How To Take Creatine

Creatine Practical Guide.

Creatine: A practical guide evolved from the thousands of questions asked by professional and amateur athletes from around the globe. Learn How To Most Effectively Combine Exercise, Nutrition And Smart Creatine Use For Explosive Muscle Growth And Improved Overall Health. Here is just a small sampling of the many questions addressed by this e-book How long can I keep creatine on the shelf? Will I lose muscle after I stop supplementing? Not all creatine brands recommend the same amount. What gives? Is mixing creatine with protein powder a bad idea? Why do so many creatine brands contain so much dextrose? Is loading really necessary? Im currently taking Accutane for nodular acne. Is it safe for me to supplement? Will creatine stunt my growth? Im training twice as much these days and Im still not making any gains! Why? If creatine isnt a steroid, then how come it gave me a positive doping result? Will creatine shrink my package?!

Creatine Practical Guide Summary


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Creatine and Creatinine

Most of the creatine in the body is found in muscle, where it exists primarily as creatine phosphate. When muscular work is performed, creatine phosphate provides the energy through hydrolysis of its high-energy phosphate bond, forming creatine with transferal of the phosphate to form an ATP. The reaction is reversible and catalyzed by the enzyme ATP-creatine transphosphorylase (also known as creatine phosphokinase). The original pathways of creatine synthesis from amino acid precursors were defined by Bloch and Schoenheimer in an elegant series of experiments using 15N-labeled compounds (35). Creatine is synthesized outside muscle in a two-step process (Fig 2.5). The first step occurs in the kidney and involves transfer of the guanidino group of arginine onto the amino group of glycine to form ornithine and guanidinoacetate. Methylation of the guanidinoacetate occurs in the liver via S-adenosylmethionine to create creatine. Although glycine donates a nitrogen and carbon backbone to...


Creatine is the precursor of phosphocreatine, which transfers phosphoryl groups during mitochondrial ATP synthesis. Creatine kinase inhibits opening of the transition pore, which is a step involved in apoptosis, and therefore its modulation could have neuroprotective properties (7). In a study involving MPTP-treated mice, a prior two week creatine supplementation markedly reduced dopaminergic degeneration (8). Based on these observations, a randomized, placebo-controlled clinical trial in untreated PD subjects was initiated with creatine supplements, 5 g BID in a futility study design (9).

Investigation of the patient in coma

Brain imaging techniques, including computerised tomography (CT) and magnetic resonance imaging (MRI), are important in coma in providing evidence of diagnosis.27 CT has a very significant role to play in identifying those patients who have a structural cause for coma. MRI can be even more informative, though there are inevitable problems in inserting the patient in coma, together with the necessary life support systems, into the field of the magnet. Other, more complex techniques, such as intracranial pressure monitoring and cerebral blood flow studies are rarely of help in the diagnosis of medical coma their role in prognosis is not fully evaluated, and their usefulness is likely to be limited by their invasiveness.28 Measures of biochemical parameters in coma are predominantly diagnostic but some measures, such as brain type creatine kinase and neuron specific enolase in the cerebrospinal fluid (CSF), may help in determining prognosis.29,30

Effect Of Ceramide On The Ltype Ca2 Channels

Ca2+ channel current recordings were obtained using the whole cell version of the patch clamp technique (1-4,27). Patch electrodes were filled with a solution containing (in mM) 70 Cs2-aspartate, 20 HEPES, 11 EGTA, 1 CaCL, 5 MgC . 6H2O, 5 glucose, 5 ATP-Na2 and 5 K-succinate. Creatine phosphokinase (50U ml) and phos-phocreatine-Na, (20 mM) were added to the pipette solution to reduce current run down. The bath solution contained (in mM) 105 Tris Cl, 0.8 MgCL. 6H2O, 5.4 KCl, 20 BaCl2, 0.02 tetrodotoxin and 10 HEPES. 20mM Ba2+ was used as the charge carrier. The membrane currents were measured using an Axopatch 1B whole cell patch clamp amplifier (Axon Instruments, Foster City, CA). The data were sampled using pClamp software (pClamp 5.7) and a Digidata 1200 analogue-to-digital interface (Axon Instruments). Analysis was performed using the pClamp software. At a holding potential of -50mV and with Cs+ in the intracellular solution, hyperpolarizing pulses did not activate any currents....

Nucleoside and deoxyribonucleoside kinases

The DmdNK enzyme has some major advantages compared to other deoxynucleoside kinases in that it has not only a very broad acceptance for different nucleoside substrates but also a high catalytic rate it is stable even at higher temperatures and requires no reducing agents in order to maintain full activity. The synthesis of dCMP, dGMP, or dAMP occurs with approximately 80 yields in 60 h using ATP, Mg2+, and creatine kinase as phosphate donor regenerating system. The Drosophila enzyme has been used for commercial production of dideoxynucleotide analogs.17

Structural Components

Morphologically, the mitochondria are remarkably similar between species in terms of structure and function (1). Cells vary in the number of mitochondria in the cytoplasm and in the shape of these organelles. The liver cell contains 800 mitochondria, while bone cells contain fewer than 400 and erythrocytes contain none. In contrast, the ovum contains 2000-20000. Mitochondria are distributed throughout the cytoplasm in a nonrandom manner by cytoskeleton motors. High-energy dependent cells tend to have their mitochondria located close to where energy is needed. For example, muscle cells have mitochondria located in close proximity to the contracting muscle fibers. Muscle contraction requires considerable energy provided by creatine phosphate and ATP. Both of these high-energy compounds are synthesized in the mito-chondrial compartment. Cells that are rapidly dividing have mitochondria close to the nucleus and to ribosomes because de novo protein synthesis is highly dependent on the...

Autosomal Recessive Forms of Chorea

Blood tests reveal presence of acanthocytosis in the blood smear and elevated creatine kinase. Similarly, AOA2 may present with a combination of eye signs (gaze nystagmus, strabismus, impaired smooth pursuit), ataxia, extrapyramidal features, including chorea, dystonia and tremor, dysphagia and neuropathy with onset in childhood or adolescence 77 . Findings of elevated cholesterol, creatine kinase, and alpha-fetoprotein support the diagnosis. In some populations AOA2 is the most common inherited cause of ataxia after Friedreich's ataxia. Similar to AOA1 the mutant protein may be involved in RNA repair 98 .

Bayesian Analyses with More Than One Conditional Probability

Often there is more than one test result, or more than one set of pedigree information, or both, that can be incorporated as conditional probabilities in a single Bayesian analysis. For example, consider the pedigree in Figure 5-4a, in which the two maternal great uncles of the consultand were affected with Duchenne muscular dystrophy (DMD OMIM 310200),a severe X-linked recessive disease caused by mutations in the DMD gene (OMIM 300377). The con-sultand's maternal grandmother's carrier risk was 1 2, her mother's carrier risk was 1 4, and therefore the consul-tand's prior carrier risk is 1 8. Suppose that her carrier testing is negative using a highly specific test (an analysis for heterozygous deletions in the DMD gene) that detects 2 3 of carriers. Suppose also that her serum creatine phos-phokinase (CPK), which is elevated in two-thirds of carriers, is within normal limits. Taking into account her prior probability of 1 8, her normal molecular and CPK test results, and, in addition,...

Clinical Utility of Testing and Available Testing

The identification of a deletion in a DMD patient not only confirms the diagnosis but also allows accurate carrier testing for other family members. Carrier status is determined by gene dosage analysis, which is used to assess whether a female at risk of being a carrier exhibits no reduction or 50 reduction in band intensity in those bands that are deleted for the affected male relative. A 50 reduction (single-copy intensity) for the deleted band or bands on the autoradiograph indicates a deletion on one of her X chromosomes and confirms her carrier status. Either Southern blot or quantitative PCR can be used for gene dosage analysis. Dosage determinations permit direct carrier analysis and eliminate the inherent problems of Southern blot analysis without gene dosage (recombinations, noninformative meioses, unavailability of family members, and spontaneous mutations). This is important since unlike affected males, carrier females are generally asymptomatic, and creatine phosphokinase...

General description and structure of skeletal muscle

This is necessarily a brief description of the molecular basis of muscle contraction, and the reader is referred to Further Reading for more details of this process. The important point is that a supply of ATP is required at the point of action at the appropriate time. There is a 'buffer store' in the form of phospho-creatine, which is in equilibrium with ATP through the action of the enzyme creatine kinase (Fig. 4.10). Since this is an equilibrium reaction, any fall in the ATP concentration will lead to the formation of further ATP from ADP, using the energy of phosphocreatine. This section covers the major fuels used by skeletal muscle to form the ATP required for contraction, and for the many other functions involved in cellular metabolism.

Neuroacanthocytosis in Japan Review of the Literature and Cases

The mean age of onset was 30.5 (range 18-42) years and the male female ratio was 18 7. Involuntary movements consisting of oro-lingual-facial dyskinesias and choreiform limb movements were seen in over 90 of cases. Self-mutilation of the lower lip was also seen with the same incidence. Depression or absence of deep tendon reflexes was noted in almost all cases. Cognitive impairment with or without psychiatric symptoms was noted in 40 of cases. The degree of acanthocytosis of peripheral red blood cells varied from 6 to 80 (mean value 24 ). Serum creatine phosphokinase activity was increased in 86 . Computed tomography of the brain revealed symmetrical atrophy of the caudate nuclei in almost all cases examined. Forty percent of patients had seizures. The mode of transmission was predominantly autosomal recessive, but four families have been reported with apparent dominant inheritance. Sural nerve biopsy showed evidence of chronic denervation with axonopathy. Grouped atrophy of muscle...

Epidemiology and Genetic Inheritance of Probable Chorea Acanthocytosis

AD autosomal dominant, AR autosomal recessive, bizarre E bizarre erythrocytes, CPK creatine phophokinase, DTR deep tendon reflexes, F female, FH inherit family history and inheritance pattern, GM grand mal type of seizure, hypo hypoactive, IVM involuntary movements, M male, ND not described, NL normal, trait, Sz seizure, Selfmutil. self-mutilation AD autosomal dominant, AR autosomal recessive, bizarre E bizarre erythrocytes, CPK creatine phophokinase, DTR deep tendon reflexes, F female, FH inherit family history and inheritance pattern, GM grand mal type of seizure, hypo hypoactive, IVM involuntary movements, M male, ND not described, NL normal, trait, Sz seizure, Selfmutil. self-mutilation

Clinical Characteristics of Probable Chorea Acanthocytosis from 25 Early Cases

Laboratory examinations including routine blood and urine analyses were unremarkable. The most important hematological finding was of acanthocytes in the peripheral wet smear preparation, with a range of 6-80 of red blood cells and a mean value of 24 . Markedly raised serum creatine phosphokinase (CPK) was noted in 19 cases out of 22. These characteristics were quite similar to the clinical data described among cases from England by Hardie and associates 7 .

Polyneuropathies presenting after admission to the ICU

Electrophysiological testing, measurements of creatine phosphokinase, and sometimes muscle biopsy are again necessary to investigate the problem thoroughly. Complications of the sepsis and multiple organ failure syndrome, now termed the systemic inflammatory response syndrome, will be the underlying cause for the neuromuscular condition in most instances (Table.3). This is an important phenomenon, since the incidence of this syndrome in ICUs may be as high as 50 per cent.

Patients presenting with neuromuscular transmission defects after admission to the ICU

Intubation and placement on a ventilator is necessary. High-dose steroids and neuromuscular blocking agents to ease ventilation are given, often for a number of days. On attempted weaning from the ventilator, it will be noted that the patient has severe neuromuscular respiratory insufficiency and limb weakness. Ophthalmoplegia may be present. Creatine kinase levels are often considerably elevated. Repetitive nerve stimulation studies are usually normal. Sensory conduction is normal, as is motor conduction, except for a low-amplitude compound muscle action potential. On needle electromyography, motor unit potentials tend to be polyphasic and of low amplitude and short duration, indicating a primary myopathy. The muscle may be electrically unexcitable on direct stimulation, suggesting inactivation of sodium, chloride, or potassium channels. Muscle biopsy shows a loss of structure centrally in muscle fibers. This has been shown by electron microscopy to be due to destruction of the thick...

Question And Answer Session

ROSS I am challenging you to do so since you see these patients. But, my next point is a comment which I discussed briefly with you earlier and then hearing Dr. Baslow's presentation, you note that creatine is a major osmolyte in the brain. If creatine is truly a major osmolyte and fluctuates with this huge 15-20 percent decrease with hypoosmolality, how do we explain the maintenance of energy metabolism because creatine and phosphocreatine are one and the same thing in your hands And in Dr. Baslow's theory, he needs to demonstrate changes in energy metabolism. DR. VERBALIS So, how can a rat have normal motor transmission and normal motor function with a 30 percent decrease in a major excitatory amino acid in addition to a 20 decrease in creatine So, I believe that creatine, glutamate, aspartate, and NAA all have an osmoregulatory role which is separate from their other cellular roles, both metabolic and neurotransmission, and that it is possible to decrease one of these pools...

Myocarditis Mimicking Acute Myocardial Infarction

Myocarditis is not infrequently associated with chest pain, which is typically pleuritic in nature and related to accompanying pericardial inflammation. Patients with myocarditis may also present with angina-like chest discomfort, despite the absence of epicardial coronary artery disease. Myocarditis has been reported at autopsy in patients who presented with acute myocardial infarction, normal coronary anatomy, and documented coxsackie B viral disease.57 Because myocarditis is associated with focal or multifocal myocardial inflammation and necrosis, it is not surprising that it may be associated with increased serum concentration of creatine kinase, electrocardiographic repolarization abnormalities, abnormal QS waves, and segmental wall motion abnormalities on left ventriculography.57-61

Clinical Features And Endomyocardial Biopsy

Myocarditis may be diagnosed with a moderate degree of certainty when a constellation of clinical features is present a preceding viral illness, acute onset of symptoms, fever, peri-cardial inflammation, supportive laboratory abnormalities (increased erythrocyte sedimentation rate, leukocytosis, increased concentration of creatine kinase), and electro-cardiographic abnormalities. As previously discussed, however, fewer than 10 of patients present with 2 or more of these supportive clinical features. Further, endomyocardial biopsy, while serving as the most appropriate way to confirm the clinically suspected diagnosis, also has substantial problems as a diagnostic tool. It is invasive, costly, and samples only a tiny portion of the myocardium. Given the focal or multifocal nature of myocarditis, it is not surprising that substantial sampling error exists. Clinicians are increasingly reluctant to recommend routine endomyocardial biopsy, even when myocarditis is clinically strongly...

Magnetic Resonance Imaging

Contrast-enhanced MRI has also been evaluated.84 Nineteen patients with clinically suspected myocarditis and the combination of electrocardiographic abnormalities, impaired left ventricular function, increased creatine kinase concentration, positive troponin T values, and positive results of antimyosin cardiac scintigraphy underwent sequential contrast-enhanced MRI. Electrocardiographic-triggered, T1-weighted images were obtained before and after administration of 0.1 mmol kg of gadolinium. Global relative signal enhancement of the left ventricular myocardium relative to skeletal muscle was obtained and compared with measurements obtained in 18 volunteers. Global left ventricular enhancement was substantially higher in the myocarditis patients than in controls on days 2, 7, 14, and 28 after onset of acute symptoms. Although enhancement was generally focal during the initial studies, global enhancement was noted during the later times. Histologic verification of myocarditis was not...

Blood Markers Of Cardiac Injury

Cardiac biomarkers, particularly of the older variety, have rarely assisted in the diagnosis of myocarditis1 except for patients who present acutely.2 In that setting, increased concentrations of creatine kinase MB (CK-MB) have been observed. Myocarditis may be confused with acute myocardial infarction because the constellation of symptoms, abnormal electrocardiograms, and increased marker protein concentrations is similar to what is seen with acute infarction. The correct diagnosis often is delineated only by demonstration of normal coronary arteries and subsequent biopsy findings.

Rhabdomyolysis and acute renal failure

Necrosis' due to profound sedation this mechanism is aggravated by hypoxia, acidosis, and hypovolemia, which often coexist. The diagnosis is easy in the presence of a dramatic increase of the muscular isoenzymes aspartate transaminase, alanine transaminase, creatine phosphokinase, and lactic dehydrogenase. If urine analysis is performed during the early phase, large amounts of heme and myoglobin may be found ( Cpo i,.e.L a 1990).

MR Spectroscopy AAcetyl Aspartate AAA

Two approaches have been used to measure NAA (i) an absolute measure of concentration and using an external standard reference of known concentration and (ii) a ratio of NAA Cr which assumes that Cr (creatine phosphocrea-tine) remains stable in pathological situations. Although both approaches have produced robust evidence that NAA is reduced in MS lesions and normal appearing tissues, abnormalities of Cr may also occur (Fernando et al., 2004). Therefore absolute measures are preferable. A methodological approach of recent interest is the quantitation of whole brain NAA (Gonen et al., 2000). As a global marker of the progressive neurodegenerative process in MS it appears promising, although any changes observed are not anatomically localized and could represent abnormality in lesions,

Phosphorus32sodium Phosphate

This radiopharmaceutical was the most widely employed agent for the treatment of bone pain from osseous metastases between 1950 and approximately 1980. It is usually administered intravenously, but there are studies showing equal efficacy with oral administration, where absorption varies between 40 and 80 . Oral P-32, which is much less expensive than any of the radiotracers to be discussed (and therefore suitable for developing countries) was compared in 1999 with intravenous Sr-89 in an study sponsored by the International Atomic Energy Agency (IAEA). There was no significant difference found in response rates from P-32 or Sr-89 treatment both were about 90 efficacious. In the early years of P-32 utilization, it was employed after a week of androgen therapy in the belief that tumor and bone uptake would be stimulated. However, the data on which this supposition was made were flawed. Androgen administration can lead to severe side effects, such as spinal cord compression in the...

Heart and pericardium

The best approach for diagnosing myocardial contusion is controversial. An electrocardiogram is generally obtained for suspected myocardial contusion. Occasionally, a right ventricular injury pattern is detected. The sensitivity of the electrocardiogram can be improved with the use of right-sided leads, although this is not done routinely. Most patients with myocardial contusion show only non-specific ECG changes, such as sinus tachycardia or minor ST-T wave alterations. Thus the ECG results are relatively unreliable as a definitive test for this injury. The same applies to determinations of creatine kinase MB fractions. These have not been found not to be very specific for this injury, and their routine measurement in patients with blunt chest trauma is questionable ( ChrlsteD en Radionuclide imaging of the heart may allow the diagnosis to be made, but it is usually not immediately available. The best test currently available is the echocardiogram, which can detect significant areas...

Proton Magnetic Resonance Spectroscopy

Water-suppressed, proton MR spectra of normal human brain at long echo times reveal four major resonances one at 3.2 ppm from tetramethylamines (mainly from choline-containing phospholipids Cho ), one at 3.0 ppm from creatine and phosphocreatine (Cr), one at 2.0 ppm from -acetyl groups (mainly NAA), and one at 1.3 ppm from the methyl resonance of lactate (Lac). NAA is a marker of axonal integrity Cho and Lac are considered as chemical correlates of acute inflammatory demyelinating changes (Filippi et al., 2001). 1H-MRS studies with shorter echo times can detect additional metabolites, such as lipids and myoinositol (mI), which are also regarded as markers of ongoing myelin damage.

Magnetic resonance imaging and movement disorders

Proton magnetic resonance spectroscopy (MRS) allows the in vivo measurement of brain metabolism. Four major hydrogen-containing metabolites may be identified a) N-acetylaspartate (NAA), a marker of neuronal integrity b) creatine (Cr), which relates to general metabolism c) choline (Cho), which is altered by membrane turnover and d) myo-inositol (MI), a marker of glial cells. There was a widespread reduction in NAA Cr ratio in the pons, putamen, and cortical white matter in MSA patients compared to control subjects, representing widespread neuronal and axonal involvement (Watanabe et al., 2004). Compared to PD patients, MSA patients had significantly reduced NAA Cr ratio in the pons and putamen. Of interest, the pontine NAA Cr ratio was reduced in MSA patients even in the absence of structural MRI findings such as the ''hot-cross bun'' sign and putaminal rim hyperintensity (Watanabe et al., 2004). Both increased and decreased NAA Cr ratios have been reported in the substantia nigra...

Gauging response to therapy by Mrs Mrsi

The concentrations of a number of metabolites can suggest whether or not treatment of a brain tumor has been successful. Usually, the choline levels fall, whereas lipids and lactate may rise 32, 87, 88 with a good therapeutic response. In a study 89 of 24 children with brain tumors, those who responded to chemotherapy or RT also showed significantly lower choline and higher total creatine. Lipids and lactate, however, were lower among the responders than among those treated only by surgery or who did not respond to treatment. The only metabolite to independently predict active tumor growth was total creatine.

Intraoperative management

Blood samples should be taken for serum K+, arterial blood gases, and an initial creatine kinase. Hyperkalemia and acidosis can be corrected in the usual way. 10. A repeat creatine kinase measurement should be performed after 24 h as it is slow to rise compared with myoglobinuria, which occurs soon after the initial event. Masseter muscle spasm occurring after the administration of succinylcholine (suxamethonium) is generally regarded as a warning sign of malignant hyperthermia. Much of the controversy surrounding the significance of masseter muscle spasm stems from the difficulty in defining the spasm itself and that succinylcholine has been shown to increase jaw tension in normal patients. Unexpected difficulty with jaw opening after succinylcholine which hinders intubation by an experienced anesthetist should be considered as masseter muscle spasm, and the patient should be presumed to be potentially at risk from malignant hyperthermia. If feasible, the procedure should be...

Recognizing tumor recurrence as opposed to response to therapy

Using the ratio of choline at the biopsy site to creatine in normal brain tissue > 1.3, Rabinov et al. 95 22 successfully identified glioma as opposed to radiation effects in 16 of 17 cases. In a study by Ng et al. 96 patients with stable disease after RT of cerebral gliomas showed lower choline to creatine ratios (mean 1.2, range 0.4 - 2.1) compared to those with tumor recurrence (mean 3.0, range 0.9 - 9.5). However,

Two Patients with Choreaacanthocytosis ChAc 31 Patient

This male caucasian patient was born in 1963 of consanguineous parents. One younger sister had been diagnosed at age 28 as having NA. She died of suicide at age 39. At the time of her diagnosis, 2 of her 3 brothers, including patient 1, had mild signs on examination, but no symptoms. These two brothers had decreased tendon reflexes, elevated creatine phosphokinase (CPK) and acanthocytes in the

Anatomical and Functional Imaging 1121 Fdgpet and CT

Mukherji et al. 33 performed in vivo proton MRS to compare seven patients with squamous cell carcinoma of the upper aerodigestive tract (oral cavity, oropharynx, nasopharynx, six with primary and one with recurrent disease), and seven healthy volunteers. These authors5 found a high choline to creatine ratio in all the patients on 1D proton MRS while in six of the seven healthy participants there were no detectable choline resonances. Star-Lack et al. 34 used proton MRS6 to assess lymph node metastases in 14 patients with head and neck cancer, and compared these spectra to those from neck muscle tissue of six healthy volunteers. They also examined tissue oxygenation with a polarographic oxygen electrode. These authors found that choline to creatine ratios were significantly higher in the nodes (2.9 1.6) than in the normal muscle (0.55 0.21) (p 0.0006), and lactate was significantly higher in the cancerous nodes than in muscle (p 0.01). There was a negative correlation between tissue...

Observation Of Drug Effect Using

In a similar protocol, although with fewer patients, gabapentin and intrathecal brain derived nerve growth factor (BDNF) did not have an observable effect.31'32 Vielhaber demonstrated a relative increase in NAA in the motor cortex of patients with ALS after one month of oral creatine supplementation.24 Interestingly, creatine supplementation decreases the combined glutamate glutamine (Glx) spectroscopic resonance intensity in the SOD1 mouse suggesting that it may have anti-glutamatergic properties in vivo in this animal model.49 A drug effect on spectroscopic indices was not observed by Bowen in ALS 15 however, the experimental paradigm was different from the aforementioned in that there was a 2 week washout period of medication before the first scan, the follow-up scans were performed at a variable interval of 2-18 weeks after starting treatment, and two drugs were tested such that each patient started either riluzole or gabapentin.

Hypersensitivity Myocarditis

Clinically, patients may present with symptoms characteristic of a drug hypersensitivity reaction, including nonspecific skin rash, malaise, fever, and eosinophilia.120 More specific signs and symptoms referable to the heart include conduction abnormalities and tachy-arrhythmias, sudden death, and increased concentrations of cardiac enzymatic markers such as creatine kinase and the creatine kinase-MB isozyme.106,120,122, 123 Acute fulminant myocarditis with hemodynamic instability has also been described.106,116 The onset of hypersensitivity myocarditis after initiation of the offending medication is highly variable, with onsets hours to months after a medication is started.106,116

Impact Of Brain Death On The Heart

Brain death has damaging effects on the cellular and subcellular level of the myocardium.49 Myocardial preservation, therefore, begins with proper donor management and manipulation of the deranged neurohormonal milieu consequent to brain death. As early as 1954 it was noted that subendocardial hemorrhage occurs subsequent to brain death,50 and that EKG changes simulating myo-cardial ischemia occur in patients dying from intracranial hemorrhage, status epilepticus, meningoencephalitis, or traumatic brain herniation.51 Neuroendocrine changes consequent to anoxic brain death are marked by an initial hypertensive response due to catecholamine release, followed by progressive vasomotor tone collapse. Free triiodothyronine (T3), thyroxine (T4), cortisol, and insulin, TSH, and ADH decrease significantly within a few hours of the onset of brain death. Myocardial ATP, creatine phosphate, glycogen stores subsequently decrease and myocardial lactate increases. The rates of glucose, pyruvate, and...

Cerebral Involvement in McLeod Syndrome The First Autopsy Revisited

Abstract Patient WA was a member of the New Zealand S family with an XK gene deletion, and was among the first patients with McLeod syndrome (MLS) comprehensively assessed by Laurence Marsh and collaborators in the 1970s. He displayed some hyperkinetic movements from his third decade of life and within 20 years developed a full picture of MLS pathognomonic Kell phenotype, hepatosplenomegaly, cardiomyopathy, creatine kinase (CK) and liver enzyme elevation, muscle weakness and atrophy, neuropathy, dysarthria, dysphagia, chorea, and neuropsychiatric abnormalities. He died at the age of 50 years of unknown cause. The post mortem findings have not been fully reported up to now, although the autopsy study was the very first known of MLS. The neuropathological changes were largely limited to the striatum and consisted of bilateral neuronal loss and astrocytosis, more severe in the caudate nucleus than in the putamen. Only two other autopsy reports on MLS are available to date. These showed a...

Adverse Effects Contraindications and Drug Interactions

The most common adverse effects of lamivudine seen at doses used to treat HBV are mild they include headache, malaise, fatigue, fever, insomnia, diarrhea, and upper respiratory infections. Elevated alanine aminotransferase (ALT), serum lipase, and creatine ki-nase may also occur. The safety and efficacy of lamivu-dine in patients with decompensated liver disease have not been established. Dosage adjustment is required in individuals with renal impairment. Coadministration of trimethoprim-sulfamethoxazole decreases the renal clearance of lamivudine.

Transporterbased Pharmacokinetic Interactions

Dopamine, serotonin, glycine, taurine, L-proline, creatine, betain dopamine, serotonin, glycine, taurine, L-proline, creatine, betain Cystine, dibasic and neutral amino acid transporters Anion exchangers, Na+ bicarbonate cotransporters Na+ glucose cotransporters, inositol transporter, sodium iodide transporter, sodium-dependent vitamin transporters, choline transporter Neurotransmitter transporters including GABA, noradrenalin, dopamine, serotonin, glycine, taurine, L-proline, creatine, betain

MR diagnostics in colorectal cancer

An in vitro study by Moreno et al. 44 using proton MRS at 9.4T compared 23 pairs of normal colonic mucosa with adenocarcinoma of the colon. They found a partial overlap between normal and adenocarcinoma in the ratio of the area of 3.2 ppm (trimethylamine-containing compounds) to that of 0.9 ppm (methyl of fatty acids). They also pointed out the possibility of artifactual decrease in that ratio due to high triglyceride content of the normal colonic submucosa. On the other hand, these authors reported that the taurine (3.4 ppm) to creatine (3.0 ppm) ratio produced excellent discrimination between normal mucosa and tumors groups (p. 111).

MR diagnostics in pancreatic cancer

There are some investigations of human pancreatic cancer cells implanted in experimental animals. Kaplan et al. 60 found that pancreatic tumors evaluated using proton MRS in rats showed elevated taurine and lactate levels compared to normal pancreas, with creatine and glutamate low in pancreatic neoplasms.

Muscular dystrophies

Muscle enzyme - creatine kinase - is substantially elevated (several thousand units) especially in early stages. The enzyme is raised at birth and is significantly elevated in the female carrier aiding detection of this state and genetic counselling. Electrocardiogram is abnormal in 80 with conduction abnormalities and rhythm disorders.

Magnetic Resonance Spectroscopy

Proton MRS is the most commonly applied technique for brain tumors because of the high natural abundance of protons in tissue. For brain tumor proton spectroscopy, the metabolites of interest include N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lactate, lipids, and certain amino acids, such as alanine and succinate.37 MRS imaging (MRSI) and chemical shift imaging (CSI) provide phase encoding of spatial information and generate metabolite maps. Multislice MRSI competes with single-voxel MRS, in which a small portion of the lesion is interrogated rather than the whole tumor volume, which is more easily implemented, with brief imaging times (less than 10min volume element, or voxel) and commercially available software. Nevertheless MRSI, with its smaller voxel size (less than 1 cm3) and superior brain coverage, is necessary for complete characterization of heterogeneous brain tumors.

FFT requires for fitting which is nonunique the number of metabolites are guessed in advance

For example, with respect to brain metabolites, most authors have attributed peaks between 3.8 and 4.0 ppm to glutamine in the alpha region, and to the second creatine peak. Opstad et al. 26 As emphasized by Bottomley 16 , the areas of the peaks of most interest most often overlap with others (p. 3). The problem of overlapping metabolites was also shown to be of importance for prostate cancer diagnostics, as recently illustrated by Swanson et al. 32 who demonstrated that separating the overlapping polyamines from choline and creatine by in vivo 2D J-resolved MRS could be used to help detect the absence or presence of recurrent or residual prostate tumor (see Chapter 9).

An illustration of the performance of the FPT for a clinical MRS signal

In the middle panel it is seen that at N 4 512, the FFT has still not predicted even 70 of the NAA concentration at 2.0 ppm, and the ratio between creatine and choline (3.0 and 3.3 ppm) appears to be nearly equal, and thus wrong. In contrast, with the FPT at N 4 512, these three major peaks are now practically identical to those at full signal length. At half signal length (N 2 1024) at the bottom panel, the FFT has still not demonstrated the accurate ratio between creatine and choline at 3.0 and 3.3 ppm, respectively these two metabolites are still incorrectly appearing as almost equal. Moreover, the triplet of glutamine and glutamate near 2.3 ppm can be discerned at half signal length only by the FPT, and not by the FFT. By contrast, it is seen that at half signal length (N 2 1024) the FPT resolves with fidelity more than twenty metabolites, in which all peak parameters are accurately extracted, including the overlapping resonances. Furthermore, while the FFT demands the total...

CGMPIndependent Pathway

FIGURE 18.2 NO regulates cardiac function via a cGMP-independent pathway. NO and its derivative (ONOO-) cause negative inotropic and lusitropic effects by directly affecting calcium cycling proteins, mitochondria, and cell death. NO can nitrosylate the L-type calcium channel (ICa) and ryanodine receptor (RyR), leading to decreased calcium transience and contractility. NO and ONOO- can also inhibit sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA 2a) by nitrosylation and nitration, leading to negative lusitropic effects. Nitrosy-lation by NO can be rapidly reversed by reducing agents such as dithiothreitol (DTT) and mercaptoethanol. Reversal of nitration caused by ONOO- is not documented. NO and ONOO-decrease mitochondrial ATP product by inhibiting complexes of respiratory chain and mito-chondrial creatine kinase. Both can cause mitochondrial permeability transition and cyto-chrome C release, resulting in apoptosis. ONOO- can also cause DNA fragmentation, initiating apoptosis...

NO Regulates Mitochondrial Respiration

Hypertrophy increases sensitivity of mitochondrial respiration to complex IV inhibition by NO, and together with increased iNOS expression, may favor the development of heart failure in rats.78 NO also inhibits mitochondrial creatine kinase coupled to oxidative phosphorylation, leading to a decreased sensitivity of mitochondrial respiration to ADP, thereby reducing ATP formation.79 NO may decrease contractile reserves through inhibition of cytosolic creatine kinase.80 Prolonged exposure to NO results in persistent inhibition of complex I via S-nitrosylation.77 Endogenous peroxynitrite formation also can cause an irreversible inhibition of multiple respiratory complexes, activating the proton leak and permeability transition pore, decreasing mitochondrial respiration, and reducing contractility.81

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that also involves gene deletion and duplication. DMD is a devastating, progressive, muscle-wasting disorder that is usually not diagnosed before the age of 3, but often results in wheelchair confinement by age 12 and death in the early twenties. Manifestations of this disease include pseudohypertrophy of muscles, joint contractures, scoliosis, respiratory compromise, cardiomyopathy, and markedly increased serum creatine kinase (CK) levels resulting from leakage of CK from diseased muscle into the bloodstream. The brain is also affected and, consequently, the IQ range of DMD patients is approx 20 points below average. However, mental abnormalities are certainly not found in all patients. The use of oral prednisone has been demonstrated to improve the strength and function of patients with DMD (100,101). This observation indicates the significance of immune-modifying factors determining the clinical expression of inherited...

Muscular Aspects of Chorea Acanthocytosis

2.2 Elevation of Serum Creatine Kinase 227 Abstract We report new insights into muscular aspects in chorea-acanthocytosis (ChAc), a hereditary disease characterized by involuntary movements and amyotrophy with elevation of serum creatine kinase (sCK). In addition, we review the literature regarding muscular aspects of genetically-confirmed ChAc cases. All ChAc cases, except for one, showed sCK elevation, while clinical neuromuscular symptoms are variously reported in most. Conventional muscle stains, such as hematoxylin and eosin (H& E), nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR), and ATPase, showed mild neurogenic changes and or mild myopathic changes. Recently, evidence has accumulated of a primary myopathy in ChAc. Increase of tTGase-derived Ne-(-y-glutamyl)lysine isopeptide cross-links was shown in skeletal muscle as well as in erythrocytes 19 . It was also reported that nemaline rods were found within myofibres in a patient with ChAc 27 . Moreover,...

High Energy Phosphates

Creatine phosphate (CP) measured in hearts procured from (A) alive animals, (B) brain-dead, (C) brain-dead T3 treated, (D) brain-dead stored, and (E) brain-dead, T3 treated and stored. A vs. B p < 0.02, D vs. A p < 0.05. The CP in T3 treated animals remained unchanged or improved C vs. A ns and E vs. A p < 0.05. Fig. 3.10. Creatine phosphate (CP) measured in hearts procured from (A) alive animals, (B) brain-dead, (C) brain-dead T3 treated, (D) brain-dead stored, and (E) brain-dead, T3 treated and stored. A vs. B p < 0.02, D vs. A p < 0.05. The CP in T3 treated animals remained unchanged or improved C vs. A ns and E vs. A p < 0.05.

Mr Imaging Of Prostate Cancer Technique

Magnetic resonance spectroscopy is currently under evaluation in prostate cancer. Initial findings indicate that there is increase in the ratio of choline plus creatine to citrate in prostate tumour tissue. This has been used to determine the presence and localisation of tumour within the prostate and to improve the assessment of extra-glandular extension.

Nutrient Interactions

Many substances that are physiologically, but not nutritionally, essential are synthesized from specific essential nutrients. If the products of the synthetic reactions are present in the diet, they may exert sparing effects that reduce the need for the precursor nutrients. Less phenylalanine and methionine are required, particularly by adults, when the diet includes tyrosine and cystine, for which they are, respectively, specific precursors. Birds, which do not synthesize arginine, have a high requirement for this amino acid. Inclusion in the diet of creatine, for which arginine is a precursor, reduces the need for arginine. Effects of this type, however, have not been explored extensively (23).

The Il6 Response To Exercise

Interleukin-6 is produced in larger amounts than any other cytokine in relation to exercise. IL-6 is produced by many different cells, but the main sources in vivo are stimulated monocytes macrophages, fibroblasts and vascular endothelial cells 28 , indicative of its role in modulation of the immune system. Other cells known to express IL-6 include keratinocytes, osteoblasts, T cells, B cells, neutrophils, eosinophils, mast cells, smooth muscle cells 28 and skeletal muscle cells 29 . Until now, IL-6 has been considered a cytokine with immunomodulatory effects and immune cells have been regarded as the main cell source of production. However, during the past few years it has also been demonstrated that the level of circulating IL-6 increases dramatically (up to 100 fold) in response to exercise 2,30,31 . Northoff and Berg 32 were the first to suggest that IL-6 might be involved in the generation of the acute phase response post-exercise. They found an increase in IL-6 levels...

Rufefr LjHiifdiJO ff cy iipraJoy KM MflTWJ L iuli

Of course, weaning difficulties are encountered in neuromuscular diseases (e.g. Guillain-Barre syndrome and motor neuron disease). Persistent paralysis in critically ill patients receiving mechanical ventilation has been reported following administration of corticosteroids or the non-depolarizing muscle relaxants vecuronium and pancuronium. The etiology is not clear, as reported features are inconsistent. Electrophysiological, serum creatine kinase, and muscle biopsy studies have revealed a neuropathic process in some afflicted patients and a myopathic process in others. An increased concentration of a vecuronium metabolite and renal dysfunction in patients who have received long-term vecuronium administration have been proposed as causes. The term 'critical illness polyneuropathy' has been used for patients reported to have unexplained persistent muscle weakness during weaning from mechanical ventilation. Again, the etiology and clinical picture are unclear, but the

Blood Donors with McLeod Phenotype

Mcleod Phenotype

We found 182 cell donations with McLeod phenotype or Kmod and 286 with Ko. Kmod red cells express Kell antigens weakly, and Ko express no Kell antigens. XK protein expression is intact or even increased in these two phenotypes as opposed to the McLeod phenotype. To identify McLeod phenotype after screening, we examine the expression level of Kell antigens by flow cytometry (Fig. 3) cell morphology (acanthocytes) by scanning electron microscopy (Fig. 4) serum creatine phosphokinase (CPK) and haptoglobin (Hp) red cells of family members (especially mothers), and the XK gene. CPK creatine phosphokinase, Hp haptoglobin a Developed McLeod syndrome at 36 years old CPK creatine phosphokinase, N normal CPK creatine phosphokinase, N normal

Acute necrotizing myopathy of intensive care

Levels of creatine phosphokinase and often myoglobinuria, in ICUs. Electrophysiological studies were consistent with a severe myopathy, and muscle biopsy showed widespread necrosis of muscle fibers. Rapid and spontaneous recovery is expected in milder cases, but in more severe cases the prognosis may be poor We have observed mild elevations of creatine kinase and scattered necrosis of muscle fibers on muscle biopsy in some critically ill patients, suggesting primary involvement of muscle as well as denervation atrophy. This may be due to a reduction in bioenergetic reserves as measured by phosphorus-31 magnetic resonance spectroscopy, since in two of our patients the ratio of phosphocreatine to inorganic phosphate was much lower than would be expected from denervation of muscle

Phytochemicals As Nutraceuticals

Originally tannins were considered antinutritional factors they form complexes with proteins and starch inhibiting their absorption. They also inhibit digestive enzymes. Further, tannins have shown an impressive range of beneficial biological activities (Table 10.8).46 Tannins have antimicrobial activity that may be associated with the inhibition of microbial enzymes such as cellulase, pectinase, and xylanase, among others another explanation is related with toxicity by their action on the membranes of the microorganisms. Tannins accelerate bloodclotting and could be used to control hemorrhage in animals. Tannic acid reduces the venom-induced elevation of blood creatine kinase activity and prolongs the survival time of mice when injected immediately after the administration of venom. Additionally, tannin acid has been reported to reduce allergen levels in house dust and is marketed for that purpose as a 1 or 3 solution. It has also been reported that a significant number of plants...

Pharmacological treatment

Parenteral administration, at a dose of approximately half the oral dose, is indicated when the oral route is not available or when rapid onset of effect is desired. Intramuscular administration is effective, but repeated injections are painful, cause elevation of creatine phosphokinase levels, and are time consuming. Intravenous administration is preferred when frequent dosing is required, i.e. in a severely agitated patient where systematic escalation of the dosage will probably be required. Intravenous injection of haloperidol requires that the intravenous line be flushed first with saline, because haloperidol precipitates with both heparin and phenytoin. The rate of infusion is not critical, but should be extended over 5 min if the patient is hypotensive. When a given dose of intravenous haloperidol fails to calm the agitated patient, doubling the previous dose after 20 min is recommended. If the patient becomes calm, the effective dose should be repeated at the next dosing...

Correlations Between Naa And Fdgpet

Choline Creatine Ratio Radiology

Metabolic imaging of myo-inositol, Choline, Creatine and N-acetylaspartate in control. Figure 5. Metabolic imaging of myo-inositol, Choline, Creatine and N-acetylaspartate in control. In a 1H MRSI study of the effects of concurrent cocaine and alcohol dependence on the brain, we compared non-dependent controls to subjects dependent on crack cocaine alone and to subjects dependent on both cocaine and alcohol. Our findings included lower NAA concentrations in cocaine-dependent and in cocaine and alcohol-dependent subjects, especially in dorsolateral prefrontal gray matter and in posterior parietal white matter, suggesting damage to neurons and axons in these brain regions of substance abusers. In that study, it was not possible to determine whether effects observed in subjects dependent on both cocaine and alcohol were due to cocaine abuse, to alcohol abuse, or to both. To answer that question, we examined in a follow-up study a fourth group of individuals dependent on alcohol...

Imaging Of Dementia In Pd

Magnetic resonance spectrosopy (MRS) is increasingly being utilized to examine metabolite content in discrete regions of brain through determination of n-acetyl aspar-tate (NAA), choline (Cho), lactate (Lact), and creatine (Cr) in proton spectra. A significant increase in the Lact NAA ratio has been reported in occipital cortex with the most prominent rise in PDD.157 Enhanced glycolytic activity, reflected in the increased lactate content, is consistent with mitochondrial dysfunction as has been implicated in the pathogenesis of PD. Age, duration of disease, and medication exposure did not impact Lact NAA.157 Diminished NAA Cr has been reported in temporoparietal cortex in nondemented PD with the greatest change contralateral to maximum clinical impairment.158 As Cr content tends to change little, reduction in NAA Cr is believed to reflect decrease in the neuronal marker NAA. Whether this represents neuronal loss or dysfunction is a subject of speculation.159 In this study, a...

Myocardial Ischemia Basic Concepts

Loss of the activity of the respiratory complexes occurs during ischemia. Progression of the ischemic damage is shown to progressively inhibit the respiratory chain with complex I activity to be lower in less severe ischemia and complex IV activity to be reduced in severe ischemia.46 Mitochondrial changes during ischemia and reperfusion result in increased production and accumulation of reactive oxygen species. The energy transport from mitochondria to cytosol is also impaired. Adenine nucleotide translocase and mitochondrial creatine kinase activity (enzymes that are required for transportation of ATP from the mitochondria to the cytosol) is reduced with subsequent impaired ATP transportation into the sites of utilization. ATP in the mitochondrial matrix is hydrolyzed by the reversal of the ATP synthase, reviewed by Opie.45

Effects of Impaired Liver Function on Pharmacokinetic Parameters

During the clinical course of cirrhosis, secondary changes in the kidneys may give rise to renal insufficiency. The renal perfusion can be decreased and the reabsorption of sodium in the proximal tubule is increased in decompensated cirrhosis. In addition, in patients with decompensated cirrhosis, serum creatinine and creatinine clearance estimated from serum creatinine are not sensitive markers for renal function and often overestimate actual GFR 42 . This may be caused by a reduced hepatic production of creatine, the precursor of creatinine, or a reduced conversion of creatine to creatinine due to decreased muscle mass 43 .

Specific syndromes of drugs and toxins

A rare life-threatening disorder induced by initiation, increase or reintroduction of neuroleptic drugs (e.g. chlorpromazine, haloperidol). The condition appears to result from acute dopamine receptor blockade and is characterised by hyperpyrexia, bradykinesia, rigidity, autonomic disturbance, alteration of consciousness and high serum muscle enzymes (creatine kinase). The causal drug should be withdrawn and the patient cooled. Give dopamine agonists with dantrolene sodium to control bradykinesia and rigidity respectively. Death occurs in 15 from renal failure and or cardiovascular collapse.

Effects Of Heavy Drinking

We used quantitative MRI and multi-slice JH MRSI at a short echo-time to compare 46 chronic heavy drinkers (HD) and 52 light drinkers (LD) on regional, tissue-specific and atrophy-corrected concentrations of NAA, myo-inositol (mI), creatine- and choline-containing metabolites. Neuropathological and neuroimaging studies show cortical and subcortical volume loss in alcohol dependent individuals. The brainstem is considered critical in the development and maintenance of drug and alcohol dependence, but it has not been the focus of neuroimaging studies. Using quantitative MRI and JH MRSI, we compared the size and metabolite measures of potential cellular injury of the brainstem in 12 chronic, active heavy drinkers and 10 light drinkers. Chronic heavy drinking was associated with a significantly smaller overall brainstem volume and with significantly smaller midsagittal areas of the brainstem, midbrain, and pons. Heavy drinking was also associated with significantly lower ratios of...

Metabolism of skeletal muscle general features

OOC-CH2-N-C + h+ * Creatine X OOC-CH2-N-C Phosphocreatine Creatine (creatine phosphate) Fig. 4.10 The creatine kinase reaction in muscle. The reaction is referred to as the Lohmann reaction after the German biochemist who elucidated it. Creatine kinase operates near to equilibrium therefore, as ATP is utilised rapidly at the beginning of contraction, the phosphocreatine pool is used to maintain the ATP concentration. In resting muscle, typical concentrations of ATP and phosphocreatine are 5 and 17 mmol per kg of muscle therefore, the presence of phosphocreatine quadruples the ability to produce rapid contraction, before more ATP can be generated by other routes.

MRSI for localization of brain tumors

Clearly, maximum precision in localization is vital for treating tumors affecting the brain. This is facilitated considerably by MRSI. MRS-guidance based upon areas of increased choline to creatine ratios has improved the yield of diagnostic tissue obtained with stereotactic biopsy 81, 82 . It has been suggested that by using multivoxel MRS the area of highest choline can be identified, and that would be the ideal site for biopsy (p. 154) 17 . The feasibility of using MRSI for intra-operative decision-making was shown by Liu et al. 83 . As noted, even lower grade gliomas are frequently infiltrative with poorly defined margins. The degree of tumor infiltration for each grade of glioma was found by Croteau et al. 37 to be best defined by the ratio of mean aggregate choline concentration at the tumor to creatine concentration in the contralateral, normal brain tissue.

Clinical Features

Neuromuscular signs comprise peripheral neuropathy and myopathy 99 . Serum creatine kinase (CK) elevation may be detected before the appearance of neurologic signs or symptoms 78 . Muscle atrophy and weakness, as well as CK elevation, may be regarded as secondary to chronic denervation. However, a primary myopathic process is suggested by nemaline rods 133 or accumulations of tissue transglutaminase 85 on muscle biopsy, and a predisposition to rhabdomyolysis 102 . In symptomatic carriers of apparently a single mutation of chorein, accumulations of chorein may be seen along the muscle cell membrane 110 (see chapter by Saiki and Tamura).


In contrast to these data, Ishiyama et al.105 found nitric oxide expression played a critical role in the resultant pathologic condition produced in a rat model of autoimmune myocarditis, after induction with cardiac myosin. Rats treated with aminoguanidine, an inhibitor of iNOS, had only focal mononuclear infiltration and reduced numbers of cardio-myocytes positive for iNOS compared with untreated animals that had considerable inflammatory infiltration and myocyte damage. In addition, serum concentrations of creatine kinase were significantly decreased in the treated animals, indicating decreased muscle damage. In a separate study of autoimmune myocarditis in the rat,106 IL-2 appeared early, whereas IL-3, TNF-a, and iNOS were present later, during the period of peak inflammation. IL-10 was detected only once inflammation began to subside and persisted during recovery. These data support the notion that changes in the Th1 and Th2 responses are important for controlling outcome, as...


Another potential mechanism by which NO may inhibit myocardial energetics is to impair phosphoryl transfer by creatine kinase (CK).48 NO donor S-nitrosoacetylcysteine prevented a Ca2+-stimulated increase in rate pressure product in the isolated rat heart associated with a decline in ATP as measured by nuclear magnetic resonance. In vitro studies indicated that NO acted by reversibly modifying CK via S-nitrosylation.

Other Compounds

6.4.3 Creatine Phosphate Creatine is used to improve athletic performance. Patients with chronic heart failure develop skeletal myopathies.240 Muscle contraction and relaxation are fueled through the dephosphorylation of ATP, which must be rapidly resynthesized. Creatine serves as a phosphate donor to maintain high levels of intracellular ATP, and creatine supplementation increases the rate of phosphocreatine resynthesis.241 Skeletal muscle strength and endurance were improved in patients with chronic heart failure after short-term oral creatine supplementation, but no effect on cardiac contractility was noted.242 Creatine administered intravenously improved ejection fraction.243,244 The improvements in skeletal muscle function were seen predominantly in patients with low levels of creatine and phosphocreatine in their skeletal muscles.245 This was not a ubiquitous finding in patients with chronic heart failure.245,246 It is possible that creatine is of benefit in some chronic heart...


A product of creatine breakdown, it is predominantly derived from skeletal muscle and is also renally excreted. Low levels are found with malnutrition and high levels with muscle breakdown (rhabdomyolysis) and impaired excretion (renal failure). In the latter case, a creatinine value > 120 pmol l suggests a creatinine clearance < 25ml min.


In contrast to acute hyponatremia, many experimental studies of chronic hyponatremia have been characterized by a relative absence of neurological symptoms and mortality. These findings suggest that more complete degrees of brain volume regulation occur after longer periods of sustained hyponatremia. Studies in rats in which hyponatremia was maintained for 21 days confirmed virtually complete normalization of brain water content (11). However, in these and other studies the measured electrolyte losses accounted for only 60 to 70 of the observed brain volume regulation, which suggested a potential contribution from losses of other brain solutes as well. Subsequent studies confirmed that brain content of most organic osmolytes also decreases markedly during induced hyponatremia in mice (12) and rats (13,14). The organic osmolytes involved in volume regulation are amino acids, methylamines, and polyols. The major organic osmolytes in the brain are glutamine, glutamate, taurine, and...


There are no characteristic abnormalities in blood chemistry, although creatine kinase and liver enzymes may be elevated and the activity of enzyme carnosinase may be reduced. Myopathic changes are consistently present in muscle biopsy specimens. Histology reveals the 'chequerboard' distribution of muscle fibres but with a selective type 2 fibre atrophy. Electron microscopy reveals the presence of strikingly abundant glycogen granules between the myofibrils and under the sarcolemma.(88>

Metabolic Control

In muscle, the NADH NAD+ and the Ca++ may be more important than ADP influx with respect to the control of OXPHOS. The working muscle uses the energy provided by the hydrolysis of creatine phosphate as well as the hydrolysis of ATP. In muscle, OXPHOS regulation also depends on the activity of creatine kinase, the enzyme that catalyzes the production of creatine phosphate. It has been suggested that the creatine creatine phosphate ratio represents a sort of feedback signal for OXPHOS in muscle mitochondria (91). Because mitochondrial creatine kinase is likely to be displaced from equilibrium (a prerequisite for metabolic control), it may be that, in muscle mitochondria, OXPHOS is limited by the creatine kinase reaction.

Muscular changes

Muscle contraction and relaxation are slowed in hypothyroidism. Intramuscular metabolism is altered because of modification of Ca 2+-ATPase activity and fluctuations of cytoplasmic Ca2+. The activities of several enzymes involved in muscle glycogen synthesis and catabolism are variable. Some muscular enzymes (transaminases, creatine phosphokinase, lactic dehydrogenase, and their isoforms) are secreted in large amounts in the bloodstream, confusing an ECG diagnosis of myocardial infarction (B rgiand K nig 1988).

Abdominal organs

The main cause of death following electric shock is cardiac arrest, usually as a result of ventricular fibrillation ( Fontanaro.s.a.,1993). Both low and high voltages can produce life-threatening arrhythmias, with some developing several hours after the accident. High current flows (> 10 A) tend to cause asystole. Although myocardial infarction is rare, areas of necrosis in heart muscle and conducting tissue have been reported after electrocution. Diagnosis of cardiac injuries after high-voltage contact is difficult. ECG abnormalities (usually non-specific ST-T changes) may be transient or even absent, presumably due to the diffuse nature of the myocardial damage. Elevation of creatine kinase MB isoenzyme suggests cardiac injury, although under conditions of electrical stimulus it can be released from skeletal muscle. Patients at high risk of myocardial injury can be identified by extensive body surface burns and the presence of upper and lower body exit and entrance wounds....

MRBased Techniques

Magnetic resonance spectroscopy uses the same concepts as MRI, but instead of imaging the spatial relationships of tissues, the concentrations of specific chemical compounds within the tissue are imaged. The radiofrequency pulse sequence of the scanner produces a signal decay, the amount of which is ultimately determined by the chemical relationships in the tissue. These series of signals can be transformed into a spectrum, where the concentration of different chemical compounds is imaged via different color intensities. By using MRS, it is possible to image the concentration of different compounds in a particular region of interest such as the brain or the orbit. The most interesting compounds for tumor characterization are choline, creatine, N-acetyl aspartate, and N-acetylaspartyl glutamate.25 Choline and creatine are present in most cells, whereas N-acetyl aspartate and N-acetylaspartyl glutamate are localized predominantly in neurons. The ratios between these compounds help to...


With the marked improvement in monitoring during anesthesia, early diagnosis of a malignant hyperthermia crisis now occurs with a dramatic fall in mortality. The signs of malignant hyperthermia can be divided into two groups metabolic stimulation and muscle abnormality. Malignant hyperthermia is often described as a metabolic storm with increased CO2 production, falling SaO2, increased heart rate, often with dysrhythmias, increased core temperature, and metabolic acidosis. The signs associated with muscle involvement include masseter muscle spasm, generalized rigidity, marked rise in creatine kinase, myoglobinuria, and a rise in serum K +.

Intracellular events

Damage to the sarcoplasmic membrane leads to loss of Mg2+ and K+. If it is severe, larger molecules, namely creatine kinase and myoglobin, are also lost. As muscle is a major source of body heat, increased activity results in an increased core temperature. Thus a disruption of the normal control of Ca 2+ regulation within the cell results in the severe metabolic disturbances seen in malignant hyperthermia and accounts for the observed clinical signs and symptoms ( Fig. 1) (MacLennan and Phillips 1992).

Laboratory tests

A complete blood cell count, coagulation and serum chemistries (creatinine, liver and pancreatic enzymes, lactate dehydrogenase, lactate, creatine phosphokinase, glucose, and electrolytes) should be drawn. Rapid serum potassium and glucose determination is crucial, as is blood gas analysis. The arterial blood gas should be analysed without temperature correction. Drug and or alcohol screening and thyroid or adrenal gland function tests are obtained as indicated. Blood, urine, and sputum cultures should be obtained if sepsis is suspected. Radiography, including CT scanning, is performed as indicated. A baseline ECG is obtained.

Typical neuroleptics

Neuroleptic malignant syndrome is a rare life-threatening side-effect related to an apparent compromise of the neuromuscular and sympathetic nervous systems. ( ) It usually occurs at the initiation of treatment with a high-potency agent but may occur with any of the typical (or atypical agents) at any point. Immediate discontinuation of the medication is essential. The condition is characterized by muscle rigidity, breakdown of muscle fibres leading to large increases in plasma creatine kinase activity, fever, autonomic instability, changing levels of consciousness, and sometimes death. It may be treated by discontinuing all antipsychotic drug treatment, applying external hypothermia, supporting blood pressure, and administering a direct-acting dopamine agonist such as bromocriptine or pergolide, and sodium dantrolene, which blocks the release of intracellular stored calcium ions. After its successful treatment, an atypical antipsychotic should be used even though these agents,...

Technical Aspects

In the typical long TE (135-288 ms) MRS of the brain, resonance peaks from three metabolites predominate. The dominant peak is from the methyl groups of NAA or W-acetylaspartylglutamate (NAAG). NAA is localized exclusively to neurons and neuronal processes in the adult human brain11-13 and provides a useful marker of neuronal integrity. Metabolites giving rise to the other peaks include membrane constituents containing choline (Cho), and creatine and phosphocreatine (Cr) which are involved in energy metabolism.

Muscular exercise

The relation between energy production (heat plus work) and creatine phosphate breakdown in frog sartorius muscles poisoned with iodoacetate and nitrogen. Each point represents a determination on one muscle after the end of a series of contractions, with different symbols for different types of contraction. From Wilkie (1968). Fig. 9.15. The relation between energy production (heat plus work) and creatine phosphate breakdown in frog sartorius muscles poisoned with iodoacetate and nitrogen. Each point represents a determination on one muscle after the end of a series of contractions, with different symbols for different types of contraction. From Wilkie (1968). 1 ATP and creatine phosphate in the muscle. This is the short term energy store, amounting to about 16 kJ or so in the human body, perhaps enough for a minute of brisk walking.

Case Report

Laboratory assessments between the ages of 34 and 50 disclosed elevated creatine kinase (CK) levels that ranged from 788 to 3240 U l (normal < 200 U l) as well as slightly elevated levels of lactate dehydrogenase (LDH) (254-367 U l, normal < 250), Alanine transminase (ALT) (43-80 U l, normal < 55 U l) and aspartate aminotransferase (AST) (60-100 U l, normal < 48 U l). Gamma-glutamyl transpeptidase (yGT), in contrast, was within normal limits as were hepatitis markers, bilirubin, and alkaline phosphatase as well as serum cholesterol, triglycerides and lipoprotein electrophoresis, and haptoglobin. Hemoglobin was 14.0-16.0 g dl, MCV 87fl, and reticulocyte count 1.8-2.0 . Serum iron was 18 imol l, iron binding capacity 72 imol l, and ferritin 144 LLg l. Blood films showed 30-40 acanthocytes.


Attempts have been made to subdivide on the basis of pelvic or shoulder girdle onset - this has not been convincing. The creatine kinase (CK) is moderately elevated. Cardiac involvement does not occur (ECG normal). EMG studies show non-specific myopathic features. Muscle biopsy confirms myopathy with connective tissue proliferation. Differentiation This distribution of weakness in proximal muscles may be a feature of chronic spinal muscular atrophy, certain metabolic myopathies, polymyositis and Becker's dystrophy. Investigation is essential to classify correctly as EMG and muscle biopsy will distinguish these disorders.

Early Events

As discussed above, soon after its entry into dopaminergic neurons, MPP+ accumulates in the mitochondria (Fig. 3). Once in the mitochondria, MPP+ impairs oxidative phosphorylation by inhibiting nicotinamide adenine dinucleotide (NADH)-ubiquinone reductase activity (120) which, as shown by photoaffinity labeling, is due to the binding of MPP+ to the PSST subunit of complex I (121). In so doing MPP+ interrupts the flow of electrons along the chain of cytochromes and provokes an acute failure in adenosine triphosphate (ATP) formation. It appears, however, that complex I activity should be reduced by > 70 to cause a significant depletion of ATP in nonsynaptic mitochondria (122) and that, in contrast to in vitro, in vivo MPTP causes only a transient 20 reduction in mouse striatal and midbrain ATP levels (123). Still, it is likely that this transient perturbation does contribute to the cell death process since different strategies aimed at boosting cellular energy stores, such as...


CK creatine kinase PAS periodic acid-Schiff reagent. CK creatine kinase PAS periodic acid-Schiff reagent. to cause respiratory failure. The muscle enzyme concentrations, including creatine kinase, are markedly increased in the plasma, and the electromyogram (EMG) shows myopathic changes and spontaneous fibrillation. A muscle biopsy is necessary to confirm the diagnosis and will show massive muscle fibre necrosis and often numerous regenerating fibres but relatively little inflammation. The neurological picture is overshadowed by the development of myoglobinuria and acute renal failure. Causes of acute rhabdomyolysis are alcohol abuse, viruses (influenza, Coxsackie B5, echo 9, adenovirus 21, Epstein-Barr), Mycoplasma,40 and a wide variety of drugs, especially potassium-lowering drugs, amphetamine-like agents including Ecstasy (MDMA) and Speed (amphetamine sulphate), barbiturates, and the combination of the muscle relaxant pancuronium and corticosteroids.41 If the causative agent is...

CreoxP in the Heart

Because of the challenges discussed above, relatively few studies have been successful with specific Cre-mediated recombination in the heart since its development (Table 1). Early studies utilized the muscle creatine kinase (MCK) promoter, which generated expression in both the heart and skeletal muscle (146-148). Other studies have reported successful Cre-mediated recombination in heart tissue induced by the a-MHC promoter (117,124,149,150), but concerns of premature lethality cast doubt on the overall effectiveness of this approach because of possible premature expression during embryogenesis and lack of temporal inducibility should recombination occur at these stages.


Treatment of polymyositis with large doses of steroids is universally recommended and so clearly helpful, at least in the short term, that a controlled trial has never been considered necessary. A typical regimen87 is prednisolone 1 mg kg daily for four to six weeks followed by gradual withdrawal at the rate of 5 mg of the daily dose per week. After the dose has reached 25-35 mg daily further reductions should be made more slowly, perhaps at 5 mg every two weeks. A wide range of doses are used and we prefer an alternate day dose, but others feel that this is not so effective.87 It is important to bring the disease under control before beginning the reduction and then to monitor the course of the disease closely with serial measurements of muscle strength and plasma creatine kinase concentrations. Although PE combined with cyclophosphamide has been reported to be beneficial in polymyositis,88,89 the usefulness of PE alone was not confirmed in a controlled trial in which three groups of...


Canavan Disease

Using rat brain extracts, it has been shown that the concentration of NAA rises rapidly to adult levels between days 10 and 20 of life.37, 57 This is also the period of active myelination in this animal. The rise in NAA has also been demonstrated by in vivo 1H-NMR spectroscopy in developing rat brain.58 The developmental changes in NAA have also been assessed in human foetal and child brains by high-resolution 1H-NMR spectroscopy. NAA was detected in the cerebral cortex and white matter of foetuses as early as16 weeks' gestation. NAA increased gradually from 24 weeks' gestation with a marked rise from 40 weeks' gestation to 1 year of age. The developmental changes in tissue NAA of postnatal brains were found to be similar to those seen by clinical proton MRS.59 Furthermore temporal studies using in vivo proton MR spectroscopy of healthy preterm, term, and infant brain also demonstrated an increase in NAA with development.60 Since myelination is a period of rapid lipid synthesis, the...

Heart FABP

Heart and skeletal muscle utilize long-chain fatty acids to provide a majority of their oxidative requirements. Studies of the regulation of HFABP expression have, therefore, focused on conditions under which mitochon-drial P-oxidation is modified.84 For instance, higher levels of HFABP are expressed in red gastrocnemius muscle than white, and expression increases following endurance training, both situations that parallel the relative mitochondrial P-oxidation levels.84 107 109 In a murine muscle cell line, HFABP content was increased in differentiated relative to undifferentiated cells, in parallel with the expression of creatine kinase activity and fatty acid P-oxidation.110

Biochemical markers

Most laboratories record serum glutamine oxaloacetic transaminase (SGOT) or serum aspartate aminotransferase (AST) and creatine kinase (CK). The CK-MB form is more useful as it is specific to heart muscle. These enzymes are usually present by 6 h from onset, peak at 24 h, and fall to normal by 3 to 4 days. The height of the peak (which may be missed by infrequent sampling) is a good guide to the amount of myocardial necrosis. Serum lactate dehydrogenase is released more slowly and persists for longer (2-4 days). The CK enzymes can be fractionated further, and so it is possible to date the time of infarction onset by comparing the ratio of MM to MB subforms.