How To Take Creatine
The BB-isozyme of creatine kinase has been also investigated as a potential marker for aortic dissection since it is abundantly present both in smooth-muscle fibers and in the neurological system. Analogous to the use of the MB-isozyme of creatine kinase for the detection of cardiac ischemia, a small study has shown that creatine kinase BB-isozyme is elevated in acute aortic dissection15. In addition, the study demonstrated that the temporal profiles of the peak level is delayed compared to smooth-muscle myosin heavy chain. Combined use of the two tests may therefore be extremely useful for temporal profiling of aortic dissection.
Clinicians individualize the treatment for HD to the needs of the patient, depending on the most prominent signs and symptoms. No known treatment prevents, halts, or cures the disorder, although several clinical trials of putative neuro-protective agents were carried out recently. Riluzole and ramecemide were shown to improve motor function. Studies of the potential neuroprotective benefit of minocycline (an apoptotic caspase inhibitor) and creatine in early symptomatic HD are in progress (Huntington Study Group 2001).
The increase in malondialdehyde-acetaldehyde protein adducts supports previous suggestions that alcohol induces cardiac lipid peroxidation 83,84 concomitant with endogenous cardiac-derived acetaldehyde formation, possibly via alcohol dehydrogenase (ADH) or cytochrome P450 actions. However, although the activity of cardiac alcohol dehydrogenase is low, catalase may also generate acetaldehyde 85-88 , The importance of these studies relates to the observation that malondialdehyde-acetaldehyde adducts are cytotoxic, inducing the release ofTNF-alpha and up-regulating ICAM-1 in endothelial cells in vitro 89 , Reactive oxygen free radical species may play a prominent role in alcohol-induced heart muscle damage. Cardiac tissue from chronic alcohol misusers shows increased 'agepigments indicative of damage by reactive oxygen species 90 , Involvement of reactive oxygen species damage is also implicated by studies showing that in alcohol-fed rats, the resulting shift in fatty acid profile is...
(Dansithong et al. 2005 Savkur et al. 2001) and in DM1 heart tissue (Timchenko et al. 2001a). In addition, transgenic mice expressing CUG-BP1 eight to ten fold above endogenous levels inhibited muscle differentiation and resulted in neonatal lethality (Timchenko et al. 2004). Histological features were variably consistent with what is observed in CDM patients including centrally positioned nuclei suggestive of immature skeletal muscle. However, type 1 slow myofiber numbers were increased while these are decreased in DM skeletal muscle. The mechanism of muscle immaturity is thought to be due to altered translation of p21 and myo-genin mRNAs by CUG-BP1. In another line of transgenic mice overexpressing CUG-BP1 in heart and skeletal muscle using the mouse creatine kinase promoter (MCKCUG-BP), transgene expression was associated with neonatal lethality (Ho et al. 2005a). Histological changes were consistent with CDM, as well as splicing changes observed for TNNT2 exon 5 and MTMR1 exons...
The palpable consistency of the muscles in affected pigs was found to be comparable to that of unaffected animals. Furthermore, unaltered plasma concentrations of creatine kinase and aspartate aminotransferase suggested that the Campus syndrome was not a primary myopathy. The immediate disappearance of tremor when the pigs lay down may also argue against a role of a primary myopathy in the Campus syndrome (Richter et al., 1995). As shown by geno-typing at the ryanodine receptor locus, an increased susceptibility to stress, an elevated body temperature of 40 to 41 C, and enhanced plasma lactate levels found in affected animals are not related to malignant hyperthermia, a common metabolic disorder of the skeletal muscle in swine (Fujii et al., 1991 Richter et al., 1995 Tammen et al., 1999). The expectancy of life is reduced to 3 to 18 months in pigs with the Campus syndrome. Most animals die before sexual maturity (Tammen et al., 1999).
During rhabdomyolysis, muscle cell integrity is lost and there is release of contents. Biochemical markers are myoglobin, creatine kinase, lactic acid dehydrogenase, aldolase, phosphate, potassium, aspartate aminotransferase, alanine aminotransferase, and neutral proteases. These move from muscle into the ECF. At the same time, sodium chloride and calcium move from the ECF into the cells, resulting in hypovolaemia, shock, metastatic calcification, prerenal and renal failure. Features include hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia, a high
Hypoglycemia in children needs to be treated with frequent feeding. A high protein diet may improve weakness in adult forms of GSD. In GSD VII patients should avoid high-carbohydrate meals that exacerbate the out-of-wind phenomenon, and a ketogenic diet may help. Other potential treatments for GSD V are pyridoxine therapy that improves symptoms in some patients and creatine monohydrate that improves anaerobic but not aerobic exercise capability. Adenoviral-mediated delivery of a myophosphorylase cDNA into myoblasts from patients with McArdle's disease restores myophosphorylase to normal levels, and may prove beneficial as a potential future treatment. Enzyme replacement therapy is also being evaluated in GSD II.
Currently there are no specific pharmacological treatments for respiratory chain Therapy disorders. Aerobic training improves exercise tolerance, cardiovascular function, and muscle metabolism in some patients. Strength training may help in some patients. A variety of mitochondrial enzyme supplements have been tried with variable success. These include coenzyme Q, creatine, carnitine, thiamine, nicotinamide, riboflavin, succinate, and menadione. Until the specific enzyme defects within a particular Mt myopathy are better defined, enzyme supplements will have a limited role in treatment of this disorder.
The use of MRI in classifying and predicting progression in mild cognitive impairment is receiving increasing attention (Jack et al., 1997). Several investigators have indicated that the hippocampal volume at the time of diagnosis may be a useful predictor of subsequent progression (Jack et al., 1999). In addition, rates of change of the volume of the hippocampus have also been useful and, more recently, functional imaging measures have shown some merit (Jack et al., 2000). Kantarci and colleagues have recently reported an MRI spectroscopy study in mild cognitive impairment (Kantarci et al., 2000). These investigators reported that persons with a mild cognitive impairment have a reduced myo-inositol creatine ratio in the posterior cingulate. This, again, differentiated patients with mild AD from those with mild cognitive impairment. In addition, N-acetyl aspartate levels were reduced when the subjects developed clinically probable AD.
A few proton MR spectroscopy (MRS) studies have demonstrated that N-acetylaspartate (NAA) and choline (Cho) were reduced in the lentiform nucleus of MSA patients (32,33). The NAA creatine (Cr) ratio was particularly decreased in MSA-P patients, probably reflecting putaminal neuronal loss (32). MRS, however, has not been widely used to help differentiate patients with MSA from patients with PD.
The most life-threatening side-effect of neuroleptic use is neuroleptic malignant syndrome (NMS). This is thought to be due to derangement of dopaminergic function, but the precise patho-physiology is unknown. Symptoms include hyperthermia, muscle rigidity, autonomic instability and fluctuating consciousness. It is an idiosyncratic reaction. The diagnosis is often missed in the early stages, but a raised level of creatine phospho-kinase is often seen. It can occur at any time. The untreated mortality rate is 20 and therefore immediate medical treatment is required. Bromocriptine (a D1 D2 agonist) and dantrolene (a skeletal muscle relaxant) are used to reverse dopamine blockade and for muscular rigidity, respectively. The management includes supportive treatment for dehydration and high temperature. Renal failure from rhabdomyolysis is the major complication and cause of mortality. NMS can recur on reintroduction of antipsychotics it is therefore recommended to wait at least 2 months...
The pathophysiology of ET is poorly understood, but several lines of evidence suggest that this disease is probably neurodegenerative. As noted above, ET is clinically progressive. In addition, the gradual development of mild incoordination and mild ataxia in some longstanding cases supports the notion that the underlying pathological process is not static, but that it becomes more pervasive, eventually extending into brain systems that produce symptoms other than tremor. Also, clinicians have observed that tremor usually begins in the arms and only later spreads to the head. These clinical findings support the notion that the underlying neuropathological changes are not static, but rather, they also develop somatotopically over time, initially involving brain regions that result in arm tremor and later, advancing into the regions that result in head tremor and more pervasive cerebellar signs, and possibly involving other systems (e.g., basal ganglia) as noted above. Finally, imaging...
MRS provides chemical information on tissue metabolites (3,4). The molecules that can be studied by MRS in human brain tissue are hydrogen 1 ( H) and phosphorus 31 (31P). Magnetic resonance sensitivity is far greater for protons than it is for phosphorus (3). Therefore, most commercial MR scanners are capable of only proton MRS. Spectra are usually obtained from localized brain regions. The brain region is defined on a single slice by placing a small voxel, on the order of 1 or 2 cm2, in the area of interest. The compounds that can be observed in proton spectra are primarily identified by their frequency (i.e., their position in the spectrum), expressed as the shift in frequency in pars per million (ppm) relative to a standard. A normal spectrum shows peaks from N-acetyl groups, especially N-acetylaspartate (NAA) at 2.0 ppm, creatine (Cr), and phosphocreatine at 3.0 ppm, and cho-line-containing phospholipids (Ch) at 3.2 ppm (3). An additional peak at 1.3 ppm arises from the methyl...
A second cluster of methyl group acceptors are involved with energy metabolism (Fig. 1). Trimethyllysine is used to make carnitine which transports fatty acids into mitochondria for the production of ATP and acetyl CoA via beta oxidation. Creatine can accept phosphate from ATP when it is present in excess and provides a reservoir of high energy phosphate in muscle cells to maintain activity when energy demands exceed the amount of ATP that can be provided by the glucose in muscle. This maintains muscle activity as cellular metabolism adjusts to draw on glycogen for additional ATP and mobilize glucose from the liver. Epinephrine is a hormone that enables the cell to respond to stress by increasing glycogen utilization. In addition, it modulates the flow of fatty acids to and from cells (Montgomery et al., 1990).
In MRS, most studies have focused on changes in NAA, a neuronal marker that is expected to decrease in degenerative disorders, and on choline and creatine, which are considered indicators of cell membranes turnover and energy supply in the tissue, respectively. Since gliosis is often prominent in various degenerative disorders, short TE techniques (such as STEAM with TE 34 ms) should be used more widely in order to evaluate myoinositol, a putative marker of gliosis.
Neuroleptic malignant syndrome (NMS), which manifests as a severe form of rigidity, fever, and unresponsive-ness, is a potentially fatal idiosyncratic reaction to DRBD (Castillo et al. 1989). Patients should be monitored for auto-nomic stress, including temperature elevations, tachycardia, elevated creatine kinase (CK) levels, and mental stupor. Specific treatment must be individualized to each patient's presentation of symptoms and severity, but in general dantrolene, levodopa, and dopamine agonists have been useful in treating the signs of muscle rigidity and hyper-thermia (Fleischacker et al. 1990).
Carrier testing is available. EMG and muscle biopsy show signs of denervation. Nerve conduction studies are normal. While these tests are often done early in the diagnosic process, they are unnecessary if a genetic diagnosis has been established. Cerebrospinal fluid analysis and serum creatine kinase are normal.
There are reports of dystrophin deletions being identified indirectly. Melis and colleagues (Melis et al. 1998) reported three unrelated cases, after more detailed dystrophin molecular studies were undertaken, subsequent to an incidental finding of elevated serum creatine kinase levels. Dystrophin exon deletions of 32-44, 48-51, and 48-53 were identified, and adult male relatives from each family found to carry one of these deletions were either normal, or had very mild muscle involvement. In another chance diagnosis, a four-year-old female was found to be a carrier of a dystrophin exon 48 deletion, after she was originally referred for evaluation for a persistent elevation of aspartate aminotransferase (Morrone et al. 1997). Four male relatives, aged between 8 and 58 years, were found to carry the same mutation and as yet had exhibited no clinical symptoms.
ATP is involved in most cellular processes, so it is sometimes called a currency metabolite. ATP can also be converted to other high energy phosphate compounds such as creatine phosphate, or other nucleotide triphos-phates. in turn, these molecules provide the higher levels of energy necessary to transcribe genes and replicate chromosomes. Energy can also be stored in different chemical forms. Carbohydrates like glycogen provide a moderate density, moderately accessible form of energy storage. Fats have very high energy storage density, but the energy stored in them takes longer to retrieve.
On the other hand, a basal ganglia disorder is a view favored by some authors based on the clinical characteristics of the involuntary movements, the absence of EEG abnormalities during attacks, the occurrence of symptomatic PKC due to lesions, or conditions known to affect basal ganglia 10 . There has been support for this extrapyramidal theory based on special electrophysiological studies known to be abnormal in basal ganglia disorders. Abnormalities of contingent negative variation (CNV), which, normalized with phenytoin therapy in PKC, have been reported 54 , as well as abnormalities of the premotor (Bereitschafts) potential in the same disorder 11 . Abnormally decreased choline creatine ratios in the basal ganglia were found on magnetic resonance spectroscopy in PKC 55 , and increased perfusion of the thalamus was noted on SPECT scans 56 . Furthermore, increased CSF dopamine metabolites have been noted following an attack in both PNKD and PED 21,57 , and decreased presynaptic...
Deficiencies of either alpha-tocopherol or selenium also occur naturally leading to, for example, white muscle disease which is seen in farm animals or horses where a combination of inadequate soil selenium is combined with poor dietary ATC 217-226 , Concomitant changes in this disorder include reduced plasma glutathione peroxidase activities and increased serum creatine kinase activities 221,227 ,
We found that acute moderate alcohol exposure directly protected cardiac myocytes from ischemia-induced damage 32 , Under normoxic conditions over 3 hours of incubation, 10 of cells demonstrated osmotic fragility, indicating that isolated myocytes remained healthy. Under simulated ischemic conditions over 3 hours of incubation, 75 of myocytes demonstrated osmotic fragility. Ten minute exposure of myocytes to 50 mM ethanol before, but not during, simulated ischemia reduced cell damage by 35 . Exposure of cardiac myocytes tojust 10 mM ethanol throughout simulated ischemia reduced cell damage by 56 . Furthermore, 20 minute Langendorff perfusion of isolated rat heart with 10 mM ethanol reduced creatine kinase release after 45 minutes of ischemia and 30 minutes of reperfusion by 70 . Therefore, brief exposure to physiological levels of ethanol induced powerful
Biochemical findings were unremarkable in calves affected with ICM. Plasma and CSF concentrations of calcium, magnesium, phosphate, glucose, urea, protein, and albumin (plasma only) were similar to concentrations in clinically normal calves. In addition, investigators observed no differences between normal and affected calves in plasma activities of alkaline phosphatase, creatine kinase, aspartate aminotransferase, gamma glutamyl transferase, or ornithine carbamoyltransferase. Creatine kinase and aspartate amino-transferase activities in CSF were also unremarkable (Dennis, 1987).
HC-Ad vectors encoding the dystrophin cDNA were developed by several groups 5, 8, 14 . Two groups incorporated a muscle-specific muscle creatine kinase (MCK) promoter 5, 8 , allowing demonstration of striated muscle-specific expression of dystrophin from the vector. Direct intramuscular injection of these dystrophin-encoding HC-Ad vectors in the dystrophin-deficient mdx mouse model resulted in expression of recombinant dystrophin that properly localized to the muscle sarcolemma 7, 14 . Furthermore, dystrophin-associated proteins, which are lost in DMD and mdx muscle secondary to the primary absence of dystrophin, were restored in muscle fibers expressing HC-Ad vector-delivered dystrophin 54 . The prevention of dystrophic morphologic changes in muscle of mdx mice receiving an intramuscular injection of dystrophin-encoding HC-Ad vector was a second indicator of normal function provided by the recombinant dystrophin that was expressed from the HC-Ad vector 7 .
Creatine kinase (CREE-uh-tin KY-nase) obtains Pj groups from an energy-storage molecule, creatine phosphate (CP), and donates them to ADP to make ATP. This is a fast-acting system that helps to maintain the ATP level while other ATP-generating mechanisms are being activated.
Some 20 years ago, Peduzzi and Bizzozero (1977) showed that the thalli of certain fish-pathogenic SaproJegnia exhibit chymotrypsin-like activity and postulated that this enzymatic activity contributed to pathogenesis. The work was extended by Rand and Munden (1992), who reported high lipase and alkaline phosphatase activity surrounding the thalli of S. dicJina infesting the egg membrane of brook char. These enzymes may alter the integrity of the chorionic membrane by solubilizing structural polymers, thereby easing penetration of the thalli. Enzyme changes noted in SaproJegnia-infected brown trout include lactate dehydrogenase, glutamate-oxyalate transaminase (GOT), glutamate-pyruvate transferase (GPT), creatine phosphokinase, alkaline phosphatase and acid phosphatase, with the presumptive liver enzymes GOT and GPT being elevated, which suggests hepatocellular damage (Duran et aJ, 1987). Fish dying from SaproJegnia infection suffer a severe haemodilution, associated with elevated...
The diagnostic hypothesis developed by the history and clinical exam can be confirmed by ancillary testing. Ancillary tests can also be used to monitor the stabilization or progression of the disease, and the impact of therapies. Standard electrophysiological tests include NCV, EMG, and repetitive nerve stimulation. Laboratory tests, such as creatine kinase, electrolyte assessment, and antibody testing (e.g. myasthenia gravis, MG) may also be necessary. Genetic testing has become an important tool in the last twenty years, and can be used in many diseases to confirm a precise diagnosis. Some other tests, like autonomic testing (such as the Ewing battery and others) and quantitative sensory testing may not be available in some areas. Finally, neuroimaging can also provide information. MRI can be used to assess muscle inflammation and atrophy, and compression or swelling of peripheral nerves.
Recent research, particularly with human spermatozoa, has concentrated on the assessment of acrosin activity in the spermatozoon head, which is reported to have a significant bearing on the variation in fertility rates reported (Menkveld et al., 1996). Acrosin activity may be assessed via fluoresceinated lectin binding (Meyers et al., 1995a,b). Total acrosin activity reflects an aspect of functional ability of the spermatozoon, as opposed to the ultrastructure, and is reported to correlate positively with fertilization rates (Reichart et al., 1993 Sharma et al., 1993 Francavilla et al., 1994). Protein, fructose and potassium concentrations within seminal plasma have also been used as indicators of likely spermatozoon viability (Castro and Augusto, 1991 Oba et al., 1991). Tests assessing levels of spermatozoan creatine kinase and semen ATP indicate that differentiation between fertile and subfertile spermatozoa may be possible. However, the likely wide variation in ATP within equine...
Mattick JS (2004b) RNA regulation a new genetics Nat Rev Genet 5 316-323 McNaughton JC, Hughes G, Jones WA, Stockwell PA, Klamut HJ, Petersen GB (1997) The evolution of an intron analysis of a long, deletion-prone intron in the human dystrophin gene. Genomics 40 294-304 Melis MA, Cau M, Muntoni F, Mateddu A, Galanello R, Boccone L, Deidda F, Loi D, Cao A (1998) Elevation of serum creatine kinase as the only manifestation of an intragenic deletion of the dystrophin gene in three unrelated families. Eur J Paediatr Neurol 2 255-261
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