis in 1. Thus, MSA and PSP each represent less than 5% of the contemporary PS cases in North America. The most common PS variant in epidemiological studies (28,38,51) is idiopathic PD (6). The proportion of those with PD, however, varies widely in different studies—e. Preponderance of PD is also noted in autopsy studies of unselected PS cases (27,52,53). Dementia with Lewy bodies (DLB) is now a well-recognized entity (54), and extrapyramidal features may also be seen in Alzheimer’s disease (AD) (55). One recent PS study (29) noted that 14% of all PS cases had dementia manifesting within one year of PS onset and classified these as ‘‘Parkinson- ism in dementia. The clinical and pathological classification of PS variants continues to evolve, but the most common variant is still PD (6,7). Life Expectancy in Parkinsonism All the PS variants limit mobility. Increased tendency to falls and dysphagia predispose these patients to life-threatening complications (56,57). Life expectancy prior to the widespread use of LD was significantly reduced. In one hospital-based PS series during the 1950s and 1960s, the mean survival after onset was 10. The PEP cases had longer survival than other PD cases (58,59). When the PEP cases were excluded, the mean survival in the remaining cases was 9. That study is frequently cited as the yardstick for the pre-LD era life expectancy. Mean survival in the contemporary PS cases cannot be compared with that study. There have been significant social and health care advances leading to longer life in the general population. One would expect that PS patients would share these survival gains. Comparison for PS patients’ survival should be made matching for year of birth, gender, and region/country.

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In contrast to PSP prednisolone 10 mg free shipping, the superior cerebellar peduncle and the subthalamic nucleus are grossly normal purchase 20 mg prednisolone otc. The cerebral white matter in affected areas is often attenuated and may have a gray discoloration 10 mg prednisolone. The corpus callosum is sometimes thinned trusted prednisolone 5mg, and the frontal horn of the lateral ventricle is frequently dilated prednisolone 5 mg lowest price. Microscopic examination of atrophic cortical sections shows neuronal loss with superficial spongiosis, gliosis, and usually many achromatic or ballooned neurons. Ballooned neurons are swollen and vacuolated neurons found in the middle and lower cortical layers. They are variably positive with silver stains and tau immunohistochemistry, but intensely stained with immunohistochemistry for alpha-B-crystallin, a small heat shock protein, and for neurofilament (Fig. Cortical neurons in atrophic areas also have tau-immunoreactive lesions. In some neurons tau is densely packed into a small inclusion body, somewhat reminiscent of a Pick body or a small NFT. In other neurons, the filamentous inclusions are more dispersed and diffuse. As in PSP, neurofibrillary lesions in CBD are not detected well with most diagnostic silver stains and thioflavin fluorescent microscopy. Neurofibrillary lesions in brainstem monoaminergic nuclei, such as the locus ceruleus and substantia nigra, sometimes resemble globose NFT. In addition to fibrillary lesions in perikarya of neurons, the neuropil of CBD invariably contains a large number of thread-like tau-immunoreactive processes. They are usually profuse in both gray and white matter, and this latter feature is an important attribute of CBD and a useful feature in differentiating it from other disorders (34). The most characteristic tau-immunoreactive lesion in the cortex in CBD is an annular cluster of short, stubby processes with fuzzy outlines that may be highly suggestive of a neuritic plaque of AD (34) (Fig. In contrast to AD plaques, they do not contain amyloid but rather tau-positive astrocytes and have been referred to as ‘‘astrocytic plaques. The astrocytic plaque may be the most specific histopathological lesion of CBD. In addition to cortical pathology, deep gray matter is consistently affected in CBD. The globus pallidus and putamen show mild neuronal loss with gliosis. In the basal ganglia, thread-like processes are often extensive, often in the pencil fibers of the striatum. Tau-positive neurons, but not NFT, are common in the striatum and globus pallidus. The internal capsule and thalamic fasciculus often have many thread-like processes. The subthalamic nucleus usually has a normal neuronal population, but neurons may have tau inclusions, and there may be many thread-like lesions in the nucleus. Fibrillary gliosis typical of PSP is not seen in the subthalamic nucleus in CBD. The substantia nigra usually shows moderate to severe neuronal loss with extraneuronal neuromelanin and gliosis. Many of the remaining neurons contain NFT, which have also been termed ‘‘corticobasal bodies’’ (35) (Fig. The locus ceruleus and raphe nuclei have similar inclusions. In contrast to PSP, where neurons in the pontine base almost always have at least a few NFT, the pontine base is largely free of NFTs in CBD. On the other hand, tau inclusions in glia and thread-like lesions are frequent in the pontine base. The cerebellum has mild Purkinje cell loss and axonal torpedoes.

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