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

Creatine is a supplement claimed to increase muscle strength and increase body mass. In addition, it may have a protective effect on nerves. Both of these possible effects are relevant to MS. Creatine is made in the liver, kidneys, and pancreas. It is involved in generating energy for muscle cells and other cells in the body. Creatine is available as a dietary supplement and may be obtained in the diet by eating meat and fish. Limited clinical studies have been done on creatine. In healthy people, creatine supplements may improve performance for brief, high-intensity exercises. In one study of 16 people with MS, creatine supplements did not improve high-intensity exercise ability or increase the muscle stores of creatine (11). In people with diseases of the muscles (such as muscular dystrophy), limited studies indicate that creatine may increase strength, decrease muscle fatigue, and improve exercise capacity. Creatine usually is well tolerated when used in appropriate doses. Rarely,...

Cardiac Marker Protocols In The Ed

Cardiac markers have undergone an amazing transformation from aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) to the three cardiac marker families available at present for routine use in ED for the evaluation of the chest discomfort myoglobin, creatine kinase (CK) and the MB isoenzyme of CK (CK-MB), and the troponins I and T (cTnl and cTnT). Each of these has well known kinetics of release from dying myocardial cells and should be carefully applied to each patient as directed by timing of symptoms and presentation (7). Myoglobin has been touted as an early marker with a high negative predictive value but low specificity. CK and CK-MB represent the gold standard for the diagnosis of MI as defined by the World Health Organization criteria. The troponins are cardiac-specific proteins with high degrees of both sensitivity and specificity for myocardial necrosis. These serum markers of necrosis have been well studied in high-risk groups with a high prevalence of AMI....

The Initial Assessment

Early in the course of evaluation in the ED, initial cardiac biomarkers of necrosis are obtained. Myoglobin, cardiac troponin T or cardiac troponin I (cTnl), and creatine kinase-MB (CK-MB) are commonly used to detect myocardial necrosis. However, the sensitivities of these cardiac biomarkers obtained on initial presentation may be poor and are dependent on the time from the onset of symptoms to presentation, the duration of ischemia, and the amount of myocardial tissue involved. Serial testing of cardiac biomarkers in the ED has substantially improved the detection ofmyocardial necrosis in this setting (9).

Formation of phosphate conjugates

Phosphate conjugates are rare compared to sulfates, yet they are of primary significance in the metabolism of anticancer and antiviral agents impacting on endogenous nucleotides. Indeed, phosphorylation is an essential metabolic step in the bioactivity of these agents, and numerous in vitro and in vivo studies document their stepwise phosphorylation to mono-, di-, and triphosphates. Such reactions are sometimes, and correctly, labeled as anabolic (i.e., biosynthetic) ones.68'69 They are known or postulated to be catalyzed by some among the very many phosphotransferases (EC 2.7), for example adenosine kinase (EC 2.7.1.20), thymidine kinase (2.7.1.21), uridine kinase (2.7.1.48), deoxycytidine kinase (EC 2.7.1.74), deoxyadenosine kinase (EC 2.7.1.76), nucleoside phosphotransferase (EC 2.7.1.77), creatine kinase (EC 2.7.3.2), adenylate kinase (EC 2.7.4.3), nucleoside-phosphate kinase (EC 2.7.4.4), guanylate kinase (EC 2.7.4.8), and (deoxy)nucleoside-phosphate kinase (EC 2.7.4.13).

Reperfusion Monitoring And Infarct Sizing

As with reperfusion monitoring, the main focus of prognostic infarct sizing using biochemical markers has been ST elevation. In this group, biochemical markers including myoglobin, the MB isoenzyme of creatine kinase (CK-MB), cardiac troponin T (cTnT) or I (cTnI), and lactate dehydrogenase or its isoenzyme hydroxybutyrate dehydrogenase (HBDH) for assessing myocardial injury have been associated with important clinical outcomes such as death, (re)MI, and CHF. On the other hand, for NSTEMI patients there is a paucity of data associating important clinical outcomes with biochemical marker release. Although such relationships may be intuitive, there is at present little evidence from clinical trials. UA patients have reversible cell injury with ischemia, and therefore monitoring biochemical markers of necrosis will show no rise and limited prognostic information in these patients.

And L Kristin Newby MD MHS

A significant proportion ( 20 ) of patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery develop elevated levels of creatine kinase MB isoform (CK-MB) afterward. Large increases in the concentration of CK-MB after PCI are associated with the risk of death, myocardial infarction, and repeat revascularization. However, the prognostic significance of modest elevations (less than five times the upper limit of normal ULN ) after PCI remains controversial. It has been shown in some studies have shown that even minor elevations in CK or CK-MB levels (more than one time the ULN) after PCI are associated with worse outcomes, but other studies have shown no association between small elevations in CK or CK-MB (less than five times the ULN) and recurrent cardiac events. Following CABG, almost all patients have elevated levels of CK-MB and the clinical significance is less well established. However, clinical studies show that large elevations...

The Use Of Biomarkers For The Detection Of Druginduced Myocardial Injury

A more recent and promising approach for the detection of myocardial injury involves monitoring the serum concentrations of cytoplasmic enzymes (creatine kinase CK , MB isoenzymes of CK CK-MB , lactic dehydrogenase LDH , LDH isozymes) or other cellular components (cardiac troponin T cTnT and cardiac troponin I cTnl ) that are released from damaged myocytes into the circulating blood (18). Most of the initial observations that detected increases in serum levels of these substances were associated with the cardiac damage produced by MI. These potential biomarkers can be classified into two categories, according to whether they are normally present in small concentrations in serum. The natriuretic peptides represent an exception to this generalization, as increases in their plasma levels indicate a response to cardiac dysfunction rather than a direct expression of myocyte damage.

Pathophysiology And Problems Of Diagnosis

Cell) and then continuing once the troponin protein or complex has been released from the cell (8). This observation has implications for comparison of various troponin assays, as different antibodies demonstrate alterations in binding parameters to troponin degradation products. Much work, both by the manufacturers as well as the research community, remains to be done to resolve this lack of standardization of troponin assay systems (6). This is not an issue for cardiac troponin T (cTnT), as there is only one manufacturer and assay available and the assays for the MB isoenzyme of creatine kinase (CK-MB) mass have been largely standardized to allow reasonable comparison between the various manufacturer's assay platforms.

Diagnosis ofBlunt Cardiac Trauma

Concentrations of both cTnI and cTnT have been shown to be increased in trauma patients, especially following cardiac contusion (13-16). Blunt cardiac injury typically results from direct compression of the heart or decelerating forces delivered to the chest. Such cardiac injury may occur even after relatively low-energy trauma without other obvious injuries. In the large majority of patients with blunt chest trauma studied, small to moderate increases in cardiac troponin were found, implying that the extent of injury is small (14,15). The results of testing for cardiac troponin were able to differentiate the majority of patients with isolated increased creatine kinase-MB (CK-MB) values related to skeletal muscle damage from those with myocardial injury. In one representative study of 44 patients with blunt chest trauma, 37 trauma patients without cardiac contusion had increases in CK-MB without a rise in cTnI (15). In the six patients with evidence of cardiac injury by...

Clinical challenges to the development of ischemia markers

The challenge of evaluating a new more sensitive and specific marker relative to an imperfect gold standard was observed in the development of cardiac troponin. Katus et al. (45) initially reported the specificity of troponin T to be only 78 when compared to a creatine kinase-MB (CK-MB) standard for AMI. This conclusion was not congruent with the hypothesis that troponin T was highly cardiac specific relative to CK-MB. However, when patients with a clinical diagnosis of unstable angina were excluded, the sensitivity

General Overdose Management

Gastrointestinal Increased gastric acidity leads to peptic ulcer, nausea and vomiting. Central nervous system (CNS) Agitation, restlessness, tremors, seizures. Metabolic Reduced serum K and Ca (chronic osteoporosis 2 cups day, 100 mg day). Muscle Increased contractility, high creatine phosphokinse (CPK), rhabdomyolysis.

E CMPNeu5Ac Regeneration

Aldolase (NanA, EC 4.1.3.3) (102,103), CMP-Neu5Ac Synthetase (NeuA, EC 2.7.7.43), CMP kinase (CMK, EC 2.7.4.14), and creatine kinase (CK, EC 2.7.3.2) coupled with an a-2,3-sialyltransferase cloned from Pasteurella multocida PM70. As shown in Scheme 10, creatine phosphate was used as an energy source instead of PEP, because creatine phosphate is a cheaper, more efficient, and convenient energy source compared to PEP, especially in large-scale synthesis of glycoconjugates (104). ManNAc can be epimerized chemically from GlcNAc under basic conditions (pH 10), thus GlcNAc can also be used as a starting material in sialyloligosaccharide synthesis.

Clinical Manifestations

Skeletal muscle Muscular hyperactivity and rigidity leading to muscle damage, high creatine phosphokinase (CPK) levels, rhabdomyolysis myoglobinuria may lead to acute tubular necrosis (ATN) and acute renal failure (ARF). Gastrointestinal vasoconstriction Gut ischemia and mesenteric thrombosis may lead to bowel necrosis with pneumatosis intestinalis. Uteroplacental and fetal Spontaneous abortion, abruptio placenta, intrauterine growth retardation (IUGR), limb autoamputation, microcephaly, and low birth weight.

New Research Areas

Antiapoptotic agents (e.g., caspase inhibitors), anti-inflammatory agents (e.g., minocycline 87), bioenergetic enhancers antioxidants (e.g., creatine, coenzyme Q, lipoic acid, dicholoroacetate, cystamine), excitotoxic anatgonists (e.g., riluzole 88, remacemide 89), histone deacetylase inhibitors (sodium butyrate and suberoylanilide hydroxamic acid), and transcriptional inhibitors (e.g., mithramycin 90) have all been examined in the R6 2 mouse model of HD and have shown some benefit.84 Some of these agents have been advanced to clinical trials (Table 2). Aggregation inhibitors are also a target.85

Unmet Medical Needs

Since the approval of riluzole, at least 10 therapeutic approaches which showed promise in preclinical models have been tested in the clinic but have failed or shown equivocal results (such as for insulin-like growth factor-1). These include neurotrophic factor replacement strategies (ciliary neurotrophic factor, BDNF glial-derived neurotrophic factor, and insulin-like growth factor-1), glutamate NMDA receptor antagonists (topiramate, dextromethorphan) or putative glutamate modulators (gabapentin, lamotrogine, N-acetylcysteine), antioxidants (vitamin E), MAO glyceraldehyde phosphate dehydrogenase inhibitors (selegeline), and mitochondrial transition pore blockers (creatine).86'87'95 Insulinlike growth factor-1 has shown improvement in quality of life and benefit in ALS patients.97

Antiinflammatory agents

Minocycline 87, a tetracycline antibiotic with anti-inflammatory activity, appears to have multiple effects on cell function, including inhibition of the mitochondrial permeability transition-mediated release of cytochrome c, an event key to the initiation of the apoptotic cascade. Additional activities of minocycline include inhibition of reactive microgliosis, caspase-1, caspase-3, and nitric oxide synthase transcriptional upregulation, and of p38 MAPK activation. It protects against motor neuron loss in a mouse ALS model (SOD-1 G93A) alone or in combination with creatine.87 The COX-2 inhibitor, celecoxib 44, preclinically slowed motor neuron deterioration in an organotypic model of motor neuron disease and improved survival up to 30 following oral administration in an ALS transgenic model.87 COX-2 is upregulated in both the transgenic SOD-1 G93A mouse model and in the CNS of ALS patients.86 COX-2 catalyzes the conversion of arachidonic acid to prostaglandin E2, a proinflammatory...

Section 2 alternative splicing

RNA splicing is very important for the maintenance of gene functions and regulation of the expression of certain genes. The mutations that affect RNA splicing can cause approximately 15 of all genetic diseases. The same pre-mRNA can be spliced variously in different tissues, cell types, and at different developmental stages, and react to various biological signals. So far only about 30,000 genes have been identified, compared with previous estimates of 100,000 or more. This indicates that one gene encodes more than one distinct mRNA hence, more than one protein may play a critical role in expanding the function of our genomes. The usage of alternative splicing can switch on and off the expression of a certain gene. In this case, one functional protein is produced by a splicing event, and the nonfunctional proteins resulted from other splicing events. A single gene can produce several different kinds of proteins, when different splicing possibilities exist. In one extreme case, the...

Klein LW Kramer BL Howard E Lesch M Reference

To assess the incidence and clinical significance of elevated total plasma creatine kinase (CK) and MB isoenzyme fraction after apparently successful coronary angioplasty, a prospective study of 272 consecutive elective procedures was undertaken. Total CK (normal < 200 lU liter) and CK MB isoenzyme (normal 4 ) were measured immediately after successful completion of the procedure and every 6 h for 24 h. All nonelective procedures results not fulfilling all American Heart Association American College of Cardiology Task Force guideline criteria for a successful result were excluded from analysis. 2. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996 94 1528-1536.

Poct Systems For Cardiac Markers

The cardiac markers available for routine clinical measurement by POCT comprise myoglobin, creatine kinase (CK) and its MB isoenzyme (CK-MB), cTnT, cTnl, BNP, and CRP. Prototype systems have been described for other markers including fatty acid binding protein (17). Although these measurement systems are designed primarily for use in the POCT environment, this distinction is artificial. POCT systems are equally usable in the emergency laboratory, in a satellite laboratory where low throughput precludes the use of a large assay platform, in the main laboratory when the main assay platform does not support the tests required, or when a stat capability is required. They can be divided into four categories.

Musculoskeletal System

Acute alcoholic myopathy (rhabdomyolysis) may cause painful, tender swelling of one or more large muscle groups. Diagnosis depends on a high index of clinical suspicion, elevation of serum creatine phosphokinase, and myoglobinuria. Chronic alcoholic myopathy may accompany alcoholic polyneuropathy, presenting as painless, progressive muscle weakness and wasting.

PAPPA as a Marker for Plaque Stability

Pathophysiology ofatherosclerosis with respect to lesion development, progression, and destabilization. A variety of biomarkers with distinct pathophysiological profiles can be used to assess disease activity. ICAM-1, intracellular adhesion molecule-1 VCAM-1, vascular cell adhesion molecule-1 HGF, hepatocyte growth factor CKMB, creatine kinase-MB. Fig. 2. Pathophysiology ofatherosclerosis with respect to lesion development, progression, and destabilization. A variety of biomarkers with distinct pathophysiological profiles can be used to assess disease activity. ICAM-1, intracellular adhesion molecule-1 VCAM-1, vascular cell adhesion molecule-1 HGF, hepatocyte growth factor CKMB, creatine kinase-MB.

Crosssectional Studies Of Quantitative Mr Techniques In People With The Clinical Diagnosis Of Ad

Proton MR spectroscopy (1H MRS) is a diagnostic imaging technique that is sensitive to the changes in the brain at the cellular level. With 1H MRS, several of the major proton-containing metabolites in the brain are measured during a common data acquisition period. The metabolite -acetyl aspartate (NAA) is a marker for neuronal integrity. NAA decreases in a variety of neurological disorders, including AD (15-19). The decrease of NAA or the NAA creatine (Cr) ratio shows a regional variation in AD (20-22). In patients with mild-to-moderate AD, NAA Cr levels are lower than normal in the posterior cingulate gyrus, whereas they are normal in the medial occipital lobe including the visual cortex (Fig. 2 ref. 23). This regional pattern is in agreement with the distribution of the neurofibril-lary pathology, and the associated neuron loss in people with mild-to-moderate AD, indicating that regional NAA Cr levels are potential surrogates for disease progression. Another metabolite that is...

CRP as a Marker of Mid to Long Term Prognosis

As for myocardial necrosis markers (i.e., creatine kinase CK ), peak CRP levels during in-hospital course of AMI have clinical implications, predicting cardiac rupture (30) and mortality (30,31), however, on a different pathophysiological basis. In fact, while CK and other markers reflect the amount of myocardial damage, CRP levels are only partially related to the amount of necrosis, being associated with clinical presentation and possibly with an individual response, as patients with preinfarction angina have higher CRP levels (32). In experimental AMI models, human CRP binds to damaged cells, activates complement, and enhances infarct size, playing a central role in mediating cellular damage during prolonged ischemia (8). This observation may help to explain the increased risk of death and cardiac rupture in patients with high CRP peak levels (30,31).

Magnetic Resonance Imaging MRI and spectroscopy

Differences in the magnetic properties of bulk cylinders like extramyocellular lipids (EMCL) and spherical vesicle-accumulated intramyocellular lipids (IMCL) give the potential to separate these two compartments. This phenomenon was observed for the first time in the early 1990s (Schicket al. 1993) and confirmed by theory (Boesch et al. 1997 Boesch & Kreis 2001) and model experiments (Szczepaniak et al. 2002) later on (Figure 13.7). Successful validation by histological and biochemical analysis of biopsies (Howald et al. 2002) and the increasing accessibility of MR equipment have led to numerous metabolic studies ever since (Krssak & Roden 2004 Boesch et al. 2006). For quantification purposes, the signal of tissue water (Boesch et al. 1997 Szczepaniak et al. 1999) or skeletal muscle creatine (Rico-Sanz et al. 1999) is taken as the internal reference. Lipid concentration can be given in these relative units (Krssak et al. 1999) or, assuming certain hydration or creatine...

Safety concerns with statins

The most important adverse effect has been the incidence of muscle pain or weakness (myopathy) and, in its severest manifestation, rhabdomyolysis, observed with all statins. Rhabdomyolysis can lead to hospitalizations and, in rare cases, renal failure. While these skeletal muscle effects occur fairly rarely (< 0.1 ), sizable numbers of patients have experienced these effects because of the large treated patient population. The incidence of skeletal muscle side effects is more pronounced at higher doses, particularly with higher potency inhibitors, which raises additional concerns as more aggressive lipid lowering is utilized to improve clinical outcomes. Patients who complain of muscle soreness are monitored for excessive plasma levels of creatine phosphokinase (CPK), and elevations in CPK 10 times above the

Prognostic Role of BNP and NTproBNP Across Spectrum of ACS

A substudy ofthe Orbofiban in Patients with Unstable Coronary Syndromes-Thrombo-lysis in Myocardial Infarction 16 (OPUS-TIMI 16) trial was among the first to evaluate the prognostic capabilities of BNP in a large population of patients across the entire spectrum of ACS (45). In this study, BNP was measured in 2525 patients at a mean of 40 h after presenting with STEMI, NSTEMI, or unstable angina. BNP levels on admission correlated with age, male gender, white race, hypertension, CHF, peripheral vascular disease, hypercholesterolemia, and smoking status. In addition, elevated levels of BNP were associated with Killip class > 1, electrocardiogram (ECG) changes, elevated creatine kinase-MB, and chronic kidney disease. A plasma concentration of BNP > 80 pg mL was a powerful

Stone GW Rogers C Hermiller J et al Reference

348 grafts were randomized to the FilterWire EX compared to 319 patients with 334 grafts in the GuardWire group. All patients received 325 mg of aspirin and were loaded with either 300 mg of clopidogrel or 500 mg of ticlodipine within 4 h after the procedure. The use of glycoprotein Ilb IIIa inhibitors was left to the individual operator's discretion. Device success rates for the devices were 95 for the FilterWire and 97 for the GuardWire. There was no statistically significant difference in the end point between the two devices (Figure 1). Postprocedural measures of epicardial coronary blood flow, procedural complications, and postprocedural creatine kinase myocardial band (CK-MB) release were similar between the two groups however, the use of glycoprotein IIb IIIa inhibitors for bailout was slightly higher in the GuardWire group.

The Blood Analysis Method for Assessing Kidney Function Using Naturally Occurring Substances

Creatinine is produced continuously in the body by the spontaneous breakdown of creatine (a constituent of muscle) to creatinine. It is scarcely broken down at all in the body (at least in normal subjects) and is excreted unchanged in the urine. An increase in plasma or serum creatinine concentration is undoubtedly the most commonly used screening test for early kidney impairment. Furthermore, a doubling of serum cre-atinine concentration does indicate that renal function is reduced by approximately half a five-fold increase indicates that renal function is reduced to approximately one-fifth and so forth similar to the idealized relationship described earlier. Normal serum creatinine concentrations are less than 1.5 mg per ml (in men) or 1.4 mg per ml (in women). First, creatinine is derived not only from the spontaneous breakdown of muscle creatine but also from the diet. For example, meat contains creatine, and if the meat you eat is well cooked, some or all of this creatine will be...

In Cardiomyocytes Of The Failing Heart

Total high-energy phosphate stores (creatine phosphate, adenosine triphosphate) are also depressed in the failing heart. Creatine kinase activity is reduced the expression of creatine kinase subunit B is up-regulated. Mitochondrial function is altered, and myocardial substrate utilization switches from free fatty acid to glucose. This imbalance between myocardial energy supply and demand impairs both cardiac contraction and relaxation (11).

Reduction of Side Effects of Chemotherapeutic Agents

A general supportive measure, as well as a means of diminishing additional oxygen radical damage occurring during chemotherapy and radiation. For example, the nephrotoxicity of cisplatin, believed to be caused by the stimulation of oxygen radical production in the kidney, was prevented by selenium in rats if administered one hour prior to the cytostatic agent (52-54). In humans, selenium protected even when given after cisplatin In patients with ovarian cancer treated with cisplatin, sodium selenate and vitamin E prevented the rise of Creatine Kinase serum values, an indicator of kidney damage (55). In addition, the selenium treatment prevented the drop of the leukocyte counts in these patients so that blood transfusions were not required. In other studies sodium se-lenite was shown to reduce the cardiotoxicity of adriamycin (56, 57) caused by oxidative damage of the cardiac muscle. The reduction of toxic side effects by sodium selenite also extends to cytotoxic agents not necessarily...

Monocyteplatelet Aggregates As A Marker Of

Standard diagnostic markers of acute MI (AMI), such as the MB isoform of creatine kinase (CK-MB) and cardiac troponin, reflect the onset ofmyonecrosis rather than the early underlying etiological processes of plaque rupture, and platelet activation. Such markers of myonecrosis do not appear in the peripheral circulation until at least 4 hours after the onset of ischemic injury. However, monocyte-platelet aggregates are elevated < 4 h following the onset of symptoms of AMI (Fig. 2) (9) and thus serve as an early marker of AMI, potentially offering the opportunity to facilitate early treatment to reduce morbidity and mortality.

Site Analysis Using Docking and Minimization

Figure 2 Site analysis of trypsin (1ppc) using docking and clustering. The surface of trypsin is in gray ligand (NAPAP) is in gray sticks too. Fragment of NAPAP is docked. The most distant cluster representatives are shown as green creatine phosphokinase models. The cluster representative closest to the position of the fragment in NAPAP is in light-green sticks other members of the same cluster are in a darker shade of green. Figure 2 Site analysis of trypsin (1ppc) using docking and clustering. The surface of trypsin is in gray ligand (NAPAP) is in gray sticks too. Fragment of NAPAP is docked. The most distant cluster representatives are shown as green creatine phosphokinase models. The cluster representative closest to the position of the fragment in NAPAP is in light-green sticks other members of the same cluster are in a darker shade of green.

Proton Mr Spectroscopy

To our knowledge, only three reports on H-MRS in adult KD have been published. In 2000, De Stefano et al. (10) described symmetrical moderate choline creatine elevation in the voxels located inside, at the margin, and outside the T2-weighted MRI signal abnormality in the subcortical white matter of both motor strips. In this 44-yr-old female with slowly progressive gait disturbance since the age of 42, N-acetylaspartate (NAA) was still the dominant peak. The NAA creatine ratio was within normal values. In 2000, Farina et al. (11) described similar diffuse H-MRSI abnormalities in the white matter of the centra semiovalia in two siblings with adult KD. These two authors used the same multivoxel point-resolved spectroscopy (PRESS) technique with a nominal voxel resolution of 2 mL. The choline creatine ratio was elevated, and NAA was mildly decreased compared with the adjacent cortical gray matter. The choline NAA ratio was close to one not only in the voxel within the T2-signal...

Markers of graft damage

In the early days of heart transplantation in the 1970s, before the advent of cyclo-sporine, conventional serological markers of cardiac damage, such as lactate dehydrogenase and creatine kinase, were used as markers of graft failure. However, they lacked sensitivity and were often found to be elevated too late to serve as an effective prompt to the treatment of cardiac allograft rejection. Troponin is a contractile regulatory complex found in striated and cardiac muscle. It consists of three distinct polypeptide components troponin C (the calcium-binding element), troponin I (the actinomyosin ATPase inhibitory element) and troponin T (the tropomyosin-binding element). The complex serves to regulate the calcium-dependent interaction of myosin and actin, and, thus, plays an integral role in muscle contraction. In the 1990s, specific enzyme immunoassays were developed against cardiac-specific isoforms of troponin T and I, which show little cross-

Importance of Novel Biomarkers

Proportion of patients with positive marker strategy at time of presentation (A) and risk of death or MI at 30 d (B) stratified by marker status in Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I study. Myo, myoglobin Freq, frequency. (Data are from ref. 20.)

Simple Multimarker Approaches Combining Markers of Necrosis

No available biomarker of necrosis offers the ideal properties of a very rapid early rise in conjunction with very high sensitivity and specificity (see Chapter 1). Thus, investigators have proposed the combined assessment of a marker with very rapid kinetics, such as myoglobin, along with a more specific marker of necrosis, such as troponin, to facilitate the diagnosis of MI. For example, in a study of 1005 patients with possible myocardial ischemia admitted to chest pain units, simultaneous quantitative testing for myoglobin, creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) reduced the time to detection of marker elevation (2.5 h) compared to either a strategy using only CK-MB and troponin (2.8 h) or local laboratory-based testing of CK-MB (3.4 h) (20). In addition, this multimarker strategy using markers of necrosis was positive in a larger proportion of patients (19 vs 5 ) at presentation (Fig. 2A) and showed a more robust discrimination of the risk of death or MI than...

Paul O Collinson Md Frcpath FACB

Point-of-care (POC) testing offers the opportunity to provide more rapid measurement of cardiac biomarkers in the environment in which clinical decisions about patient management are made. The technology of POC testing utilizes whole blood to measure one or more analytes including cardiac biomarkers such as creatine kinase-MB isoenzyme, myoglobin, cardiac troponins T and I, and B-type natriuretic peptide. Measurement methods include immunochromatographic separation usually combined with a quantitative reader, dedicated heterogeneous immunoassay systems, and those suitable for POC and emergency laboratory testing. Analytic performance of these systems approaches but does not always equal those of conventional laboratory methods. Evaluation of POC testing of cardiac biomarker measurement has shown good analytic and clinical diagnostic performance. These systems are entirely suitable for rule-in diagnosis of myocardial infarction (MI). Although POC testing has also been shown to be...

Methodological Aspects

The current available technology for POC testing can be divided into three categories (Table 1) visually read test devices, dedicated POC instruments, and instruments suitable for either POC testing or use in the emergency stat laboratory. The first developments in cardiac POC testing evolved from glucose test strip methodology using initially serum, then whole-blood measurements of creatine kinase (CK) and its MB isoenzyme (CK-MB). These methods were superseded by the development of immunoassay formats based on whole-blood separation and antigen-antibody complex formation, streptavidin-biotin binding ofthe complex, and visual detection. The antibody is labeled with gold (goldlabeled optically read immunoassay GLORIA ) or a dye. This produced the first generation of POC testing cardiac marker testing, often referred to as stick testing (Fig. 2). Although visually read test devices have been shown to be suitable for routine clinical use, they are more prone to operator error. Visually...

Neurochemistry Of Proton

Spectra acquired from white matter at (A) short echo time (TE 30), demonstrating NAA, choline, creatine, as well as a-glutamine glutamate, y-glutamine glutamate, and myo-inositol peaks and (B) long echo time (144 ms), demonstrating NAA, choline, and creatine. Fig. 2. Spectra acquired from white matter at (A) short echo time (TE 30), demonstrating NAA, choline, creatine, as well as a-glutamine glutamate, y-glutamine glutamate, and myo-inositol peaks and (B) long echo time (144 ms), demonstrating NAA, choline, and creatine. 3.2.3. Creatine 3.02 ppm Creatine is a measure of energy in brain tissue, serving as a buffer in the ATP-ADP reservoir and as a reserve of high-energy phosphates (17,18). It is a fairly stable metabolite and is often used in metabolite ratios as an internal reference. However, creatine levels too can drop, often in the setting of severe brain tissue damage. Choline is identified in elements needed for membrane synthesis and myelination, well as membrane...

Additional Technical Factors

Short echo time proton MRS allows for improved demonstration of peaks related to myo-inositol and glutamate glutamine. It can be helpful in distinguishing lactate from lipid signal and in the evaluation of macromolecular resonances. However, short TE proton MRS can be complicated by more baseline variability, making data processing more difficult. In addition, issues of peak overlap often render quantification efforts impossible for some peaks. Long TE MRS allows for the reliable demonstration of NAA, creatine, choline, and lactate lipid. At our institution, we routinely use a longer TE sequence unless metabolites identified with short TE imaging (a glutamine glutamate, p y glutamine glutamate, myo-inositol peaks) are of interest.

Mrs In The Developing Brain

Aside from differences of metabolite levels in different regions of the brain (decreased NAA in white matter and lower creatine in white matter (38), the evaluation of proton MR spectra in the pediatric patient is complicated by known developmental changes in metabolites. As such, quantified changes in spectra should be compared with known age-matched and regional controls to avoid misinterpretation of what may be normal changes in metabolite content. Reference to published quantitative data of normal individuals may be helpful in these regards (18,39). Regional NAA increases occur in concordance with neuronal density and myelination, which are seen in higher amounts in the thalami early, with subsequent increase in the occipito-parietal and periventricular white matter afterward (40). Newborn NAA is observed to be almost half that of adult values, with subsequent increase to adult levels. As a marker of cell membrane turnover and lipid metabolism, increased choline and myoinositol is...

Future Strategies And Developments In Mrbased In Vivo Metabolic Imaging

In theory, higher field systems should provide improved spectral resolution and increased SNR (162) However, issues of shimming, coil design, and alterations in metabolite T1 T2 may degrade these advantages. Gonen et al. (163) found in a comparison of 3D-CSI of the brain with 1.5 T vs 3.0 T systems assuming similar sequence, shim, and anatomy, that SNR was improved 23-46 . This improvement in SNR could be used to increase sensitivity to changes in metabolites detected on MRS or be exchanged for shorter acquisition time. They also found that spectral resolution was improved, with improved peak discrimination, most notably between choline and creatine. At a TE of 135 or 144 ms, a generally flatter baseline was also noted, easing peak area estimation. The application of phased array coil technology has allowed for prominent gain in SNR. The application of a GRASE sequence has been discussed with dual advantages of significant improvement in acquisition time as well as effective...

Application Of Mri To Study Metabolic Disorders

MRS is a method whereby the chemical composition of magnetically active nuclei, such as H or 31P, within a tissue can be determined. The technique requires a large main magnetic field to orient the nuclear magnetic spins parallel or antiparallel with it. No magnetic field gradients are applied. The frequencies of the nuclei will differ depending upon what chemical group they are in. For example, protons on a methyl group, such as in lactate, will give an MRS signal at a slightly lower frequency than protons on an aromatic ring such as phenylalanine. The differences in frequency are small in the order of parts per million (ppm). 1H MRS is capable of producing information on a large number of brain chemicals. The most common chemicals studied via the identification and integration of the spectral peaks found in the proton (1H) spectra include N-acetyl- ,-aspartate (NAA), creatine, phosphocreatine, choline, myo-inositol, lactate, glutamate, and glutamine. In addition, amino acids,...

Peroxisomal Disorders

Brain involvement evidenced by MRI is rare in female subjects heterozygous for X-linked adrenoleukodystrophy, including those who have clinical evidence of spinal cord involvement, although in some cases, these females can have white matter abnormalities resembling homozygotes. 1H MRS in female heterozygotes have shown the NAA choline ratio to be significantly reduced in the parieto-occipital white matter, but NAA creatine and Cho creatine ratios are not significantly different from the normal range. In the frontal white matter the choline creatine ratio are significantly elevated, but other ratios did not demonstrate significant differences. NAA choline and NAA creatine ratios were significantly reduced along the white matter of the internal capsule and corticospinal projection fibers, suggesting that NAA was decreased. There were no significant differences in the calcarine or parietal gray matter (92).

Mitochondrial Cytopathies

Several laboratory studies may be useful to screen for impaired energy metabolism such as serum lactate, pyruvate, plasma amino acids, complete blood count, electrolytes, car-nitine, acylcarnitine profile, ammonia, and creatine phospho-kinase. Renal tubular acidosis as part of a Fanconi syndrome may be seen, especially in patients with complex IV defects. Renal disease is more common in pediatric presentations. Elevated lactate is suggestive but not specific for mitochondrial disorders. Lactate levels are not entirely reliable markers of mitochondrial dysfunction. Many children do not have elevated serum lactate or may have elevations only under certain provocations, such as after glucose loading, illness, or exercise. Blood lactate values may be spuriously elevated when a tourniquet is used, or as a result of a child struggling with the venipuncture. In these cases, arterial lactate level may be more reliable. In infants and young children with encephalopathy, CSF lactate may be...

Final results of the balloon vs optimal atherectomy trial BOAT

BACKGROUND Previous directional coronary atherectomy (DCA) trials have shown no significant reduction in angiographic restenosis, more in-hospital complications, and higher 1-year mortality than conventional balloon angioplasty (percutaneous transluminal coronary angio-plasty PTCA ). DCA, however, has subsequently evolved toward a more optimal technique (larger devices, more extensive tissue removal, and routine postdilation to obtain diameter stenosis < 20 ). METHODS AND RESULTS The Balloon vs. Optimal Atherectomy Trial (BOAT) was conducted to evaluate whether optimal DCA provides short- and long-term benefits compared with balloon angioplasty. One thousand patients with single de novo, native vessel lesions were randomized to either DCA or PTCA at 37 participating centers. Lesion success was obtained in 99 versus 97 (p 0.02) of patients to a final residual diameter stenosis of 15 versus 28 (p < 0.001) for DCA and PTCA, respectively, the latter including stents in 9.3 of the...

Acute vs Chronic Amphetamine Toxicity

Labs Hyperglycemia, leukocytosis, elevated liver function tests (LFTs), elevated creatine phosphokinase (CPK) from rhabdomyolysis with myoglobinuria. False-positive urine drug screens may result from ephedrine, pseudoephedrine, or phenylpropanolamine (PPA), often found in over-the-counter (OTC) cold medications.

Medications for High Cholesterol

Also, muscle damage can occur from statins and can lead to the release into the blood of a protein from damaged muscle, myoglobin, that can cause the kidneys to shut down entirely. This form of acute renal failure has caused the deaths of a number of patients and recently has led to the withdrawal from the market of one of the statins, Baycol. Muscle pain is the first sign of this condition. It also can be detected by monitoring the blood level of an enzyme from muscle called creatine kinase, but this test is not used much for monitoring purposes muscle pain is more likely to signal this problem.

Gg4g26624

Bioimaging is in the forefront of medicine for the diagnosis and treatment of neurodegenerative disease. Conventional magnetic resonance imaging (MRI) uses interactive external magnetic fields and resonant frequencies of protons from water molecules. However, newer sequences, such as magnetization-prepared rapid acquisition gradient echo (MPRAGE), are able to seek higher levels of anatomic resolution by allowing more rapid temporal imaging. Magnetic resonance spectroscopy (MRS) images metabolic changes, enabling underlying pathophysiologic dysfunction in neurodegeneration to be deciphered. Neurochemicals visible with proton H MRS include N-acetyl aspartate (NAA), creatine phosphocreatine (Cr), and choline (Cho) NAA is considered to act as an in vivo marker for neuronal loss and or neuronal dysfunction. By extending imaging to the study of elements such as iron elevated in several neurodegenerative diseases laser microprobe studies have become extremely useful, followed by X-ray...

Abbreviations

ACS, Acute coronary syndrome(s) AMI, acute myocardial infarction AST, aspartate aminotransferase CAPTURE, Chimeric c7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment Trial CI, confidence interval CK, creatine kinase CPUs, chest pain units CRP, C-reactive protein cTnT and cTnl, cardiac troponins T and I ECG, electrocardiogram ED, emergency department FRISC, Fragmin in Unstable Coronary Artery Disease GP IIb IIIa, glycoprotein IIb IIIa GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes LDH, lactate dehydrogenase POCT, point-of-care testing PRISM, Platelet Receptor Inhibition in Ischemic Syndrome Management PURSUIT, Platelet Glycoprotein IIb IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy SMARTT, Serial Markers, Acute Myocardial Infarction, and Rapid Treatment Trial TIMI, Thrombolysis in Myocardial Infarction.

Mrs In Parkinsonism

Most clinical MRS studies have concentrated on the metabolites visible with proton ( H) spectroscopy and measured in single, localized tissue volumes in the brain. The metabolites of interest that can be most readily studied with H-MRS at long echo times include -acetyl aspartate (NAA), creatine phosphocreatine (Cr), and choline (Cho). Altered neuronal membrane synthesis and degradation can produce changes in Cho (53). NAA is contained almost exclusively within neurons (54) and is therefore considered to act as an in vivo marker of neuronal loss or dysfunction. Reduced regional NAA concentration has been reported in conditions characterized by neuronal or axonal loss (55-59). Most frequently, NAA measurements have been based on the regional NAA Cr ratio. The rationale for the use of the Cr resonance as the denominator is based on the concept that creatine and phosphocreatine are in chemical equilibrium and that the total concentration of both compounds is expected to...

The clinical problem

In the early 1990s, studies showed, for the first time, that creatine kinase (CK)-MB (mass) and troponins were frequently elevated in patients considered at the time to have presented with unstable angina, and that these elevations are associated with an adverse prognosis (4-6). Since then, markers of myocardial damage in general, and the troponins in particular, have become central elements in early risk assessment of patients with NSTEACS.

Cardiac Troponin

As a more sensitive biomarker of myocardial inury, cardiac troponin is elevated more frequently than creatine kinase (CK) or CK-MB in patients with PE. The release oftropo-nin in patients with PE is often quantitatively small, far less than typically observed in an ST-elevation MI (10). The release of troponin in this setting most likely results from acute RV pressure overload, impaired coronary blood flow, and severe hypoxemia that cause micronecrosis of the right ventricle.

Muscle Development

Differentiation to become mature muscle fibers (72). This process is under precise control through the interaction of muscle cells with the extracellular environment. Growth factors like FGF-2 and TGF-(3 are strong stimulators or inhibitors of muscle cell proliferation and differentiation, and interact with the cell by binding to proteoglycans. Syndecans-1 through -4 have been identified in skeletal muscle (42,73,74). In vitro studies with C2Q2 mouse skeletal muscle cells have shown that syndecan-1, syndecan-3, and syndecan-4 are down-regulated with muscle differentiation with expression being higher during the proliferation stage. Syndecan-2 expression remained constant during both in vitro muscle cell proliferation and differentiation. Larrain et al. (75) showed that C2Ci2 cells overexpressing syndecan-1 had a 6- to 7-fold increase in fibroblast growth factor responsiveness and a corresponding decrease in the expression of, myogenin, creatine kinase, and myosin, key factors...

Myocarditis

Cause of release of the MB isoenzyme of creatine kinase (CK-MB) in the absence of coronary artery obstruction and myocardial ischemia (5). Given the difficulty in definitively establishing the presence of myocarditis in the appropriate clinical setting, sensitive and specific indicators of myocardial injury, such as the cardiac troponins, have been viewed as a potential valuable aid to diagnosis (5). Viewed from an alternative perspective, abnormal concentrations of troponins resulting from unsuspected myocarditis may also be an important source of diagnostic confusion in patients with undifferentiated chest pain.

Introduction

Abbreviations a1,3GalT, a-1,3-galactosyltransferase Agml, phosphoacetylglucosamine mutase ATP, adenosine triphosphate CK, creatine kinase CMK, CMP kinase CTP, cytidine triphosphate Gal-1-P, galactose-1-phosphate GalK, galactokinase GalPUT, galactose-1-phosphate uridylyltransferase GalU, glucose-1-phosphate uridylyltransferase GFS, GDP-fucose synthetase GMP, GDP-mannose pyrophosphorylase LgtA, p-1,3-N-acetylglucosaminyltransferase LgtC, a-1,4-galactosyltransferase LgtD, NDP, nucleoside diphosphate NTP, nucleoside triphosphate PEP, phosphoenolpyruvate PMI, phosphomannose isomerase PMM, phosphomannose mutase PPi, pyrophosphate PPA, inorganic pyrophosphatase PTA, phosphate acetyltransferase (EC 2.3.1.8) PykF, pyruvate kinase UDP, uridine diphosphate UGD, UDP-glucose 6-dehydrogenase UTP, uridine triphosphate WbgU, UDP-GlcNAc 4-epimerase.

Clinical Correlation

The ability to accurately detect ever smaller amounts of myocardial necrosis has led to confusion regarding clinical diagnoses. Early work comparing troponin with creatine kinase (CK) MB isoenzyme of CK (CK-MB), suggested that approximately one third of patients with a clinical diagnosis of unstable angina had small elevations in either cTnT or cTnI (12). In contrast to the two-level troponin cutoff proposed by in the National Academy of Clinical Biochemistry Standards of Laboratory Practice (13), the ESC ACC consensus statement took the definitive stance that any troponin elevation resulting from ischemia be diagnostic for an AMI (12). However, it must be remembered that, regardless of the nomenclature, the occurrence of myocardial necrosis is in fact a terminal event and includes inherent delays in time to detection due to the release kinetics specific to a given marker. Thus, relying on these markers as the sole diagnostic criterion will be relatively late in the course of ACS,...

Sarcopenia

The causes of sarcopenia are multifactorial (Table 3). Aging itself is associated with a decline in physical activity. Small increases in cytokines, especially interleukin (IL)-6, have been implicated in the proteolysis of muscle involved in the pathophysiology of sarcopenia 32 . Decreased food intake can lead to loss of muscle protein, as it is broken down for use in more essential proteins. The amino acid creatine is found only in meat and is essential for muscle function. Older persons who are anorectic or vegetarian have inadequate crea-tine intake for muscle maintenance. Decreased creatine intake Peripheral vascular disease Hypogonadism Cytokine excess Myostatin excess

Laboratory Testing

In general, the diagnostic workup should include complete blood count with differential, CD4 lymphocyte count, HIV-1 viral load, serum chemistries (including liver and renal function tests, fasting glucose and creatine phosphokinase), chest X-ray, electrocardiogram, blood and urine cultures (if indicated), toxicology screen, and psychotropic medication serum levels (when available). Based on the clinical presentation,

Additional Agents

Adenosine 5'-triphosphate has been studied with some evidence of benefit in patients with advanced lung cancer 160, 161 . Another way of increasing high-energy phosphate compounds may be by supplementing with oral creatine. This is recognised as having beneficial effects in certain types of athletic performance (although there are conflicting reports 162, 163 ), and in a clinical study of older men it improved their muscular performance 164 . There have been some concerns over safety, which has been reviewed recently 165 .

Early enzyme studies

These early reports demonstrated increased enzyme activity in serum in many head-injured patients, but these markers did not have sufficient specificity for brain injury 4 . In the 1980s, promising results were observed in studies of the creatine kinase isoenzyme BB (CK-BB). Recent research has been focused on neurone-specific enolase (NSE) and S-1000 protein. These are specific markers of damage to neurones and astroglial cells, respectively. Interesting reports on two other markers of astroglial damage, myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP), have also been published.

Other Agents

Tion, despite the fact that it has not yet been studied in cancer patients, is creatine. Commonly used by 'body builders', creatine is about to undergo active clinical investigation for the cancer anorexia weight loss syndrome. In a collaborative trial, the North Central Cancer Treatment Group and the National Cancer Institute of Canada are about to open a phase III, placebo-controlled trial to study this amino acid derivative. Although potential mechanisms of action have not been well characterised, over 50 clinical trials have investigated creatine supplementation in other disease settings. Empiric observations suggest that creatine merits testing in the clinical setting in cancer patients and in aggregate can be summarised with the five following observations 30,31 . First, creatine supplementation is associated with weight gain, including augmentation of lean tissue, in healthy individ-

S100a11

S100A1 is released into the blood during ischemic periods and can serve as a marker for myocardial ischemia together with creatine kinase isoenzymes, myoglobin, troponin I and T (Kiewitz et al., 2000a). Extracellular S100A1 was reported to be endocytosed into the endosomal compartment of neonatal rat cardiomyocytes and to inhibit apoptosis via activation of extracellular signalregulated protein kinase 1 2 (ERK1 2) (Most et al., 2003a). Endocytosed S100A1 was further demonstrated to result in decreased diastolic Ca2+-concentrations and a diminished SR Ca2+ load (Most et al., 2005). In rodent cardiomyocytes, the extracellular application and subsequent endocytotic internalization of S100A1 resulted in increased L-type Ca2+ currents (IC++), accelerated fast inactivation kinetics of IC+ and a shift of the I V relationship of IC+ to negative potentials (Reppel et al., 2005).

Neuroimaging

A reduction in N-acetylaspartate (NAA), a marker for neuronal loss, using in vivo proton 1H MRS in patients with advanced HIV disease (Chang et al., 1999a, 1999b). The ratio of NAA to creatine (CR) reflects neuronal density and correlates with cognitive impairment in HIV-1-associated cognitive dysfunction (Becker et al., 1997). 1H MRS has also demonstrated progressive neuronal loss over time in HIV-infected individuals, and the degree of neuronal loss observed correlates with neurological impairment (Swindells et al., 1995, 1999). Similarly, the ratio of both choline (CHO) and myoinositol (MI) to CR reflects glial density, and both are elevated in HAD (McConnell et al., 1994 Jarvik et al., 1996 Tracey et al., 1998). Increased CHO levels reflect glial membrane turnover indicative of the astrocytosis that follows HIV encephalitis (HIVE).