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The indices and chapter headings of each text were examined to identify references to ice discount 500mg depakote with mastercard nature medicine, cryotherapy purchase 250mg depakote treatment tracker, soft tissue injury, muscle, bruise or other possible guidance on management of soft tissue injury, looking in particular for advice on duration, frequency and mode of application. This study included forty-five general textbooks (Table 4. This search strategy identified 148 references to original research examining the effect of cold application. Additional references were identified from the reference lists of review articles (n = 12). Results Textbooks Many physicians use textbooks to guide their clinical practice. Of the 45 textbooks, there was no specific guidance on the duration, frequency or length of ice treatment in 17. There was advice on the length of treatment in 28 texts but the recommendations varied with the type of injury, its location and severity, and the type of ice therapy recommended. There was advice given on the frequency of treatment in 21 texts and 22 advised on the optimum duration of treatment. It was clear from this small study, which is open to many possible criticisms, that there is little consensus among textbooks on one of the most common treatments in soft tissue injury management. If there is little agreement in textbooks, answer may be found in the original research. This was searched and organised into a number of key areas, looking first at the effect on skin temperature. As expected, the drop in skin temperature was proportional to the temperature and duration of application. Direct application of a wet ice pack for 5 minutes reduced skin temperature to 7⋅6ºC, and, after 10 minutes, the skin temperature was 5ºC. Ice may be applied using various modalities and in one study comparing wet ice, dry ice and cryogen packs, the mean skin temperatures were 12ºC, 9⋅9ºC and 7⋅3ºC respectively after 15 minutes. Other studies confirmed these general findings, and using a standard ice pack (1kg ice in a plastic bag) the initial skin temperature of 19ºC dropped to 14ºC at 30 minutes. Animal studies Researchers have used animal models to examine the effect of cold on muscle physiology. There are, of course, limitations to this research and temperature effect cannot always be generalised to humans. A number of studies confirm the effect of ice in reducing muscle temperature and, in a study of ice application for 20 minutes in sheep,21 intramuscular temperature reduction did not return to pretreatment levels after two hours. When ice was applied a second time, intramuscular temperature continued to fall. Higher temperatures were recorded in the traumatised limb. In a study of cold applied to the skin of the mouse, increased blood vessel permeability with fluid extravasation and oedema occurred with temperatures below 15ºC. In a study of the effect of ice on injured rat muscle, however, cryotherapy did not reduce microvascular diameters or decrease microvascular perfusion. Human studies Animal studies can help us understand the physiological effect of temperature reduction but the key to clinical care is to understand the therapeutic effect in clinical practice. A number of researchers have examined the effect of tissue temperature reduction, but it is difficult to compare the results of the different studies because of variation in research methods and measurements. The temperature reduction at tissue level is illustrated in one study where ice was applied continuously for 85 minutes27 and the temperature dropped by 5ºC, 9ºC and 7ºC at depths of 7 cm, 6 cm and 4 cm. Compression may also enhance temperature reduction28 with the changes at 1 cm below the fat layer and at 2 cm below the fat layer being greater with compression at 12⋅8ºC and 10⋅1ºC. Subcutaneous fat, being an insulating material, inhibits the cooling effect and while significant cooling occurs with 10 minutes of ice application to a depth of 2 cm in those with less than 1 cm of fat,29 athletes with more than 2 cm of fat, required 20–30 minutes. There is an inverse relationship between adipose tissue and temperature decrease so that subcutaneous fat may mean that short duration ice application may be ineffective in cooling deeper tissue levels. The above paragraphs highlight only some of the studies on ice application. The consensus from studies of ice application, for periods varying from five minutes to 85 minutes, is that the temperature is reduced in the first 10 minutes with little further reduction from 10 to 20 minutes. The temperature drop is determined by the area of contact between the ice and the skin, the temperature difference and tissue conductivity but most published studies do not measure the area of ice application, subcutaneous fat, nor use comparable methods of calculating depth, or measuring temperature. Where temperature is 48 The role of ice in soft tissue injury management measured, in human and animal studies, there is wide variation in the temperature recorded at different depths in different studies with wide standard deviations.

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One is dissociation from the glycogen parti- cle generic depakote 250mg visa medicine in french, such that the substrates are no longer available to the phosphatase cheap 250mg depakote with mastercard medicine wheel. A second is the binding of inhibitor proteins, such as the protein called inhibitor-1, which, when phosphorylated by a glucagon (or epinephrine)-directed mechanism, binds to and inhibits phosphatase action. Insulin indirectly activates hepatic PP-1 through its own signal transduction cascade initiated at the insulin receptor Most of the enzymes that are regu- tyrosine kinase. INSULIN IN LIVER GLYCOGEN METABOLISM thase b, the less active form of glycogen syn- thase, can be activated by the accumulation Insulin is antagonistic to glucagon in the degradation and synthesis of glycogen. Glucose stimulates insulin release and suppresses glucagon release; one by glucose 6-phosphate may be important in increases while the other decreases after a high carbohydrate meal. However, individuals with glucose 6-phosphatase defi- insulin levels in the blood change to a greater degree with the fasting-feeding cycle ciency, a disorder known as type I or von than the glucagon levels, and thus insulin is considered the principal regulator of Gierke’s glycogen storage disease. The role of insulin in glycogen metabolism is glucose 6-phosphate produced from gluco- often overlooked because the mechanisms by which insulin reverses all of the neogenesis accumulates in the liver, it acti- effects of glucagon on individual metabolic enzymes is still under investigation. In vates glycogen synthesis even though the addition to the activation of hepatic PP-1 through the insulin receptor tyrosine individual may be hypoglycemic and have kinase phosphorylation cascade, insulin may activate the phosphodiesterase that low insulin levels. Glucose 1-phosphate is also elevated, resulting in the inhibition of converts cAMP to AMP, thereby decreasing cAMP levels and inactivating protein glycogen phosphorylase. Regardless of the mechanisms involved, insulin is able to reverse all of large glycogen deposits accumulate, and the effects of glucagon and is the most important hormonal regulator of blood hepatomegaly occurs. CHAPTER 28 / FORMATION AND DEGRADATION OF GLYCOGEN 521 7. BLOOD GLUCOSE LEVELS AND GLYCOGEN SYNTHESIS An inability of liver and muscle to AND DEGRADATION store glucose as glycogen con- tributes to the hyperglycemia in When an individual eats a high-carbohydrate meal, glycogen degradation immedi- patients, such as Di Abietes, with type 1 dia- ately stops. Although the changes in insulin and glucagon levels are relatively rapid betes mellitus and in patients, such as Ann (10–15 minutes), the direct inhibitory effect of rising glucose levels on glycogen Sulin, with type 2 diabetes mellitus. Glucose, as an allosteric effector, inhibits liver absence of insulin in type 1 diabetes mellitus glycogen phosphorylase a by stimulating dephosphorylation of this enzyme. As patients and the high levels of glucagon result insulin levels rise and glucagon levels fall, cAMP levels decrease and protein kinase in decreased activity of glycogen synthase. Glycogen synthesis in skeletal muscles of type A reassociates with its inhibitory subunits and becomes inactive. The protein phos- 1 patients is also limited by the lack of insulin- phatases are activated, and phosphorylase a and glycogen synthase b are dephos- stimulated glucose transport. The collective result of these effects is rapid inhibition of glycogen ance in type 2 patients has the same effect. An injection of insulin suppresses gluc- agon release and alters the insulin/glucagon ratio. EPINEPHRINE AND CALCIUM IN THE REGULATION into skeletal muscle and rapid conversion of OF LIVER GLYCOGEN glucose to glycogen in skeletal muscle and Epinephrine, the “fight-or-flight” hormone, is released from the adrenal medulla in liver. To flee from a dangerous situation, skeletal muscles use increased amounts of blood glucose to generate ATP. As a result, liver glycogenolysis must be stimulated. In the liver, epinephrine stimulates glycogenolysis through two different types of receptors, the In the neonate, the release of epi- - and -agonist receptors. EPINEPHRINE ACTING AT THE -RECEPTORS did not have adequate liver glycogen stores Epinephrine, acting at the -receptors, transmits a signal through G proteins to to support a rise in her blood glucose levels. Hence, regulation of glycogen degradation and synthesis in liver by epinephrine and glucagon are similar (see Fig. EPINEPHRINE ACTING AT -RECEPTORS Epinephrine also binds to -receptors in the liver. This binding activates glycogenolysis and inhibits glycogen synthesis principally by increasing the Ca2 levels in the liver. The effects of epinephrine at the -agonist receptor are mediated by the phosphatidylinositol bisphosphate (PIP )-Ca2 signal transduction system, 2 one of the principal intracellular second messenger systems employed by many hormones (Fig. In the PIP -Ca2 signal transduction system, the signal is transferred from the 2 epinephrine receptor to membrane-bound phospholipase C by G proteins. Phos- pholipase C hydrolyzes PIP2 to form diacylglycerol (DAG) and inositol trisphos- phate (IP ). IP stimulates the release of Ca2 from the endoplasmic reticulum.

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STRUCTURE OF RNA Dramatic deviations from this ratio imply the occurrence of an additional hemoglobin A order depakote 500mg line symptoms diverticulitis. Like DNA buy depakote 500mg fast delivery medications before surgery, it is composed of nucleotides joined by 3 - to 5 -phosphodiester bonds, the purine bases adenine and guanine, and the pyrimidine base cytosine. However, its other pyrimidine base is uracil rather than thymine. O O Uracil and thymine are identical bases except that thymine has a methyl group at C C position 5 of the ring (Fig. In RNA, the sugar is ribose, which contains a HN 4 CH HN 3 5 3 hydroxyl group on the 2´-carbon (see Fig 12. The prime refers to the position on C2 6 C the ribose ring). However, RNA still has considerable secondary and ter- (in RNA) (in DNA) tiary structure because base pairs can form in regions where the strand loops back Fig. As in DNA, pairing between the bases is complementary and antiparallel. They differ in structure But in RNA, adenine pairs with uracil rather than thymine (Fig. C N 5-FU inhibits the synthesis of the thymine C N H C C H nucleotides required for DNA replication. N C C H Thymine is normally produced by a reaction N N C C N catalyzed by thymidylate synthase, an C N enzyme that converts deoxyuridine O H monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thus, thymine nucleotides cannot be generated for DNA important for the binding of molecules, such as enzymes, that interact with specific synthesis, and the rate of cell proliferation regions of the RNA. The three major types of RNA (mRNA, rRNA, and tRNA) participate directly in O the process of protein synthesis. Other less abundant RNAs are involved in replica- tion or in the processing of RNA, that is, in the conversion of RNA precursors to HN F their mature forms. Some RNA molecules are capable of catalyzing reactions. Thus, RNA, as well N H as protein, can have enzymatic activity. Certain rRNA precursors can remove inter- nal segments of themselves, splicing the remaining fragments together. Because this 5–Fluorouracil, an analogue of uracil or thymine RNA is changed by the reaction that it catalyzes, it is not truly an enzyme and there- fore has been termed a “ribozyme. Structure of mRNA Each mRNA molecule contains a nucleotide sequence that is converted into the amino acid sequence of a polypeptide chain in the process of translation. In eukary- otes, messenger RNA (mRNA) is transcribed from protein-coding genes as a long primary transcript that is processed in the nucleus to form mRNA. The various pro- cessing intermediates, which are mRNA precursors, are called pre-mRNA or hnRNA (heterogenous nuclear RNA). Eukaryotic mRNA consists of a leader sequence at the 5´ end, a coding region, and a trailer sequence at the 3 end (Fig 12. The leader sequence begins with a guanosine cap structure at its 5 end. The coding region begins with a trinucleotide start codon that signals the beginning of translation, followed by the trinucleotide Coding codons for amino acids, and ends at a termination signal. The trailer terminates at Leader region Trailer its 5 end with a poly(A) tail that may be up to 200 nucleotides long. However, the termi- codon codon tail nal guanosine in the cap structure and the poly(A) tail do not have complementary Fig. The wavy line indicates the polynucleotide chain of the mRNA and the As constituting the C. The 5 -cap consists of a guano- sine residue linked at its 5 hydroxyl group to Ribosomes are subcellular ribonucleoprotein complexes on which protein synthesis three phosphates, which are linked to the 5 - occurs. Different types of ribosomes are found in prokaryotes and in the cytoplasm hydroxyl group of the next nucleotide in the and mitochondria of eukaryotic cells (Fig.

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