Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency.

PubMed

Trotier-Faurion, Alexandra; Dézard, Sophie; Taran, Frédéric; Valayannopoulos, Vassili; de Lonlay, Pascale; Mabondzo, Aloïse

2013-06-27

The creatine transporter deficiency is a neurological disease caused by impairment of the creatine transporter SLC6A8, resulting in mental retardation associated with a complete absence of creatine within the brain and cellular energy perturbation of neuronal cells. One of the therapeutic hypotheses was to administer lipophilic creatine derivatives which are (1) thought to have better permeability through the cell membrane and (2) would not rely on the activity of SLC6A8 to penetrate the brain. Here, we synthesized creatine fatty esters through original organic chemistry process. A screening on an in vitro rat primary cell-based blood-brain barrier model and on a rat primary neuronal cells model demonstrated interesting properties of these prodrugs to incorporate into endothelial, astroglial, and neuronal cells according to a structure-activity relationship. Dodecyl creatine ester showed then a 20-fold increase in creatine content in pathological human fibroblasts compared with the endogenous creatine content, stating that it could be a promising drug candidate.

Electrolysis stimulates creatine transport and transporter cell surface expression in incubated mouse skeletal muscle: potential role of ROS.

PubMed

Derave, Wim; Straumann, Nadine; Olek, Robert A; Hespel, Peter

2006-12-01

Electrical field stimulation of isolated, incubated rodent skeletal muscles is a frequently used model to study the effects of contractions on muscle metabolism. In this study, this model was used to investigate the effects of electrically stimulated contractions on creatine transport. Soleus and extensor digitorum longus muscles of male NMRI mice (35-50 g) were incubated in an oxygenated Krebs buffer between platinum electrodes. Muscles were exposed to [(14)C]creatine for 30 min after either 12 min of repeated tetanic isometric contractions (contractions) or electrical stimulation of only the buffer before incubation of the muscle (electrolysis). Electrolysis was also investigated in the presence of the reactive oxygen species (ROS) scavenging enzymes superoxide dismutase (SOD) and catalase. Both contractions and (to a lesser degree) electrolysis stimulated creatine transport severalfold over basal. The amount of electrolysis, but not contractile activity, induced (determined) creatine transport stimulation. Incubation with SOD and catalase at 100 and 200 U/ml decreased electrolysis-induced creatine transport by approximately 50 and approximately 100%, respectively. The electrolysis effects on creatine uptake were completely inhibited by beta-guanidino propionic acid, a competitive inhibitor of (creatine for) the creatine transporter (CRT), and were accompanied by increased cell surface expression of CRT. Muscle glucose transport was not affected by electrolysis. The present results indicate that electrical field stimulation of incubated mouse muscles, independently of contractions per se, stimulates creatine transport by a mechanism that depends on electrolysis-induced formation of ROS in the incubation buffer. The increased creatine uptake is paralleled by an increased cell surface expression of the creatine transporter.

Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

PubMed

Thurm, Audrey; Himelstein, Daniel; DʼSouza, Precilla; Rennert, Owen; Jiang, Susanqi; Olatunji, Damilola; Longo, Nicola; Pasquali, Marzia; Swedo, Susan; Salomons, Gajja S; Carrillo, Nuria

2016-05-01

Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders. Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability. We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD. Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation.

PubMed

Santacruz, Lucia; Arciniegas, Antonio Jose Luis; Darrabie, Marcus; Mantilla, Jose G; Baron, Rebecca M; Bowles, Dawn E; Mishra, Rajashree; Jacobs, Danny O

2017-08-01

Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing V max and K m Pharmacological activation of AMP-activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF-1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF-1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Proton magnetic resonance spectroscopic creatine correlates with creatine transporter protein density in rat brain.

PubMed

Sartorius, Alexander; Lugenbiel, Patrick; Mahlstedt, Magdalena M; Ende, Gabriele; Schloss, Patrick; Vollmayr, Barbara

2008-07-30

Creatine (Cr) is an amino acid, which upon phosphorylation is utilized as an energy reservoir in cells with high-energy demand. The ongoing catabolism of creatine to creatinine requires a permanent creatine replenishment into the cells. Because neurons themselves cannot synthesize creatine, they have to take it up via the creatine transporter (CrT). Thus, the concentration of intracellular Cr available for the Cr/PCr shuttle system depends on the expression level of CrT protein. The proton magnetic resonance spectroscopy (MRS) creatine peak (total creatine=tCr) constitutes of two metabolites, namely Cr and phosphocreatine (PCr). We have quantified the level of CrT protein expression with western blotting and compared it to tCr content as estimated by in vitro MRS in Sprague-Dawley rats. Under the assumption of hemispheric symmetry, we took identical samples from left and right hemisphere, which were used for in vitro MRS (tCr) and for western blotting (CrT), respectively. Altogether, it was possible to take 90 corresponding brain samples from 31 animals. A Pearson linear regression analysis for CrT and tCr revealed p<0.0001, explaining 14% of the variance. Since MR-detectable alterations of tCr in the human brain are widespread (e.g. in most major psychiatric disorders proton MRS detectable tCr alterations have been described as regionally and usually state dependent) it is stringent to elucidate their meaning. An influence of tCr on the brain's energy regulating system seems plausible.

Creatine transporter deficiency: prevalence among patients with mental retardation and pitfalls in metabolite screening.

PubMed

Arias, Angela; Corbella, Marc; Fons, Carmen; Sempere, Angela; García-Villoria, Judit; Ormazabal, Aida; Poo, Pilar; Pineda, Mercé; Vilaseca, María Antonia; Campistol, Jaume; Briones, Paz; Pàmpols, Teresa; Salomons, Gajja S; Ribes, Antonia; Artuch, Rafael

2007-11-01

To report the prevalence of creatine transporter deficiency in males with mental retardation and to study whether a protein-rich food intake might be a potential diagnostic pitfall. We determined creatine/creatinine ratio in urine samples from 1600 unrelated male patients with mental retardation and/or autism. Urine creatine was analyzed by HPLC-MS/MS. Thirty-three of 1600 cases showed increased urine creatine/creatinine ratio. Four out of these thirty-three cases were definitively diagnosed with creatine transporter deficiency, while the other 29 were false positive results. Significantly higher values were observed for urine Cr/Crn ratio in healthy volunteers after a meal based on beef or oily fish as compared to eggs, pasta or salad (Wilcoxon test: p<0.005). False positive results may be observed in biochemical screening for creatine transporter deficiency, and they may be due to intake of meals rich in creatine prior to urine samples analysis.

Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction

PubMed Central

Lygate, Craig A.; Bohl, Steffen; ten Hove, Michiel; Faller, Kiterie M.E.; Ostrowski, Philip J.; Zervou, Sevasti; Medway, Debra J.; Aksentijevic, Dunja; Sebag-Montefiore, Liam; Wallis, Julie; Clarke, Kieran; Watkins, Hugh; Schneider, Jürgen E.; Neubauer, Stefan

2012-01-01

Aims Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury. Methods and results CrT-OE mice were selected for left ventricular (LV) creatine 20–100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury. Conclusion Elevation of myocardial creatine by 20–100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia. PMID:22915766

Creatine biosynthesis and transport by the term human placenta.

PubMed

Ellery, Stacey J; Della Gatta, Paul A; Bruce, Clinton R; Kowalski, Greg M; Davies-Tuck, Miranda; Mockler, Joanne C; Murthi, Padma; Walker, David W; Snow, Rod J; Dickinson, Hayley

2017-04-01

Creatine is an amino acid derivative that is involved in preserving ATP homeostasis. Previous studies suggest an important role for the creatine kinase circuit for placental ATP turnover. Creatine is obtained from both the diet and endogenous synthesis, usually along the renal-hepatic axis. However, some tissues with a high-energy demand have an inherent capacity to synthesise creatine. In this study, we determined if the term human placenta has the enzymatic machinary to synthesise creatine. Eleven placentae were collected following elective term caesarean section. Samples from the 4 quadrants of each placenta were either fixed in formalin or frozen. qPCR was used to determine the mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and the creatine transporter (SLC6A8). Protein expression of AGAT and GAMT was quantified by Western blot, and observations of cell localisation of AGAT, GAMT and SLC6A8 made with immunohistochemistry. Synthesis of guanidinoacetate (GAA; creatine precursor) and creatine in placental homogenates was determined via GC-MS and HPLC, respectively. AGAT, GAMT and SLC6A8 mRNA and protein were detected in the human placenta. AGAT staining was identified in stromal and endothelial cells of the fetal capillaries. GAMT and SLC6A8 staining was localised to the syncytiotrophoblast of the fetal villi. Ex vivo, tissue homogenates produce both GAA (4.6 nmol mg protein -1 h -1 ) and creatine (52.8 nmol mg protein -1 h -1 ). The term human placenta has the capacity to synthesise creatine. These data present a new understanding of placental energy metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

Assignment of the creatine transporter gene (SLC6A8) to human chromosome Xq28 telomeric to G6PD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gregor, P.; Nash, S.R.; Caron, M.G.

1995-01-01

The creatine-phosphocreatine shuttle has important functions in the temporal and spatial maintenance of the energy supply to skeletal and cardiac muscle. Muscle cells do not synthesize creatine, but take it up via a specific sodium-dependent transporter - the creatine transporter. Thus, the creatine transporter has an important role in muscular physiology. Furthermore, inhibition of creatine transport in experimental animals causes muscle weakness. Recently, creatine transporter cDNAs have been isolated and characterized from rabbit and human. In this communication we report mapping of the creatine transporter gene to human chromosome Xq28. 12 refs., 1 fig.

Human, rat and chicken small intestinal Na+-Cl−-creatine transporter: functional, molecular characterization and localization

PubMed Central

Peral, M J; García-Delgado, M; Calonge, M L; Durán, J M; De La Horra, M C; Wallimann, T; Speer, O; Ilundáin, A A

2002-01-01

In spite of all the fascinating properties of oral creatine supplementation, the mechanism(s) mediating its intestinal absorption has(have) not been investigated. The purpose of this study was to characterize intestinal creatine transport. [14C]Creatine uptake was measured in chicken enterocytes and rat ileum, and expression of the creatine transporter CRT was examined in human, rat and chicken small intestine by reverse transcription-polymerase chain reaction, Northern blot, in situ hybridization, immunoblotting and immunohistochemistry. Results show that enterocytes accumulate creatine against its concentration gradient. This accumulation was electrogenic, Na+- and Cl−-dependent, with a probable stoichiometry of 2 Na+: 1 Cl−: 1 creatine, and inhibited by ouabain and iodoacetic acid. The kinetic study revealed a Km for creatine of 29 μm. [14C]Creatine uptake was efficiently antagonized by non-labelled creatine, guanidinopropionic acid and cyclocreatine. More distant structural analogues of creatine, such as GABA, choline, glycine, β-alanine, taurine and betaine, had no effect on intestinal creatine uptake, indicating a high substrate specificity of the creatine transporter. Consistent with these functional data, messenger RNA for CRT was detected only in the cells lining the intestinal villus. The sequences of partial clones, and of the full-length cDNA clone, isolated from human and rat small intestine were identical to previously cloned CRT cDNAs. Immunological analysis revealed that CRT protein was mainly associated with the apical membrane of the enterocytes. This study reports for the first time that mammalian and avian enterocytes express CRT along the villus, where it mediates high-affinity, Na+- and Cl−-dependent, apical creatine uptake. PMID:12433955

Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders.

PubMed

Stockler-Ipsiroglu, Sylvia; van Karnebeek, Clara D M

2014-07-01

Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus. Patients with GAMT deficiency exhibit the most severe clinical spectrum. Myopathy is a distinct feature in AGAT deficiency. Guanidinoacetate (GAA) is the immediate product in the creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for AGAT deficiency, while high GAA concentrations are characteristic markers for GAMT deficiency. An elevated ratio of urinary creatine /creatinine excretion serves as a diagnostic marker in males with SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose creatine-monohydrate for all three CDD. Guanidinoacetate-reducing strategies (high-dose ornithine, arginine-restricted diet) are additionally employed in GAMT deficiency. Supplementation of substrates for intracerebral creatine synthesis (arginine, glycine) has been used additionally to treat SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and GAMT deficiency suggest a potential benefit of newborn screening for these disorders. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

PubMed

Baroncelli, Laura; Molinaro, Angelo; Cacciante, Francesco; Alessandrì, Maria Grazia; Napoli, Debora; Putignano, Elena; Tola, Jonida; Leuzzi, Vincenzo; Cioni, Giovanni; Pizzorusso, Tommaso

2016-10-01

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dietary creatine supplementation during pregnancy: a study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice.

PubMed

Ellery, Stacey J; LaRosa, Domenic A; Kett, Michelle M; Della Gatta, Paul A; Snow, Rod J; Walker, David W; Dickinson, Hayley

2016-08-01

Recent evidence obtained from a rodent model of birth asphyxia shows that supplementation of the maternal diet with creatine during pregnancy protects the neonate from multi-organ damage. However, the effect of increasing creatine intake on creatine homeostasis and biosynthesis in females, particularly during pregnancy, is unknown. This study assessed the impact of creatine supplementation on creatine homeostasis, body composition, capacity for de novo creatine synthesis and renal excretory function in non-pregnant and pregnant spiny mice. Mid-gestation pregnant and virgin spiny mice were fed normal chow or chow supplemented with 5 % w/w creatine for 18 days. Weight gain, urinary creatine and electrolyte excretion were assessed during supplementation. At post mortem, body composition was assessed by Dual-energy X-ray absorptiometry, or tissues were collected to assess creatine content and mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) and the creatine transporter (CrT1). Protein expression of AGAT and GAMT was also assessed by Western blot. Key findings of this study include no changes in body weight or composition with creatine supplementation; increased urinary creatine excretion in supplemented spiny mice, with increased sodium (P < 0.001) and chloride (P < 0.05) excretion in pregnant dams after 3 days of supplementation; lowered renal AGAT mRNA (P < 0.001) and protein (P < 0.001) expressions, and lowered CrT1 mRNA expression in the kidney (P < 0.01) and brain (P < 0.001). Creatine supplementation had minimal impact on creatine homeostasis in either non-pregnant or pregnant spiny mice. Increasing maternal dietary creatine consumption could be a useful treatment for birth asphyxia.

Treatment outcome of creatine transporter deficiency: international retrospective cohort study.

PubMed

Bruun, Theodora U J; Sidky, Sarah; Bandeira, Anabela O; Debray, Francoise-Guillaume; Ficicioglu, Can; Goldstein, Jennifer; Joost, Kairit; Koeberl, Dwight D; Luísa, Diogo; Nassogne, Marie-Cecile; O'Sullivan, Siobhan; Õunap, Katrin; Schulze, Andreas; van Maldergem, Lionel; Salomons, Gajja S; Mercimek-Andrews, Saadet

2018-06-01

To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with CRTR deficiency on a treatment, including creatine and/or arginine, and/or glycine. Clinical severity score included 1) global developmental delay/intellectual disability; 2) seizures; 3) behavioural disorder. Phenotype scored 1-3 = mild; 4-6 = moderate; and 7-9 = severe. We applied the clinical severity score pre- and on-treatment. Seventeen patients, 14 males and 3 females, from 16 families were included. Four patients had severe, 6 patients had moderate, and 7 patients had a mild phenotype. The phenotype ranged from mild to severe in patients diagnosed at or before 2 years of age or older than 6 years of age. The phenotype ranged from mild to severe in patients with mildly elevated urine creatine to creatinine ratio. Fourteen patients were on the combined creatine, arginine and glycine therapy. On the combined treatment with creatine, arginine and glycine, none of the males showed either deterioration or improvements in their clinical severity score, whereas two females showed improvements in the clinical severity score. Creatine monotherapy resulted in deterioration of the clinical severity score in one male. There seems to be no correlation between phenotype and degree of elevation in urine creatine to creatinine ratio, genotype, or age at diagnosis. Combined creatine, arginine and glycine therapy might have stopped disease progression in males and improved phenotype in females.

Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene.

PubMed

DesRoches, Caro-Lyne; Patel, Jaina; Wang, Peixiang; Minassian, Berge; Salomons, Gajja S; Marshall, Christian R; Mercimek-Mahmutoglu, Saadet

2015-07-10

Creatine transporter deficiency (CRTR-D) is an X-linked inherited disorder of creatine transport. All males and about 50% of females have intellectual disability or cognitive dysfunction. Creatine deficiency on brain proton magnetic resonance spectroscopy and elevated urinary creatine to creatinine ratio are important biomarkers. Mutations in the SLC6A8 gene occur de novo in 30% of males. Despite reports of high prevalence of CRTR-D in males with intellectual disability, there are no true prevalence studies in the general population. To determine carrier frequency of CRTR-D in the general population we studied the variants in the SLC6A8 gene reported in the Exome Variant Server database and performed functional characterization of missense variants. We also analyzed synonymous and intronic variants for their predicted pathogenicity using in silico analysis tools. Nine missense variants were functionally analyzed using transient transfection by site-directed mutagenesis with In-Fusion HD Cloning in HeLa cells. Creatine uptake was measured by liquid chromatography tandem mass spectrometry for creatine measurement. The c.1654G>T (p.Val552Leu) variant showed low residual creatine uptake activity of 35% of wild type transfected HeLa cells and was classified as pathogenic. Three variants (c.808G>A; p.Val270Met, c.942C>G; p.Phe314Leu and c.952G>A; p.Ala318Thr) were predicted to be pathogenic based on in silico analysis, but proved to be non-pathogenic by our functional analysis. The estimated carrier frequency of CRTR-D was 0.024% in females in the general population. We recommend functional studies for all novel missense variants by transient transfection followed by creatine uptake measurement by liquid chromatography tandem mass spectrometry as fast and cost effective method for the functional analysis of missense variants in the SLC6A8 gene. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

Effects of whole-body x irradiation on the biogenesis of creatine in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thyagarajan, P.; Vakil, U.K.; Sreenivasan, A.

1977-06-01

Influences of whole-body x irradiation on various aspects of creatine metabolism have been studied. Exposures to sublethal or lethal doses of x radiation results in excessive urinary excretion as well as higher accumulation of creatine in the skeletal muscle of x-irradiated rats. A sudden fall in CPK activity in muscle with a concomitant rise in serum suggests that changes in serum and tissue CPK activity are of an adaptive nature in rats exposed to sublethal doses of x radiation. In vitro studies on creatine synthesis shows that transaminidase and methyl transferase activities in kidneys and liver, respectively, are decreased onmore » the 5th day in the x-irradiated, are decreased on the 5th day in the x-irradiated rat. However, on the 8th day, the enzyme activities are restored to normal.« less

Cloning and characterization of the promoter regions from the parent and paralogous creatine transporter genes.

PubMed

Ndika, Joseph D T; Lusink, Vera; Beaubrun, Claudine; Kanhai, Warsha; Martinez-Munoz, Cristina; Jakobs, Cornelis; Salomons, Gajja S

2014-01-10

Interconversion between phosphocreatine and creatine, catalyzed by creatine kinase is crucial in the supply of ATP to tissues with high energy demand. Creatine's importance has been established by its use as an ergogenic aid in sport, as well as the development of intellectual disability in patients with congenital creatine deficiency. Creatine biosynthesis is complemented by dietary creatine uptake. Intracellular transport of creatine is carried out by a creatine transporter protein (CT1/CRT/CRTR) encoded by the SLC6A8 gene. Most tissues express this gene, with highest levels detected in skeletal muscle and kidney. There are lower levels of the gene detected in colon, brain, heart, testis and prostate. The mechanism(s) by which this regulation occurs is still poorly understood. A duplicated unprocessed pseudogene of SLC6A8-SLC6A10P has been mapped to chromosome 16p11.2 (contains the entire SLC6A8 gene, plus 2293 bp of 5'flanking sequence and its entire 3'UTR). Expression of SLC6A10P has so far only been shown in human testis and brain. It is still unclear as to what is the function of SLC6A10P. In a patient with autism, a chromosomal breakpoint that intersects the 5'flanking region of SLC6A10P was identified; suggesting that SLC6A10P is a non-coding RNA involved in autism. Our aim was to investigate the presence of cis-acting factor(s) that regulate expression of the creatine transporter, as well as to determine if these factors are functionally conserved upstream of the creatine transporter pseudogene. Via gene-specific PCR, cloning and functional luciferase assays we identified a 1104 bp sequence proximal to the mRNA start site of the SLC6A8 gene with promoter activity in five cell types. The corresponding 5'flanking sequence (1050 bp) on the pseudogene also had promoter activity in all 5 cell lines. Surprisingly the pseudogene promoter was stronger than that of its parent gene in 4 of the cell lines tested. To the best of our knowledge, this is the first

Maternal dietary creatine supplementation does not alter the capacity for creatine synthesis in the newborn spiny mouse.

PubMed

Dickinson, Hayley; Ireland, Zoe J; Larosa, Domenic A; O'Connell, Bree A; Ellery, Stacey; Snow, Rod; Walker, David W

2013-09-01

We have previously reported that maternal creatine supplementation protects the neonate from hypoxic injury. Here, we investigated whether maternal creatine supplementation altered expression of the creatine synthesis enzymes (arginine:glycine amidinotransferase [AGAT], guanidinoaceteate methyltransferase [GAMT]) and the creatine transporter (solute carrier family 6 [neurotransmitter transporter, creatine] member 8: SLC6A8) in the term offspring. Pregnant spiny mice were fed a 5% creatine monohydrate diet from midgestation (day 20) to term (39 days). Placentas and neonatal kidney, liver, heart, and brain collected at 24 hours of age underwent quantitative polymerase chain reaction and Western blot analysis. Maternal creatine had no effect on the expression of AGAT and GAMT in neonatal kidney and liver, but mRNA expression of AGAT in brain tissues was significantly decreased in both male and female neonates born to mothers who were fed the creatine diet. SLC6A8 expression was not affected by maternal dietary creatine loading in any tissues. Maternal dietary creatine supplementation from midgestation in the spiny mouse did not alter the capacity for creatine synthesis or transport.

The genomic organization of a human creatine transporter (CRTR) gene located in Xq28

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sandoval, N.; Bauer, D.; Brenner, V.

1996-07-15

During the course of a large-scale sequencing project in Xq28, a human creatine transporter (CRTR) gene was discovered. The gene is located approximately 36 kb centromeric to ALD. The gene contains 13 exons and spans about 8.5 kb of genomic DNA. Since the creatine transporter has a prominent function in muscular physiology, it is a candidate gene for Barth syndrome and infantile cardiomyopathy mapped to Xq28. 19 refs., 1 fig., 1 tab.

Free creatine available to the creatine phosphate energy shuttle in isolated rat atria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Savabi, F.

1988-10-01

To measure the actual percentage of intracellular free creatine participating in the process of energy transport, the incorporation of (1-{sup 14}C)creatine into the free creatine and phosphocreatine (PCr) pools in spontaneously beating isolated rat atria, under various conditions, was examined. The atria were subjected to three consecutive periods, control, anoxia, and postanoxic recover, in medium containing tracers of (1-{sup 14}C)creatine. The tissue content and specific activity of creatine and PCr were determined at the end of each period. The higher specific activity found for tissue PCr (1.87 times) than creatine, independent of the percentage of total intracellular creatine that wasmore » present as free creatine, provides evidence for the existence of two separate pools of free creatine. Analysis of the data shows that in the normal oxygenated state {approx} 9% of the total intracellular creatine is actually free to participate in the process of energy transport (shuttle pool). About 36% of the total creatine is bound to unknown intracellular components and the rest exists as PCr. The creatine that was taken up and the creatine that was released from the breakdown of PCr have much greater access to the site of phosphorylation than the rest of the intracellular creatine. A sharp increase in the specific activity of residual PCr on prolongation of anoxic time was also observed. This provides evidence for a nonhomogeneous pool of PCr, for the most recently formed (radioactive) PCr appeared to be hydrolyzed last.« less

Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency

PubMed Central

2012-01-01

Background SLC6A8, an X-linked gene, encodes the creatine transporter (CRTR) and its mutations lead to cerebral creatine (Cr) deficiency which results in mental retardation, speech and language delay, autistic-like behaviour and epilepsy (CRTR-D, OMIM 300352). CRTR-D represents the most frequent Cr metabolism disorder but, differently from Cr synthesis defects, that are partially reversible by oral Cr supplementation, does not respond to Cr treatment even if precociously administrated. The precursors of Cr are the non-essential amino acids Glycine (Gly) and Arginine (Arg), which have their own transporters at the brain–blood barrier level and, therefore, their supplementation appears an attractive and feasible therapeutic option aimed at stimulating Cr endogenous synthesis and, in this way, at overcoming the block of Cr transport within the brain. However, until now the effects of Arg and/or Gly supplementation on Cr brain levels and behaviour have been controversial. Methods In this study five Italian male patients affected by CRTR-D were supplemented with oral L-Arg at a dosage of 300 mg/kg/day divided into 3 doses, for 24–36 months. Biochemical and plasmatic amino acids examinations and thyroid hormone dosages were periodically performed. Moreover, Proton and Phosphorus Magnetic Resonance Spectroscopy (MRS) was monitored during follow-up in concurrence with neuropsychological evaluations. Results During L-Arg treatment a clinical improvement in motor skills and to a lesser extent in communication and attention was observed. In addition, all patients had a reduction in the number and frequency of epileptic seizures. Daily living skills appeared also to be positively influenced by L-Arg treatment. Moreover, Total Cr and especially PhosphoCr, evaluated by proton and phosphorus spectroscopy, showed a mild increase, although well below the normal range. Conclusion This study provides information to support the effectiveness of L-Arg supplement treatment in

Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?

PubMed

Hanna-El-Daher, Layane; Braissant, Olivier

2016-08-01

While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood-brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.

Creatine uptake in mouse hearts with genetically altered creatine levels

PubMed Central

Hove, Michiel ten; Makinen, Kimmo; Sebag-Montefiore, Liam; Hunyor, Imre; Fischer, Alexandra; Wallis, Julie; Isbrandt, Dirk; Lygate, Craig; Neubauer, Stefan

2008-01-01

Creatine plays an important role in energy metabolism in the heart. Cardiomyocytes accumulate creatine via a specific creatine transporter (CrT), the capacity of which is reduced in the failing heart, resulting in lower myocardial creatine concentration. Therefore, to gain insight into how the CrT is regulated, we studied two mouse models of severely altered myocardial creatine levels. Cardiac creatine uptake levels were measured in isolated hearts from creatine-free guanidinoacetate-N-methyl transferase knock out (GAMT−/−) mice and from mice overexpressing the myocardial CrT (CrT-OE) using 14C-radiolabeled creatine. CrT mRNA levels were measured using real time RT-PCR and creatine levels with HPLC. Hearts from GAMT−/− mice showed a 7-fold increase in Vmax of creatine uptake and a 1.4-fold increase in CrT mRNA levels. The increase in Cr uptake and in CrT mRNA levels, however, was almost completely prevented when mice were fed a creatine supplemented diet, indicating that creatine uptake is subject to negative feedback regulation. Cardiac creatine uptake levels in CrT-OE mice were increased on average 2.7-fold, showing a considerable variation, in line with a similar variation in creatine content. Total CrT mRNA levels correlated well with myocardial creatine content (r = 0.67; p < 0.0001) but endogenous CrT mRNA levels did not correlate at all with myocardial creatine content (r = 0.01; p = 0.96). This study shows that creatine uptake can be massively upregulated in the heart, by almost an order of magnitude and that this upregulation is subject to feedback inhibition. In addition, our results strongly suggest that CrT activity is predominantly regulated by mechanisms other than alterations in gene expression. PMID:18602925

Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?

PubMed Central

Allen, Patricia J.

2012-01-01

Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington’s Disease and Parkinson’s Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatine has therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies. PMID:22465051

Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?

PubMed

Allen, Patricia J

2012-05-01

Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington's Disease and Parkinson's Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatine has therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

Creatine for women: a review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy.

PubMed

Ellery, Stacey J; Walker, David W; Dickinson, Hayley

2016-08-01

The creatine/phosphocreatine/creatine kinase circuit is instrumental in regulating high-energy phosphate metabolism, and the maintenance of cellular energy turnover. The mechanisms by which creatine is able to buffer and regulate cellular energy balance, maintain acid-base balance, and reduce the effects of oxidative stress have led to a large number of studies into the use of creatine supplementation in exercise performance and to treat diseases associated with cellular energy depletion. Some of these studies have identified sex-specific responses to creatine supplementation, as such; there is the perception, that females might be less receptive to the benefits of creatine supplementation and therapy, compared to males. This review will describe the differences in male and female physique and physiology that may account for such differences, and discuss the apparent endocrine modulation of creatine metabolism in females. Hormone-driven changes to endogenous creatine synthesis, creatine transport and creatine kinase expression suggest that significant changes in this cellular energy circuit occur during specific stages of a female's reproductive life, including pregnancy and menopause. Recent studies suggest that creatine supplementation may be highly beneficial for women under certain conditions, such as depression. A greater understanding of these pathways, and the consequences of alterations to creatine bioavailability in females are needed to ensure that creatine is used to full advantage as a dietary supplement to optimize and enhance health outcomes for women.

Augmentation of Creatine in the Heart.

PubMed

Zervou, Sevasti; Whittington, Hannah J; Russell, Angela J; Lygate, Craig A

2016-01-01

Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators.

Urine screening for patients with developmental disabilities detected a patient with creatine transporter deficiency due to a novel missense mutation in SLC6A8.

PubMed

Kato, Hidekazu; Miyake, Fuyu; Shimbo, Hiroko; Ohya, Makoto; Sugawara, Hidenori; Aida, Noriko; Anzai, Rie; Takagi, Mariko; Okuda, Mitsuko; Takano, Kyoko; Wada, Takahito; Iai, Mizue; Yamashita, Sumimasa; Osaka, Hitoshi

2014-08-01

Creatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Augmentation of Creatine in the Heart

PubMed Central

Zervou, Sevasti; Whittington, Hannah J.; Russell, Angela J.; Lygate, Craig A.

2016-01-01

Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators. PMID:26202199

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms

PubMed Central

2012-01-01

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability. PMID:23234264

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

PubMed

Cheillan, David; Joncquel-Chevalier Curt, Marie; Briand, Gilbert; Salomons, Gajja S; Mention-Mulliez, Karine; Dobbelaere, Dries; Cuisset, Jean-Marie; Lion-François, Laurence; Portes, Vincent Des; Chabli, Allel; Valayannopoulos, Vassili; Benoist, Jean-François; Pinard, Jean-Marc; Simard, Gilles; Douay, Olivier; Deiva, Kumaran; Afenjar, Alexandra; Héron, Delphine; Rivier, François; Chabrol, Brigitte; Prieur, Fabienne; Cartault, François; Pitelet, Gaëlle; Goldenberg, Alice; Bekri, Soumeya; Gerard, Marion; Delorme, Richard; Tardieu, Marc; Porchet, Nicole; Vianey-Saban, Christine; Vamecq, Joseph

2012-12-13

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

Effects of Combined Creatine Plus Fenugreek Extract vs. Creatine Plus Carbohydrate Supplementation on Resistance Training Adaptations

PubMed Central

Taylor, Lem; Poole, Chris; Pena, Earnest; Lewing, Morgan; Kreider, Richard; Foster, Cliffa; Wilborn, Colin

2011-01-01

The purpose of this study was to evaluate the effects of combined creatine and fenugreek extract supplementation on strength and body composition. Forty- seven resistance trained men were matched according to body weight to ingest either 70 g of a dextrose placebo (PL), 5 g creatine/70 g of dextrose (CRD) or 3.5 g creatine/900 mg fenugreek extract (CRF) and participate in a 4-d/wk periodized resistance-training program for 8-weeks. At 0, 4, and 8-weeks, subjects were tested on body composition, muscular strength and endurance, and anaerobic capacity. Statistical analyses utilized a separate 3X3 (condition [PL vs. CRD vs. CRF] x time [T1 vs. T2 vs. T3]) ANOVAs with repeated measures for all criterion variables (p ≤ 0.05). No group x time interaction effects or main effects (p > 0.05) were observed for any measures of body composition. CRF group showed significant increases in lean mass at T2 (p = 0.001) and T3 (p = 0.001). Bench press 1RM increased in PL group (p = 0.050) from T1-T3 and in CRD from T1-T2 (p = 0. 001) while remaining significant at T3 (p < 0.001). CRF group showed a significant increase in bench press 1RM from T1-T2 (p < 0.001), and also increased from T2-T3 (p = 0.032). Leg press 1RM significantly increased at all time points for PL, CRD, and CRF groups (p < 0.05). No additional between or within group changes were observed for any performance variables and serum clinical safety profiles (p > 0.05). In conclusion, creatine plus fenugreek extract supplementation had a significant impact on upper body strength and body composition as effectively as the combination of 5g of creatine with 70g of dextrose. Thus, the use of fenugreek with creatine supplementation may be an effective means for enhancing creatine uptake while eliminating the need for excessive amounts of simple carbohydrates. Key points Fenugreek plus creatine supplementation may be a new means of increasing creatine uptake. Creatine plus fenugreek seems to be just as effective as the

Creatine and guanidinoacetate content of human milk and infant formulas: implications for creatine deficiency syndromes and amino acid metabolism.

PubMed

Edison, Erica E; Brosnan, Margaret E; Aziz, Khalid; Brosnan, John T

2013-09-28

Creatine is essential for normal neural development; children with inborn errors of creatine synthesis or transport exhibit neurological symptoms such as mental retardation, speech delay and epilepsy. Creatine accretion may occur through dietary intake or de novo creatine synthesis. The objective of the present study was to determine how much creatine an infant must synthesise de novo. We have calculated how much creatine an infant needs to account for urinary creatinine excretion (creatine's breakdown product) and new muscle lay-down. To measure an infant's dietary creatine intake, we measured creatine in mother's milk and in various commercially available infant formulas. Knowing the amount of milk/formula ingested, we calculated the amount of creatine ingested. We have found that a breast-fed infant receives about 9 % of the creatine needed in the diet and that infants fed cows' milk-based formula receive up to 36 % of the creatine needed. However, infants fed a soya-based infant formula receive negligible dietary creatine and must rely solely on de novo creatine synthesis. This is the first time that it has been shown that neonatal creatine accretion is largely due to de novo synthesis and not through dietary intake of creatine. This has important implications both for infants suffering from creatine deficiency syndromes and for neonatal amino acid metabolism.

Creatine and creatine forms intended for sports nutrition.

PubMed

Andres, Susanne; Ziegenhagen, Rainer; Trefflich, Iris; Pevny, Sophie; Schultrich, Katharina; Braun, Hans; Schänzer, Wilhelm; Hirsch-Ernst, Karen Ildico; Schäfer, Bernd; Lampen, Alfonso

2017-06-01

Creatine is a popular ergogenic supplement in sports nutrition. Yet, supplementation of creatine occasionally caused adverse effects such as gastrointestinal complaints, muscle cramps and an increase in body weight. Creatine monohydrate has already been evaluated by different competent authorities and several have come to the conclusion that a daily intake of 3 g creatine per person is unlikely to pose safety concerns, focusing on healthy adults with exclusion of pregnant and breastfeeding women. Possible vulnerable subgroups were also discussed in relation to the safety of creatine. The present review provides an up-to-date overview of the relevant information with special focus on human studies regarding the safety of creatine monohydrate and other marketed creatine forms, in particular creatine pyruvate, creatine citrate, creatine malate, creatine taurinate, creatine phosphate, creatine orotate, creatine ethyl ester, creatine pyroglutamate, creatine gluconate, and magnesium creatine chelate. Limited data are available with regard to the safety of the latter creatine forms. Considering an acceptable creatine intake of 3 g per day, most of the evaluated creatine forms are unlikely to pose safety concerns, however some safety concerns regarding a supplementary intake of creatine orotate, creatine phosphate, and magnesium creatine chelate are discussed here. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Creatine Monohydrate Enhances Energy Status and Reduces Glycolysis via Inhibition of AMPK Pathway in Pectoralis Major Muscle of Transport-Stressed Broilers.

PubMed

Zhang, Lin; Wang, Xiaofei; Li, Jiaolong; Zhu, Xudong; Gao, Feng; Zhou, Guanghong

2017-08-16

Creatine monohydrate (CMH) contributes to reduce transport-induced muscle rapid glycolysis and improve meat quality of broilers, but the underlying mechanism is still unknown. Therefore, this study aimed to investigate the molecular mechanisms underlying the ameliorative effects of CMH on muscle glycolysis metabolism of transported broilers during summer. The results showed that 3 h transport during summer elevated chicken live weight loss and plasma corticosterone concentration; decreased muscle concentrations of ATP, creatine, and energy charge value; increased muscle AMP concentration and AMP/ATP ratio; and upregulated muscle mRNA expression of LKB1 and AMPKα2, as well as protein expression of p-LKB1 Thr189 and p-AMPKα Thr172 , which subsequently resulted in rapid glycolysis in the pectoralis major muscle and consequent reduction of meat quality. Dietary addition of CMH at 1200 mg/kg ameliorated transport-induced rapid muscle glycolysis and reduction of meat quality via enhancement of the energy-buffering capacity of intramuscular phosphocreatine/creatine system and inhibition of AMPK pathway.

Co-administration of creatine and guanidinoacetic acid for augmented tissue bioenergetics: A novel approach?

PubMed

Ostojic, Sergej M

2017-07-01

A confined absorption of exogenous creatine through creatine transporter (CRT1) seems to hamper its optimal uptake in bioenergetical deficits. Co-administration of guanidinoacetic acid (GAA) along with creatine could target other transport channels besides CRT1, and supremely improve cellular levels of creatine. This innovative approach might tackle tissues difficult to reach with conventional creatine interventions, providing a potentially more effective and safe mixture in clinical pharmacology and therapeutics. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Creatine metabolism: detection of creatine and guanidinoacetate in saliva of healthy subjects.

PubMed

Martínez, Lidia D; Bezard, Miriam; Brunotto, Mabel; Dodelson de Kremer, Raquel

2016-04-01

Creatine (Cr) plays an important role in storage and transmission of phosphate-bound energy. Cerebral creatine deficiency syndromes comprise three inherited defects in Cr biosynthesis and transport. The aim of this study was to investigate whether Cr and Guanidinoacetate (GAA) can be detected in saliva of healthy subjects and to establish the relationship between salivary and plasma levels of these molecules. An adapted gas chromatography (GC) method is described for the quantification of Cr and GAA biomarkers in saliva. Reference values were established for GAA and Cr in saliva. These values were age dependent (p= 0.001). No difference between genders was observed. We detected a difference between GAA and Cr concentrations in saliva and in plasma. The GC method for simultaneous determination of GAA and Cr in human saliva is fast, reliable, sensitive, non-invasive and precise to use as a biochemical approach in early detection of cerebral creatine deficiency syndromes. Sociedad Argentina de Investigación Odontológica.

Analysis of creatine, creatinine, creatine-d3 and creatinine-d3 in urine, plasma, and red blood cells by HPLC and GC-MS to follow the fate of ingested creatine-d3.

PubMed

MacNeil, Lauren; Hill, Lisa; MacDonald, Daniel; Keefe, Lori; Cormier, James F; Burke, Darren G; Smith-Palmer, Truis

2005-12-05

Creatine, which is increasingly being used as an oral supplement, is naturally present in the body. Studies on the fate of a particular dose of creatine require that the creatine be labeled, and for studies in humans the use of a stable isotopic label is desirable. The concentrations of total creatine and total creatinine were determined using HPLC. Creatine and creatinine were then separated using cation exchange chromatography and each fraction was derivatized with trifluoroacetic anhydride and the ratio of the deuterated:undeuterated species determined using GC-MS. Ratios of creatine:creatine-d(3), and creatinine:creatinine-d(3), and the concentrations of each of these species, were able to be determined in urine, plasma and red blood cells. Thus, the uptake of labeled creatine into plasma and red blood cells and its excretion in urine could be followed for a subject who ingested creatine-d(3). Creatine-d(3) was found in the plasma and red blood cells 10 min after ingestion, while creatine-d(3) and creatinine-d(3) were found in the urine collected after the first hour.

Manipulation of Muscle Creatine and Glycogen Changes Dual X-ray Absorptiometry Estimates of Body Composition.

PubMed

Bone, Julia L; Ross, Megan L; Tomcik, Kristyen A; Jeacocke, Nikki A; Hopkins, Will G; Burke, Louise M

2017-05-01

Standardizing a dual x-ray absorptiometry (DXA) protocol is thought to provide a reliable measurement of body composition. We investigated the effects of manipulating muscle glycogen and creatine content independently and additively on DXA estimates of lean mass. Eighteen well-trained male cyclists undertook a parallel group application of creatine loading (n = 9) (20 g·d for 5 d loading; 3 g·d maintenance) or placebo (n = 9) with crossover application of glycogen loading (12 v 6 g·kg BM per day for 48 h) as part of a larger study involving a glycogen-depleting exercise protocol. Body composition, total body water, muscle glycogen and creatine content were assessed via DXA, bioelectrical impedance spectroscopy and standard biopsy techniques. Changes in the mean were assessed using the following effect-size scale: >0.2 small, >0.6, moderate, >1.2 large and compared with the threshold for the smallest worthwhile effect of the treatment. Glycogen loading, both with and without creatine loading, resulted in substantial increases in estimates of lean body mass (mean ± SD; 3.0% ± 0.7% and 2.0% ± 0.9%) and leg lean mass (3.1% ± 1.8% and 2.6% ± 1.0%) respectively. A substantial decrease in leg lean mass was observed after the glycogen depleting condition (-1.4% ± 1.6%). Total body water showed substantial increases after glycogen loading (2.3% ± 2.3%), creatine loading (1.4% ± 1.9%) and the combined treatment (2.3% ± 1.1%). Changes in muscle metabolites and water content alter DXA estimates of lean mass during periods in which minimal change in muscle protein mass is likely. This information needs to be considered in interpreting the results of DXA-derived estimates of body composition in athletes.

Creatine and Phosphocreatine: A Review of Their Use in Exercise and Sport

PubMed Central

Clark, Joseph F.

1997-01-01

Objective: Creatine and phosphocreatine (PCr) are important compounds in the normal energy metabolism of muscle. Recently, it has been shown that dietary creatine (5 to 20 g/day) can increase muscle creatine and PCr, with enhancement in anaerobic exercise performance after two weeks of administration caused by an increase in anaerobic capacity. Data Sources: MEDLINE was searched from 1983 to 1996 using key word “creatine” along with “humans,” “muscle,” “exercise,” and “transport.” Also, APStracts, the American Physiology Society search engine for abstracts, was searched from 1994 to 1996. Data Synthesis: Creatine is transported into the muscle cell by a specific transporter, resulting in increased intracellular creatine and PCr. The PCr is capable of acting as an energy buffer, protecting the adenosine triphosphate (ATP) concentration. Maintaining muscle nucleotides therefore enhances exercise performance and recovery. There have been reports that PCr protects the cells from ischemic damage and decreases the loss of nucleotides by stabilizing cell membranes. Indeed, intravenous PCr (2-4 g/day) has been administered to cyclists, resulting in a faster recovery time between training sessions. Conclusions/Recommendations: It is becoming evident that oral creatine supplementation may yield certain benefits to enhance the athlete's performance during maximal anaerobic exercise and interval training. PMID:16558432

21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Creatine phosphokinase/creatine kinase or... Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system. (a) Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device...

Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.

PubMed

Comeaux, Matthew S; Wang, Jing; Wang, Guoli; Kleppe, Soledad; Zhang, Victor Wei; Schmitt, Eric S; Craigen, William J; Renaud, Deborah; Sun, Qin; Wong, Lee-Jun

2013-07-01

Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing. Copyright © 2013 Elsevier Inc. All rights reserved.

In silico investigation of molecular effects caused by missense mutations in creatine transporter protein

NASA Astrophysics Data System (ADS)

Zhang, Zhe; Schwatz, Charles; Alexov, Emil

2011-03-01

Creatine transporter (CT) protein, which is encoded by SLC6A8 gene, is essential for taking up the creatine in the cell, which in turn plays a key role in the spatial and temporal maintenance of energy in skeletal and cardiac muscle cells. It was shown that some missense mutations in CT cause mental retardation, while others are harmless non-synonymous single nucleoside polymorphism (nsSNP). Currently fifteen missense mutations in CT are known, among which twelve are disease-causing. Sequence analysis reveals that there is no clear trend distinguishing disease-causing from harmless missense mutations. Because of that, we built 3D model of the CT using highly homologous template and use the model to investigate the effects of mutations of CT stability and hydrogen bond network. It is demonstrated that disease-causing mutations affect the folding free energy and ionization states of titratable group in much greater extend as compared with harmless mutations. Supported by grants from NLM, NIH, grant numbers 1R03LM009748 and 1R03LM009748-S1.

Creatine

MedlinePlus

... inherited disorders that affect the senses and movement, schizophrenia, muscle breakdown in the spine, and recovery from ... the effects of creatine alone are not clear. Schizophrenia. Early research shows that taking creatine by mouth ...

A simple LC method with UV detection for the analysis of creatine and creatinine and its application to several creatine formulations.

PubMed

Dash, Alekha K; Sawhney, Angeli

2002-07-31

The objective of this study was to develop a simple and sensitive LC method for the determination of creatine and creatinine in various creatine supplement formulations. The chromatographic system comprised of a LC-600 pump, SCL-6B system controller, and SPD-6AV detector (Shimadzu, Japan). The mobile phase consisted of 0.045 M ammonium sulfate in water. The chromatographic separation was achieved at ambient temperature on a Betabasic C-18 column (250 x 4.6 mm, Keystone Sci.). The flow rate was maintained at 0.75 ml/min and effluents are monitored at 205 nm. 4-(2-Aminoethyl)benzene sulfonamide was used as an internal standard (IS). This method required less than 7 min of chromatographic time. The standard curves were linear over the concentration range of 1-100 microg/ml for creatine and 2-100 microg/ml for creatinine, respectively. The relative standard deviations (RSD) for the within-day and day-to-day precision for creatine were within 1.0-4.6 and 2.2-4.7%, respectively. The RSD for the accuracy of creatine assay was in the range of 2.4-4.7%. The RSD values for the within-day precision, day-to-day precision and accuracy for creatinine validation were 1.7-4.4, 2.3-5.4 and 2.4-4.8%, respectively. This method was used to determine: (i) the creatine concentration in various marketed products; (ii) saturated solubility of various creatine salts; and (iii) stability of creatine in aqueous solution. In conclusion, a simple and sensitive LC method with UV detection was developed for the simultaneous determination of creatine and creatinine in formulations. Di-creatine citrate salt showed a higher aqueous solubility (at 25 degrees C) as compared to creatine and creatine monohydrate. Some of the over-the-counter (OTC) products tested contained a very low level of creatine in contrast to their label claim. Substantial conversion of creatine into creatinine was noticed in liquid formulation.

Creatine kinase and mitochondrial respiration in hearts of trout, cod and freshwater turtle.

PubMed

Birkedal, R; Gesser, H

2003-08-01

The importance of the creatine kinase system in the cardiac muscle of ectothermic vertebrates is unclear. Mammalian cardiac muscle seems to be structurally organized in a manner that compartmentalizes the intracellular environment as evidenced by the substantially higher mitochondrial apparent Km for ADP in skinned fibres compared to isolated mitochondria. A mitochondrial fraction of creatine kinase is functionally coupled to the mitochondrial respiration, and the transport of phosphocreatine and creatine as energy equivalents of ATP and ADP, respectively, increases the mitochondrial apparent ADP affinity, i.e. lowers the Km. This function of creatine kinase seems to be absent in hearts of frog species. To find out whether this applies to hearts of ectothermic vertebrate species in general, we investigated the effect of creatine on the mitochondrial respiration of saponin-skinned fibres from the ventricle of rainbow trout, Atlantic cod and freshwater turtle. For all three species, the apparent Km for ADP appeared to be substantially higher than for isolated mitochondria. Creatine lowered this Km in trout and turtle, thus indicating a functional coupling between mitochondrial creatine kinase and respiration. However, creatine had no effect on Km in cod ventricle. In conclusion, the creatine kinase-system in trout and turtle hearts seems to fulfil the same functions as in the mammalian heart, i.e. facilitating energy transport and communication between cellular compartments. In cod heart, however, this does not seem to be the case.

Enzymes of creatine biosynthesis, arginine and methionine metabolism in normal and malignant cells.

PubMed

Bera, Soumen; Wallimann, Theo; Ray, Subhankar; Ray, Manju

2008-12-01

The creatine/creatine kinase system decreases drastically in sarcoma. In the present study, an investigation of catalytic activities, western blot and mRNA expression unambiguously demonstrates the prominent expression of the creatine-synthesizing enzymes l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase in sarcoma, Ehrlich ascites carcinoma and Sarcoma 180 cells, whereas both enzymes were virtually undetectable in normal muscle. Compared to that of normal animals, these enzymes remained unaffected in the kidney or liver of sarcoma-bearing mice. High activity and expression of mitochondrial arginase II in sarcoma indicated increased ornithine formation. Slightly or moderately higher levels of ornithine, guanidinoacetate and creatinine were observed in sarcoma compared to muscle. Despite the intrinsically low level of creatine in Ehrlich ascites carcinoma and Sarcoma 180 cells, these cells could significantly take up and release creatine, suggesting a functional creatine transport, as verified by measuring mRNA levels of creatine transporter. Transcript levels of arginase II, ornithine-decarboxylase, S-adenosyl-homocysteine hydrolase and methionine-synthase were significantly upregulated in sarcoma and in Ehrlich ascites carcinoma and Sarcoma 180 cells. Overall, the enzymes related to creatine and arginine/methionine metabolism were found to be significantly upregulated in malignant cells. However, the low levels of creatine kinase in the same malignant cells do not appear to be sufficient for the building up of an effective creatine/phosphocreatine pool. Instead of supporting creatine biosynthesis, l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase appear to be geared to support cancer cell metabolism in the direction of polyamine and methionine synthesis because both these compounds are in high demand in proliferating cancer cells.

Does maternal-fetal transfer of creatine occur in pregnant sheep?

PubMed

Baharom, Syed; De Matteo, Robert; Ellery, Stacey; Della Gatta, Paul; Bruce, Clinton R; Kowalski, Greg M; Hale, Nadia; Dickinson, Hayley; Harding, Richard; Walker, David; Snow, Rodney J

2017-07-01

Our aim was to determine the disposition of creatine in ovine pregnancy and whether creatine is transferred across the placenta from mother to fetus. Pregnant ewes received either 1 ) a continuous intravenous infusion of creatine monohydrate or saline from 122 to 131 days gestation, with maternal and fetal arterial blood and amniotic fluid samples collected daily for creatine analysis and fetal tissues collected at necropsy at 133 days for analysis of creatine content, or 2 ) a single systemic bolus injection of [ 13 C]creatine monohydrate at 130 days of gestation, with maternal and fetal arterial blood, uterine vein blood, and amniotic fluid samples collected before and for 4 h after injection and analyzed for creatine, creatine isotopic enrichment, and guanidinoacetic acid (GAA; precursor of creatine) concentrations. Presence of the creatine transporter-1 (SLC6A8) and l-arginine:glycine amidinotransferase (AGAT; the enzyme synthesizing GAA) proteins were determined by Western blots of placental cotyledons. The 10-day creatine infusion increased maternal plasma creatine concentration three- to fourfold ( P < 0.05) without significantly changing fetal arterial, amniotic fluid, fetal tissues, or placental creatine content. Maternal arterial 13 C enrichment was increased ( P < 0.05) after bolus [ 13 C]creatine injection without change of fetal arterial 13 C enrichment. SLC6A8 and AGAT proteins were identified in placental cotyledons, and GAA concentration was significantly higher in uterine vein than maternal artery plasma. Despite the presence of SLC6A8 protein in cotyledons, these results suggest that creatine is not transferred from mother to fetus in near-term sheep and that the ovine utero-placental unit releases GAA into the maternal circulation. Copyright © 2017 the American Physiological Society.

Creatine Use in Sports.

PubMed

Butts, Jessica; Jacobs, Bret; Silvis, Matthew

The use of creatine as a dietary supplement has become increasingly popular over the past several decades. Despite the popularity of creatine, questions remain with regard to dosing, effects on sports performance, and safety. PubMed was searched for articles published between 1980 and January 2017 using the terms creatine, creatine supplementation, sports performance, and dietary supplements. An additional Google search was performed to capture National Collegiate Athletic Association-specific creatine usage data and US dietary supplement and creatine sales. Clinical review. Level 4. Short-term use of creatine is considered safe and without significant adverse effects, although caution should be advised as the number of long-term studies is limited. Suggested dosing is variable, with many different regimens showing benefits. The safety of creatine supplementation has not been studied in children and adolescents. Currently, the scientific literature best supports creatine supplementation for increased performance in short-duration, maximal-intensity resistance training. While creatine appears to be safe and effective for particular settings, whether creatine supplementation leads to improved performance on the field of play remains unknown.

A Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat

PubMed Central

Kazak, Lawrence; Chouchani, Edward T.; Jedrychowski, Mark P.; Erickson, Brian K.; Shinoda, Kosaku; Cohen, Paul; Vetrivelan, Ramalingam; Lu, Gina Z.; Laznik-Bogoslavski, Dina; Hasenfuss, Sebastian C.; Kajimura, Shingo; Gygi, Steve P.; Spiegelman, Bruce M.

2015-01-01

SUMMARY Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial Creatine Kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole body energy expenditure after administration of a β3-agonist and reduces the adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. PMID:26496606

A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat.

PubMed

Kazak, Lawrence; Chouchani, Edward T; Jedrychowski, Mark P; Erickson, Brian K; Shinoda, Kosaku; Cohen, Paul; Vetrivelan, Ramalingam; Lu, Gina Z; Laznik-Bogoslavski, Dina; Hasenfuss, Sebastian C; Kajimura, Shingo; Gygi, Steve P; Spiegelman, Bruce M

2015-10-22

Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a β3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. PAPERCLIP. Copyright © 2015 Elsevier Inc. All rights reserved.

Arginine-guanidinoacetate-creatine pathway in preterm newborns: creatine biosynthesis in newborns.

PubMed

Lage, Sergio; Andrade, Fernando; Prieto, José Angel; Asla, Izaskun; Rodríguez, Amaya; Ruiz, Nerea; Echeverría, Juncal; Luz Couce, María; Sanjurjo, Pablo; Aldámiz-Echevarría, Luis

2013-01-01

The phosphocreatine/creatine system is fundamental for the proper development of the embryonic brain. Being born prematurely might alter the creatine biosynthesis pathway, in turn affecting creatine supply to the developing brain. We enrolled 53 preterm and very preterm infants and 55 full-term newborns. The levels of urinary guanidinoacetate, creatine, creatinine and amino acids were measured in the preterm and very preterm groups, 48 h and 9 days after birth and at discharge, and 48 h after birth in the full-term group. Guanidinoacetate concentrations of both preterm and very preterm newborns were significantly higher at discharge than the values for the full-term group at 48 h, while very preterm infants showed urinary creatine values significantly lower than those measured in the full-term group. Our results suggest an impairment of the creatine biosynthesis pathway in preterm and very preterm newborns, which could lead to creatine depletion affecting the neurological outcome in prematurely born infants.

Macro creatine kinase: determination and differentiation of two types by their activation energies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stein, W.; Bohner, J.; Steinhart, R.

1982-01-01

Determination of the MB isoenzyme of creatine kinase in patients with acute myocardial infarction may be disturbed by the presence of macro creatine kinase. The relative molecular mass of this form of creatine kinase in human serum is at least threefold that of the ordinary enzyme, and it is more thermostable. Here we describe our method for determination of macro creatine kinases and an easy-to-perform test for differentiating two forms of macro creatine kinase, based on their distinct activation energies. The activation energies of serum enzymes are mostly in the range of 40-65 kJ/mol of substrate. Unlike normal cytoplasmatic creatinemore » kinases and IgG-linked CK-BB (macro creatine kinase type 1) a second form of macro creatine kinase (macro creatine kinase type 2) shows activation energies greater than 80 kJ/mol of substrate. The exact composition of macro creatine kinase type 2 is still unknown, but there is good reason to believe that it is of mitochondrial origin.« less

Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia.

PubMed

Baum, Michel; Syal, Ashu; Quigley, Raymond; Seikaly, Mouin

2006-08-01

X-linked hypophosphatemia is an X-linked dominant disorder resulting from a mutation in the PHEX gene. PHEX stands for phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. The renal phosphate wasting is not intrinsic to the kidney but likely due to an increase in serum levels of fibroblast growth factor-23 (FGF-23), and perhaps other phosphate-wasting peptides previously known as phosphatonins. Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. In this review, we describe recent observations using Hyp mice; mice with the same mutation as patients with X-linked hypophosphatemia. We have recently found that Hyp mice have abnormal renal prostaglandin production, which may be an important factor in the pathogenesis of this disorder. Administration of FGF-23 in vivo results in phosphaturia and an increase in prostaglandin excretion, and FGF-23 increases proximal tubule prostaglandin production in vitro. In Hyp mice, indomethacin improves the phosphate transport defect in vitro and in vivo. Whether indomethacin has the same effect in patients with X-linked hypophosphatemia is unknown.

Creatine in the central nervous system: From magnetic resonance spectroscopy to creatine deficiencies.

PubMed

Rackayova, Veronika; Cudalbu, Cristina; Pouwels, Petra J W; Braissant, Olivier

2017-07-15

Creatine (Cr) is an important organic compound acting as intracellular high-energy phosphate shuttle and in energy storage. While located in most cells where it plays its main roles in energy metabolism and cytoprotection, Cr is highly concentrated in muscle and brain tissues, in which Cr also appears to act in osmoregulation and neurotransmission. This review discusses the basis of Cr metabolism, synthesis and transport within brain cells. The importance of Cr in brain function and the consequences of its impaired metabolism in primary and secondary Cr deficiencies are also discussed. Cr and phosphocreatine (PCr) in living systems can be well characterized using in vivo magnetic resonance spectroscopy (MRS). This review describes how 1 H MRS allows the measurement of Cr and PCr, and how 31 P MRS makes it possible to estimate the creatine kinase (CK) rate constant and so detect dynamic changes in the Cr/PCr/CK system. Absolute quantification by MRS using creatine as internal reference is also debated. The use of in vivo MRS to study brain Cr in a non-invasive way is presented, as well as its use in clinical and preclinical studies, including diagnosis and treatment follow-up in patients. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of dietary creatine.

PubMed

Brosnan, Margaret E; Brosnan, John T

2016-08-01

The daily requirement of a 70-kg male for creatine is about 2 g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body Creatine is a carninutrient, which means that it is only available to adults via animal foodstuffs, principally skeletal muscle, or via supplements. Infants receive creatine in mother's milk or in milk-based formulas. Vegans and infants fed on soy-based formulas receive no dietary creatine. Plasma and muscle creatine levels are usually somewhat lower in vegetarians than in omnivores. Human intake of creatine was probably much higher in Paleolithic times than today; some groups with extreme diets, such as Greenland and Alaskan Inuit, ingest much more than is currently typical. Creatine is synthesized from three amino acids: arginine, glycine and methionine (as S-adenosylmethionine). Humans can synthesize sufficient creatine for normal function unless they have an inborn error in a creatine-synthetic enzyme or a problem with the supply of substrate amino acids. Carnivorous animals, such as lions and wolves, ingest much larger amounts of creatine than humans would. The gastrointestinal tract and the liver are exposed to dietary creatine in higher concentrations before it is assimilated by other tissues. In this regard, our observations that creatine supplementation can prevent hepatic steatosis (Deminice et al. J Nutr 141:1799-1804, 2011) in a rodent model may be a function of the route of dietary assimilation. Creatine supplementation has also been reported to improve the intestinal barrier function of the rodent suffering from inflammatory bowel disease.

INFLUENCE OF TOTAL BODY X-IRRADIATION ON THE LEVELS OF CREATINE PHOSPHATE, INORGANIC PHOSPHORUS AND ATP IN MUSCLE AND ON THE LEVELS OF CREATINE, CREATININE, N'-METHYL-NICOTINAMIDE AND NITROGEN IN URINE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumta, U.S.; Gurnani, S.U.; Sahasrabudhe, M.B.

1957-09-01

The influence of total-body irradiation on the levels of creatine phosphate (CP), adenosine triphosphate (ATP) and inorganic phosphorus (IP) in muscle has been investigated in rats. CP and ATP levels decrease by about 33% while those of 1P increase 4 times in irradiated rats. Studies on the influence of irradiation on the excretion of creatine, creatinine, and N'-methyl- nicotinamide in urine show that the excretion of creatine and N'-methyl- nlcotinamide is increased two-fold while that of creatinine is increased by 160%. It is suggested that the low levels of creatine phosphate are probably due to an impairment in the phosphorylationmore » of creatine or due to an adaptive breakdown of creatine phosphate leading to increased excretion of creatine and creatinine. (auth)« less

Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study.

PubMed

Merege-Filho, Carlos Alberto Abujabra; Otaduy, Maria Concepción Garcia; de Sá-Pinto, Ana Lúcia; de Oliveira, Maira Okada; de Souza Gonçalves, Lívia; Hayashi, Ana Paula Tanaka; Roschel, Hamilton; Pereira, Rosa Maria Rodrigues; Silva, Clovis Artur; Brucki, Sonia Maria Dozzi; da Costa Leite, Claudia; Gualano, Bruno

2017-02-01

It has been hypothesized that dietary creatine could influence cognitive performance by increasing brain creatine in developing individuals. This double-blind, randomized, placebo-controlled, proof-of-principle study aimed to investigate the effects of creatine supplementation on cognitive function and brain creatine content in healthy youth. The sample comprised 67 healthy participants aged 10 to 12 years. The participants were given creatine or placebo supplementation for 7 days. At baseline and after the intervention, participants undertook a battery of cognitive tests. In a random subsample of participants, brain creatine content was also assessed in the regions of left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe by proton magnetic resonance spectroscopy (1H-MRS) technique. The scores obtained from verbal learning and executive functions tests did not significantly differ between groups at baseline or after the intervention (all p > 0.05). Creatine content was not significantly different between groups in left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe (all p > 0.05). In conclusion, a 7-day creatine supplementation protocol did not elicit improvements in brain creatine content or cognitive performance in healthy youth, suggesting that this population mainly relies on brain creatine synthesis rather than exogenous creatine intake to maintain brain creatine homeostasis.

Impaired plasticity of macrophages in X-linked adrenoleukodystrophy.

PubMed

Weinhofer, Isabelle; Zierfuss, Bettina; Hametner, Simon; Wagner, Magdalena; Popitsch, Niko; Machacek, Christian; Bartolini, Barbara; Zlabinger, Gerhard; Ohradanova-Repic, Anna; Stockinger, Hannes; Köhler, Wolfgang; Höftberger, Romana; Regelsberger, Günther; Forss-Petter, Sonja; Lassmann, Hans; Berger, Johannes

2018-05-30

X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses

Genetics Home Reference: X-linked thrombocytopenia

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked thrombocytopenia X-linked thrombocytopenia Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description X-linked thrombocytopenia is a bleeding disorder that primarily ...

Creatine phosphokinase test

MedlinePlus

... this page: //medlineplus.gov/ency/article/003503.htm Creatine phosphokinase test To use the sharing features on this page, please enable JavaScript. Creatine phosphokinase (CPK) is an enzyme in the body. ...

In the absence of phosphate shuttling, exercise reveals the in vivo importance of creatine-independent mitochondrial ADP transport.

PubMed

Miotto, Paula M; Holloway, Graham P

2016-09-15

The transport of cytosolic adenosine diphosphate (ADP) into the mitochondria is a major control point in metabolic homeostasis, as ADP concentrations directly affect glycolytic flux and oxidative phosphorylation rates within mitochondria. A large contributor to the efficiency of this process is thought to involve phosphocreatine (PCr)/Creatine (Cr) shuttling through mitochondrial creatine kinase (Mi-CK), whereas the biological importance of alterations in Cr-independent ADP transport during exercise remains unknown. Therefore, we utilized an Mi-CK knockout (KO) model to determine whether in vivo Cr-independent mechanisms are biologically important for sustaining energy homeostasis during exercise. Ablating Mi-CK did not alter exercise tolerance, as the time to volitional fatigue was similar between wild-type (WT) and KO mice at various exercise intensities. In addition, skeletal muscle metabolic profiles after exercise, including glycogen, PCr/Cr ratios, free ADP/adenosine monophosphate (AMP), and lactate, were similar between genotypes. While these data suggest that the absence of PCr/Cr shuttling is not detrimental to maintaining energy homeostasis during exercise, KO mice displayed a dramatic increase in Cr-independent mitochondrial ADP sensitivity after exercise. Specifically, whereas mitochondrial ADP sensitivity decreased with exercise in WT mice, in stark contrast, exercise increased mitochondrial Cr-independent ADP sensitivity in KO mice. As a result, the apparent ADP Km was 50% lower in KO mice after exercise, suggesting that in vivo activation of voltage-dependent anion channel (VDAC)/adenine nucleotide translocase (ANT) can support mitochondrial ADP transport. Altogether, we provide insight that Cr-independent ADP transport mechanisms are biologically important for regulating ADP sensitivity during exercise, while highlighting complex regulation and the plasticity of the VDAC/ANT axis to support adenosine triphosphate demand. © 2016 The Author

Creatine and guanidinoacetate reference values in a French population.

PubMed

Joncquel-Chevalier Curt, Marie; Cheillan, David; Briand, Gilbert; Salomons, Gajja S; Mention-Mulliez, Karine; Dobbelaere, Dries; Cuisset, Jean-Marie; Lion-François, Laurence; Des Portes, Vincent; Chabli, Allel; Valayannopoulos, Vassili; Benoist, Jean-François; Pinard, Jean-Marc; Simard, Gilles; Douay, Olivier; Deiva, Kumaran; Tardieu, Marc; Afenjar, Alexandra; Héron, Delphine; Rivier, François; Chabrol, Brigitte; Prieur, Fabienne; Cartault, François; Pitelet, Gaëlle; Goldenberg, Alice; Bekri, Soumeya; Gerard, Marion; Delorme, Richard; Porchet, Nicole; Vianey-Saban, Christine; Vamecq, Joseph

2013-11-01

Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and

Whole Body Creatine and Protein Kinetics in Healthy Men and Women: Effects of creatine and amino acid supplementation

PubMed Central

Kalhan, Satish C; Gruca, Lourdes; Marczewski, Susan; Bennett, Carole; Kummitha, China

2015-01-01

Creatine kinetics were measured in young healthy subjects, eight males and seven females, age 20–30 years, after an overnight fast on creatine free diet. Whole body turnover of glycine and its appearance in creatine was quantified using [1-13C] glycine and the rate of protein turnover was quantified using L-ring [2H5] phenylalanine. The creatine pool size was estimated by the dilution of a bolus [C2H3] creatine. Studies were repeated following a five days supplement creatine 21g.day−1 and following supplement amino acids 14.3 g.day−1. Creatine caused a ten folds increase in the plasma concentration of creatine and a 50% decrease in the concentration of guanidinoacetic acid. Plasma amino acids profile showed a significant decrease in glycine, glutamine and taurine and a significant increase in citrulline, valine, lysine and cysteine. There was a significant decrease in the rate of appearance of glycine, suggesting a decrease in de-novo synthesis (p=0.006). The fractional and absolute rate of synthesis of creatine was significantly decreased by supplemental creatine. Amino acid supplement had no impact on any of the parameters. Creatine supplement caused a significant decrease in the rate of synthesis of creatine. This is the first detailed analysis of creatine kinetics and the effects of creatine supplement in healthy young men and women. These methods can be applied for the analysis of creatine kinetics in different physiological states. PMID:26480831

Plasma Creatine Kinetics After Ingestion of Microencapsulated Creatine Monohydrate with Enhanced Stability in Aqueous Solutions.

PubMed

Hone, Michelle; Kent, Robert M; Scotto di Palumbo, Alessandro; Bleiel, Sinead B; De Vito, Giuseppe; Egan, Brendan

2017-07-04

Creatine monohydrate represents one of the largest sports supplement markets. Enhancing creatine (CRE) stability in aqueous solutions, such as with microencapsulation, represents innovation potential. Ten physically active male volunteers were randomly assigned in a double-blind design to either placebo (PLA) (3-g maltodextrin; n = 5) or microencapsulated CRE (3-g creatine monohydrate; n = 5) conditions. Experimental conditions involved ingestion of the samples in a 70-mL ready-to-drink format. CRE was delivered in a novel microencapsulation matrix material consisting entirely of hydrolyzed milk protein. Three hours after ingestion, plasma creatine concentrations were unchanged during PLA, and averaged ∼45 μM. During CRE, plasma creatine concentration peaked after 30 min at 101.6 ± 14.9 μM (p < 0.05), representing a 2.3-fold increase over PLA. Thereafter, plasma creatine concentration gradually trended downwards but remained significantly elevated (∼50% above resting levels) 3 hr after ingestion. These results demonstrate that the microencapsulated form of creatine monohydrate reported herein remains bioavailable when delivered in aqueous conditions, and has potential utility in ready-to-drink formulations for creatine supplementation.

21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

Biochemical changes in the skin of rats exposed to radiation against the background of thermal stress. [X rays; ATPase and creatine kinase activities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matyushichev, V.B.; Taratukhin, V.R.; Shamratova, V.G.

1978-01-01

The effectiveness of exposing rats to different doses of x radiation after submitting them to a heat load, according to the tests of ATPase and creatine kinase activity of aqueous extracts of skin at the relatively late observation period was compared. The effects of the combined factors were monitored by means of a heat load (one group) and exposure to radiation alone in doses of 25, 50, 100, 250, and 400 R (5 groups). The obtained data are indicative of marked specificity of ATPase and creatine kinase reactions to the combined factors. Creatine kinase activity undergoes a 157% change, whereasmore » the mean relative deviation of ATPase activity constitutes only 71% of the normal level. The most effect loads are 36/sup 0/C + 25 R and 36/sup 0/C + 400 R. With all tested doses the extent of the effect of radiation on creatine kinase activity is only negligibly lower than the effectiveness of combined loads, whereas according to the ATPase test, radiation alone induces virtually the same changes in activity as combined factors. ATPase undergoes maximum change after irradiation in doses of 250 and 400 R; delivery of 25 to 100 R is associated with much less marked changes in activity. In contrast, creatine kinase demonstrates maximum sensitivity to radiation in a dosage of 25 R and minimum sensitivity, with a dosage of 100 R. Thermal stress (according to ATPase and creatine kinase activity) has a profound and quite substantial effect on processes of development of radiation lesion. It can be manifested by complete or partial summation of effects of each of the factors, mutual attenuation of effects, or absence of interaction between factors in the combination. All this is indicative of the complexity and differences in mechanisms of expression of effects of the factors used. (ERB)« less

Creatine supplementation in high school football players.

PubMed

McGuine, T A; Sullivan, J C; Bernhardt, D T

2001-10-01

To describe creatine supplementation patterns and behaviors associated with creatine supplementation in high school football players. A cross-sectional, multisite, anonymous, descriptive survey was conducted between October 1999 and February 2000. 37 public high schools in Wisconsin. A total of 1,349 high school football players, grades 9-12. Self-reported prevalence of creatine use, as well as perceived benefits and risks. In addition, sources of information and influence regarding creatine supplementation were assessed. 30% of the respondents reported using creatine. Creatine use was lowest in the 9th grade (10.4%) and highest in the 12th grade (50.5%). 41% of the players at small schools stated they used creatine compared with 29% of the players in large schools. Enhanced recovery following a workout was the most likely perceived benefit of creatine supplementation, while dehydration was cited most often as a risk of creatine use. Users were encouraged to take creatine most often by their friends while their parents discouraged creatine use. Creatine use is widespread in high school football players. High school football players who use creatine may not be aware of the risks and benefits associated with creatine supplementation. Sports medicine professionals who work with this population need to educate athletes, coaches, and parents about the use of creatine as a performance-enhancing supplement.

The metabolic burden of creatine synthesis.

PubMed

Brosnan, John T; da Silva, Robin P; Brosnan, Margaret E

2011-05-01

Creatine synthesis is required in adult animals to replace creatine that is spontaneously converted to creatinine and excreted in the urine. Additionally, in growing animals it is necessary to provide creatine to the expanding tissue mass. Creatine synthesis requires three amino acids: glycine, methionine and arginine, and three enzymes: L-arginine:glycine amidinotransferase (AGAT), methionine adenosyltransferase (MAT) and guanidinoacetate methyltransferase (GAMT). The entire glycine molecule is consumed in creatine synthesis but only the methyl and amidino groups, respectively, from methionine and arginine. Creatinine loss averages approximately 2 g (14.6 mmol) for 70 kg males in the 20- to 39-year age group. Creatinine loss is lower in females and in older age groups because of lower muscle mass. Approximately half of this creatine lost to creatinine can be replaced, in omnivorous individuals, by dietary creatine. However, since dietary creatine is only provided in animal products, principally in meat and fish, virtually all of the creatine loss in vegetarians must be replaced via endogenous synthesis. Creatine synthesis does not appear to place a major burden on glycine metabolism in adults since this amino acid is readily synthesized. However, creatine synthesis does account for approximately 40% of all of the labile methyl groups provided by S-adenosylmethionine (SAM) and, as such, places an appreciable burden on the provision of such methyl groups, either from the diet or via de novo methylneogenesis. Creatine synthesis consumes some 20-30% of arginine's amidino groups, whether provided in the diet or synthesized within the body. Creatine synthesis is, therefore, a quantitatively major pathway in amino acid metabolism and imposes an appreciable burden on the metabolism of methionine and of arginine.

Whole body creatine and protein kinetics in healthy men and women: effects of creatine and amino acid supplementation.

PubMed

Kalhan, Satish C; Gruca, Lourdes; Marczewski, Susan; Bennett, Carole; Kummitha, China

2016-03-01

Creatine kinetics were measured in young healthy subjects, eight males and seven females, age 20-30 years, after an overnight fast on creatine-free diet. Whole body turnover of glycine and its appearance in creatine was quantified using [1-(13)C] glycine and the rate of protein turnover was quantified using L-ring [(2)H5] phenylalanine. The creatine pool size was estimated by the dilution of a bolus [C(2)H3] creatine. Studies were repeated following a five days supplement creatine 21 g.day(-1) and following supplement amino acids 14.3 g day(-1). Creatine caused a ten-fold increase in the plasma concentration of creatine and a 50 % decrease in the concentration of guanidinoacetic acid. Plasma amino acids profile showed a significant decrease in glycine, glutamine, and taurine and a significant increase in citrulline, valine, lysine, and cysteine. There was a significant decrease in the rate of appearance of glycine, suggesting a decrease in de-novo synthesis (p = 0.006). The fractional and absolute rate of synthesis of creatine was significantly decreased by supplemental creatine. Amino acid supplement had no impact on any of the parameters. This is the first detailed analysis of creatine kinetics and the effects of creatine supplement in healthy young men and women. These methods can be applied for the analysis of creatine kinetics in different physiological states.

A new method to synthesize creatine derivatives.

PubMed

Garbati, Patrizia; Salis, Annalisa; Adriano, Enrico; Galatini, Andrea; Damonte, Gianluca; Balestrino, Maurizio; Millo, Enrico

2013-10-01

Creatine is an amino acid that has a pivotal role in energy metabolism of cells. Creatine acts as an "ATP shuttle", carrying ATP to the sites where it is utilized, through its reversible phosphorylation by creatine kinase. Moreover, the creatine-phosphocreatine system delays ATP depletion during anoxia or ischemia, thus exerting a neuroprotective role during those pathological conditions. Thus, its administration has been advocated as a treatment or prevention of several conditions involving the central nervous system. However, creatine crosses poorly the blood-brain barrier and the cell plasma membrane, thus its administration has but a limited effect. The use of more lipophilic creatine derivatives has thus been suggested. However, such a synthesis is complicated by the intrinsic characteristics of the creatine molecule that hardly reacts with other molecules and easily cyclizes to creatinine. We obtained amide derivatives from creatine starting from a new protected creatine molecule synthesized by us, the so-called (Boc)2-creatine. We used a temporary protection only on the creatine guanidine group while allowing a good reactivity on the carboxylic group. This temporary protection ensured efficient creatine dissolution in organic solvents and offered simultaneous protection of creatine toward intramolecular cyclization to creatinine. In this manner, it was possible to selectively conjugate molecules on the carboxylic group. The creatine guanidine group was easily released from the protection at the end of the reaction, thus obtaining the desired creatine derivative.

NMR studies on /sup 15/N-labeled creatine (CR), creatinine (CRN), phosphocreatine (PCR), and phosphocreatinine (PCRN), and on barriers to rotation in creatine kinase-bound creatine in the enzymatic reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kenyon, G.L.; Reddick, R.E.

1986-05-01

Recently, the authors have synthesized /sup 15/N-2-Cr, /sup 15/N-3-Crn, /sup 15/N-2-Crn, /sup 15/N-3-PCrn, /sup 15/N-3-PCr, and /sup 15/N-2-PCr. /sup 1/H, /sup 15/N, /sup 31/P NMR data show that Crn protonates exclusively at the non-methylated ring nitrogen, confirm that PCrn is phosphorylated at the exocyclic nitrogen, and demonstrate that the /sup 31/P-/sup 15/N one-bond coupling constant in /sup 15/N-3-PCr is 18 Hz, not 3 Hz as previously reported by Brindle, K.M., Porteous, R. and Radda, G.K.. The authors have found that creatine kinase is capable of catalyzing the /sup 14/N//sup 15/N positional isotope exchange of 3-/sup 15/N-PCr in the presence ofmore » MgADP, but not in its absence. Further, the exchange does not take place when labeled PCr is resynthesized exclusively from the ternary complex E X Cr X MgATP as opposed to either E X Cr or free Cr. This suggests that the enzyme both imparts an additional rotational barrier to creatine in the complex and catalyzes the transfer of phosphoryl group with essentially complete regiospecificity.« less

Genetics Home Reference: X-linked dilated cardiomyopathy

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... Twitter Home Health Conditions X-linked dilated cardiomyopathy X-linked dilated cardiomyopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked dilated cardiomyopathy is a form of heart ...

Genetics Home Reference: X-linked myotubular myopathy

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... Twitter Home Health Conditions X-linked myotubular myopathy X-linked myotubular myopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked myotubular myopathy is a condition that primarily ...

Genetics Home Reference: X-linked sideroblastic anemia

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... Twitter Home Health Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that ...

ALTERATIONS IN BRAIN CREATINE CONCENTRATIONS UNDER LONG-TERM SOCIAL ISOLATION (EXPERIMENTAL STUDY).

PubMed

Koshoridze, N; Kuchukashvili, Z; Menabde, K; Lekiashvili, Sh; Koshoridze, M

2016-02-01

Stress represents one of the main problems of modern humanity. This study was done for understanding more clearly alterations in creatine content of the brain under psycho-emotional stress induced by long-term social isolation. It was shown that under 30 days social isolation creatine amount in the brain was arisen, while decreasing concentrations of synthesizing enzymes (AGAT, GAMT) and creatine transporter protein (CrT). Another important point was that such changes were accompanied by down-regulation of creatine kinase (CK), therefore the enzyme's concentration was lowered. In addition, it was observed that content of phosphocreatine (PCr) and ATP were also reduced, thus indicating down-regulation of energy metabolism of brain that is really a crucial point for its normal functioning. To sum up the results it can be underlined that long-term social isolation has negative influence on energy metabolism of brain; and as a result reduce ATP content, while increase of free creatine concentration, supposedly maintaining maximal balance for ATP amount, but here must be also noted that up-regulated oxidative pathways might have impact on blood brain barrier, resulting on its permeability.

Diagnosis and therapeutic monitoring of inborn errors of creatine metabolism and transport using liquid chromatography-tandem mass spectrometry in urine, plasma and CSF.

PubMed

Haas, Dorothea; Gan-Schreier, Hongying; Langhans, Claus-Dieter; Anninos, Alexandros; Haege, Gisela; Burgard, Peter; Schulze, Andreas; Hoffmann, Georg F; Okun, Jürgen G

2014-03-15

Biochemical detection of inborn errors of creatine metabolism or transport relies on the analysis of three main metabolites in biological fluids: guanidinoacetate (GAA), creatine (CT) and creatinine (CTN). Unspecific clinical presentation of the diseases might be the cause that only few patients have been diagnosed so far. We describe a LC-MS/MS method allowing fast and reliable diagnosis by simultaneous quantification of GAA, CT and CTN in urine, plasma and cerebrospinal fluid (CSF) and established reference values for each material. For quantification deuterated stable isotopes of each analyte were used as internal standards. GAA, CT and CTN were separated by reversed-phase HPLC. The characterization was carried out by scanning the ions of each compound by negative ion tandem mass spectrometry. Butylation is needed to achieve sufficient signal intensity for GAA and CT but it is not useful for analyzing CTN. The assay is linear in a broad range of analyte concentrations usually found in urine, plasma and CSF. Comparison of the "traditional" cation-exchange chromatography and LC-MS/MS showed proportional differences but linear relationships between the two methods. The described method is characterized by high speed and linearity over large concentration ranges comparable to other published LC-MS methods but with higher sensitivity for GAA and CT. In addition, we present the largest reference group ever published for guanidino compounds in all relevant body fluids. Therefore this method is applicable for high-throughput approaches for diagnosis and follow-up of inborn errors of creatine metabolism and transport. Copyright © 2014 Elsevier B.V. All rights reserved.

Mapping the x-linked lymphoproliferative syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skare, J.C.; Milunsky, A.; Byron, K.S.

1987-04-01

The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predictmore » which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.« less

Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine

PubMed Central

Faller, Kiterie M E; Atzler, Dorothee; McAndrew, Debra J; Zervou, Sevasti; Whittington, Hannah J; Simon, Jillian N; Aksentijevic, Dunja; ten Hove, Michiel; Choe, Chi-un; Isbrandt, Dirk; Casadei, Barbara; Schneider, Jurgen E; Neubauer, Stefan; Lygate, Craig A

2018-01-01

Abstract Aims Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesized that AGAT-/- mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality. Methods and results Withdrawal of dietary creatine in AGAT-/- mice provided an estimate of myocardial creatine efflux of ∼2.7%/day; however, in vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT-/- mice naïve to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT-/- mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naïve AGAT-/- mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy, and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalization of myocardial creatine. AGAT-/- mice had low plasma HA and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT-/- was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that HA is necessary for normal cardiac function. Conclusions Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that HA deficiency can impair cardiac function, which may explain why low HA is an independent risk factor for multiple cardiovascular diseases

Living Without Creatine: Unchanged Exercise Capacity and Response to Chronic Myocardial Infarction in Creatine-Deficient Mice

PubMed Central

Lygate, Craig A.; Aksentijevic, Dunja; Dawson, Dana; Hove, Michiel ten; Phillips, Darci; de Bono, Joseph P.; Medway, Debra J.; Sebag-Montefiore, Liam; Hunyor, Imre; Channon, Keith M.; Clarke, Kieran; Zervou, Sevasti; Watkins, Hugh; Balaban, Robert S.; Neubauer, Stefan

2014-01-01

Rationale Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress. Objective We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction. Methods and Results Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase – GAMT) voluntarily ran just as fast and as far as controls (>10km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent LV remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT−/− proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT−/− hearts accumulated the creatine pre-cursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function. Conclusions Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle. PMID:23325497

Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages.

PubMed

Leland, Korey M; McDonald, Thomas L; Drescher, Kristen M

2011-09-01

Despite the widespread availability and use of dietary supplements, minimal work has been performed to assess the potential dangers many of these supplements may have on the host's well-being, in particular the host's ability to respond to infection. One supplement extensively used by both adolescents and adults is creatine. Using Real-time PCR, we examined the impact of short-term exposure of a mouse macrophage cell line (RAW 264.7 cells) to two readily available forms of creatine used in supplements--creatine monohydrate (CR) and creatine ethyl ester (CEE) as well as the end product of creatine metabolism, creatinine (CRN), on expression of toll-like receptor-2 (TLR-2), TLR-3, TLR-4, and TLR-7. CR down-regulated TLR-2, TLR-3, TLR-4 and TLR-7 mRNA levels in RAW cells. Similar results were observed following exposure of RAW cells to CRN. Conversely CEE appears to possess immunostimulatory properties and increases expression of TLR-2, TLR-3, TLR-4, and TLR-7 in RAW cells. These data are supported by immunostaining using antibodies specific for the individual TLRs before and after exposure of RAW cells to CR, CRN, or CEE. To extend these findings, we isolated murine splenocytes and exposed the cells to CR, CEE, or CRN for 24 hours and performed immunofluorescent staining for TLR-2, TLR-3, TLR-4 and TLR-7. The results obtained from this study with primary splenocytes were consistent with the studies using RAW cells. Together, these data suggest that creatine and creatine derivatives may impact the ability of immune cells to sense a wide array of viral and bacterial pathogens. Of great interest, CRN--largely considered to be a waste product of the argenine biosynthesis pathway may also have immunosuppressive properties similar to those of CR. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages

PubMed Central

Leland, Korey M.; McDonald, Thomas L.; Drescher, Kristen M.

2011-01-01

Despite the widespread availability and use of dietary supplements, minimal work has been performed to assess the potential dangers many of these supplements may have on the host’s well-being, in particular the host’s ability to respond to infection. One supplement extensively used by both adolescents and adults is creatine. Using Real-time PCR, we examined the impact of short-term exposure of a mouse macrophage cell line (RAW 264.7 cells) to two readily available forms of creatine used in supplements – creatine monohydrate (CR) and creatine ethyl ester (CEE) as well as the end product of creatine metabolism, creatinine (CRN), on expression of toll-like receptor-2 (TLR-2), TLR-3, TLR-4, and TLR-7. CR down-regulated TLR-2, TLR-3, TLR-4 and TLR-7 mRNA levels in RAW cells. Similar results were observed following exposure of RAW cells to CRN. Conversely CEE appears to possess immunostimulatory properties and increases expression of TLR-2, TLR-3, TLR-4, and TLR-7 in RAW cells. These data are supported by immunostaining using antibodies specific for the individual TLRs before and after exposure of RAW cells to CR, CRN, or CEE. To extend these findings, we isolated murine splenocytes and exposed the cells to CR, CEE, or CRN for 24 hours and performed immunofluorescent staining for TLR-2, TLR-3, TLR-4 and TLR-7. The results obtained from this study with primary splenocytes were consistent with the studies using RAW cells. Together, these data suggest that creatine and creatine derivatives may impact the ability of immune cells to sense a wide array of viral and bacterial pathogens. Of great interest, CRN - largely considered to be a waste product of the argenine biosynthesis pathway may also have immunosuppressive properties similar to those of CR. PMID:21575742

Beyond muscles: The untapped potential of creatine.

PubMed

Riesberg, Lisa A; Weed, Stephanie A; McDonald, Thomas L; Eckerson, Joan M; Drescher, Kristen M

2016-08-01

Creatine is widely used by both elite and recreational athletes as an ergogenic aid to enhance anaerobic exercise performance. Older individuals also use creatine to prevent sarcopenia and, accordingly, may have therapeutic benefits for muscle wasting diseases. Although the effect of creatine on the musculoskeletal system has been extensively studied, less attention has been paid to its potential effects on other physiological systems. Because there is a significant pool of creatine in the brain, the utility of creatine supplementation has been examined in vitro as well as in vivo in both animal models of neurological disorders and in humans. While the data are preliminary, there is evidence to suggest that individuals with certain neurological conditions may benefit from exogenous creatine supplementation if treatment protocols can be optimized. A small number of studies that have examined the impact of creatine on the immune system have shown an alteration in soluble mediator production and the expression of molecules involved in recognizing infections, specifically toll-like receptors. Future investigations evaluating the total impact of creatine supplementation are required to better understand the benefits and risks of creatine use, particularly since there is increasing evidence that creatine may have a regulatory impact on the immune system. Copyright © 2016 Elsevier B.V. All rights reserved.

Guanidinoacetic acid versus creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men.

PubMed

Ostojic, Sergej M; Ostojic, Jelena; Drid, Patrik; Vranes, Milan

2016-09-01

In this randomized, double-blind, crossover trial, we evaluated whether 4-week supplementation with guanidinoacetic acid (GAA) is superior to creatine in facilitating creatine levels in healthy men (n = 5). GAA (3.0 g/day) resulted in a more powerful rise (up to 16.2%) in tissue creatine levels in vastus medialis muscle, middle-cerebellar peduncle, and paracentral grey matter, as compared with creatine (P < 0.05). These results indicate that GAA as a preferred alternative to creatine for improved bioenergetics in energy-demanding tissues.

Fenugreek increases insulin-stimulated creatine content in L6C11 muscle myotubes.

PubMed

Tomcik, Kristyen A; Smiles, William J; Camera, Donny M; Hügel, Helmut M; Hawley, John A; Watts, Rani

2017-04-01

Creatine uptake by muscle cells is increased in the presence of insulin. Accordingly, compounds with insulin-like actions may also augment creatine uptake. The aim of this study was to investigate whether Trigonella foenum-graecum (fenugreek), an insulin mimetic, increases total intracellular creatine levels in vitro. Total cellular creatine content was measured fluorometrically in L6C11 muscle myotubes treated for 1, 4, and 24 h with 0.5 mM creatine (CR), CR and 20 μg/mL fenugreek seed extract (CR + FEN), CR and 100 nM insulin (CR + INS), and CR + INS + FEN (n = 6 per treatment group). Alterations in the expression of the sodium- and chloride-dependent creatine transporter, SLC6A8, and key signaling proteins in the PI3-K/Akt pathway were determined. Compared to control (CON), CR + INS + FEN increased total creatine content after 4 h (P < 0.05), whereas all conditions increased SLC6A8 protein expression above CON at this time (P < 0.05). Changes in insulin signaling were demonstrated via increases in Akt Thr308 phosphorylation, with CR + INS > CON and CR at 1 h (P < 0.05) and with CR + INS + FEN > CON, CR, and CR + INS at 4 h (P < 0.05). In contrast, no changes in PKCζ/λ or GLUT4 phosphorylation were detected. Fenugreek, when combined with insulin, modulates creatine content via a mechanism which is independent of the activity of SLC6A8, suggesting that an alternative mechanism is responsible for the regulation and facilitation of insulin-mediated creatine uptake in skeletal muscle cells.

Creatine and creatine pyruvate reduce hypoxia-induced effects on phrenic nerve activity in the juvenile mouse respiratory system.

PubMed

Scheer, Monika; Bischoff, Anna M; Kruzliak, Peter; Opatrilova, Radka; Bovell, Douglas; Büsselberg, Dietrich

2016-08-01

Adequate concentrations of ATP are required to preserve physiological cell functions and protect tissue from hypoxic damage. Decreased oxygen concentration results in ATP synthesis relying increasingly on the presence of phosphocreatine. The lack of ATP through hypoxic insult to neurons that generate or regulate respiratory function, would lead to the cessation of breathing (apnea). It is not clear whether creatine plays a role in maintaining respiratory phrenic nerve (PN) activity during hypoxic challenge. The aim of the study was to test the effects of exogenously applied creatine or creatine pyruvate in maintaining PN induced respiratory rhythm against the deleterious effects of severe hypoxic insult using Working Heart-Brainstem (WHB) preparations of juvenile Swiss type mice. WHB's were perfused with control perfusate or perfusate containing either creatine [100μM] or creatine pyruvate [100μM] prior to hypoxic challenge and PN activity recorded throughout. Results showed that severe hypoxic challenge resulted in an initial transient increase in PN activity, followed by a reduction in that activity leading to respiratory apnea. The results demonstrated that perfusing the WHB preparation with creatine or creatine pyruvate, significantly reduced the onset of apnea compared to control conditions, with creatine pyruvate being the more effective substance. Overall, creatine and creatine pyruvate each produced time-dependent degrees of protection against severe hypoxic-induced disturbances of PN activity. The underlying protective mechanisms are unknown and need further investigations. Copyright © 2016 Elsevier Inc. All rights reserved.

Total-body creatine pool size and skeletal muscle mass determination by creatine-(methyl-D3) dilution in rats.

PubMed

Stimpson, Stephen A; Turner, Scott M; Clifton, Lisa G; Poole, James C; Mohammed, Hussein A; Shearer, Todd W; Waitt, Greg M; Hagerty, Laura L; Remlinger, Katja S; Hellerstein, Marc K; Evans, William J

2012-06-01

There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-(methyl-d(3)) (D(3)-creatinine) in urine after a defined oral tracer dose of D(3)-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D(3)-creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D(3)-creatine in muscle and D(3)-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D(3)-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D(3)-creatine (<1 mg/rat) was >99% bioavailable with 0.2-1.2% urinary spillage. Isotopic steady state was achieved within 24-48 h. Creatine pool size calculated from urinary D(3)-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass (r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D(3)-creatine followed by the measurement of D(3)-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass.

Creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players.

PubMed

Claudino, João G; Mezêncio, Bruno; Amaral, Sérgio; Zanetti, Vinícius; Benatti, Fabiana; Roschel, Hamilton; Gualano, Bruno; Amadio, Alberto C; Serrão, Julio C

2014-01-01

Studies involving chronic creatine supplementation in elite soccer players are scarce. Therefore, the aim of this study was to examine the effects of creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players (n = 14 males) during pre-season training. This was a randomized, double-blind, placebo-controlled parallel-group study. Brazilian professional elite soccer players participated in this study. During the pre-season (7 weeks), all the subjects underwent a standardized physical and specific soccer training. Prior to and after either creatine monohydrate or placebo supplementation, the lower-limb muscle power was measured by countermovement jump performance. The Jumping performance was compared between groups at baseline (p = 0.99). After the intervention, jumping performance was lower in the placebo group (percent change = - 0.7%; ES = - 0.3) than in the creatine group (percent change = + 2.4%; ES = + 0.1), but it did not reach statistical significance (p = 0.23 for time x group interaction). Fisher's exact test revealed that the proportion of subjects that experienced a reduction in jumping performance was significantly greater in the placebo group than in the creatine group (5 and 1, respectively; p = 0.05) after the training. The magnitude-based inferences demonstrated that placebo resulted in a possible negative effect (50%) in jumping performance, whereas creatine supplementation led to a very likely trivial effect (96%) in jumping performance in the creatine group. Creatine monohydrate supplementation prevented the decrement in lower-limb muscle power in elite soccer players during a pre-season progressive training.

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Creatine test system. 862.1210 Section 862.1210....1210 Creatine test system. (a) Identification. A creatine test system is a device intended to measure creatine (a substance synthesized in the liver and pancreas and found in biological fluids) in plasma...

Genetics Home Reference: X-linked severe combined immunodeficiency

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... Facebook Twitter Home Health Conditions X-linked SCID X-linked severe combined immunodeficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked severe combined immunodeficiency (SCID) is an inherited ...

Genetics Home Reference: X-linked adrenal hypoplasia congenita

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... Home Health Conditions X-linked adrenal hypoplasia congenita X-linked adrenal hypoplasia congenita Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked adrenal hypoplasia congenita is a disorder that ...

Genetics Home Reference: X-linked chondrodysplasia punctata 1

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... Home Health Conditions X-linked chondrodysplasia punctata 1 X-linked chondrodysplasia punctata 1 Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked chondrodysplasia punctata 1 is a disorder of ...

Myocardial Creatine Levels Do Not Influence Response to Acute Oxidative Stress in Isolated Perfused Heart

PubMed Central

Aksentijević, Dunja; Zervou, Sevasti; Faller, Kiterie M. E.; McAndrew, Debra J.; Schneider, Jurgen E.; Neubauer, Stefan; Lygate, Craig A.

2014-01-01

Background Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role in cellular energy metabolism. The functional significance for the heart has yet to be established, but antioxidant activity could contribute to the cardioprotective effect of creatine in ischaemia/reperfusion injury. Objectives To determine whether intracellular creatine levels influence responses to acute reactive oxygen species (ROS) exposure in the intact beating heart. We hypothesised that mice with elevated creatine due to over-expression of the creatine transporter (CrT-OE) would be relatively protected, while mice with creatine-deficiency (GAMT KO) would fare worse. Methods and Results CrT-OE mice were pre-selected for creatine levels 20–100% above wild-type using in vivo 1H–MRS. Hearts were perfused in isovolumic Langendorff mode and cardiac function monitored throughout. After 20 min equilibration, hearts were perfused with either H2O2 0.5 µM (30 min), or the anti-neoplastic drug doxorubicin 15 µM (100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCδ expression were quantified in perfused hearts as markers of oxidative damage and apoptotic signalling. Wild-type hearts responded to ROS challenge with a profound decline in contractile function that was ameliorated by co-administration of catalase or dexrazoxane as positive controls. In contrast, the functional deterioration in CrT-OE and GAMT KO hearts was indistinguishable from wild-type controls, as was the extent of oxidative damage and apoptosis. Exogenous creatine supplementation also failed to protect hearts from doxorubicin-induced dysfunction. Conclusions Intracellular creatine levels do not influence the response to acute ROS challenge in the intact beating heart, arguing against creatine exerting (patho-)physiologically relevant anti-oxidant activity. PMID:25272153

Pigmented Creatine Deposits in Amyotrophic Lateral Sclerosis Central Nervous System Tissues Identified by Synchrotron Fourier Transform Infrared Microspectroscopy and X-ray Fluorescence Spectromicroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kastyak, M.; Szczerbowska-Boruchowska, M; Adamek, D

2010-01-01

Amyotrophic Lateral Sclerosis (ALS) is an untreatable, neurodegenerative disease of motor neurons characterized by progressive muscle atrophy, limb paralysis, dysarthria, dysphagia, dyspnae and finally death. Large motor neurons in ventral horns of spinal cord and motor nuclei in brainstem, large pyramidal neurons of motor cortex and/or large myelinated axons of corticospinal tracts are affected. In recent synchrotron Fourier Transform Infrared microspectroscopy (sFTIR) studies of ALS CNS autopsy tissue, we discovered a small deposit of crystalline creatine, which has a crucial role in energy metabolism. We have now examined unfixed, snap frozen, post-autopsy tissue sections of motor cortex, brain stem, spinalmore » cord, hippocampus and substantia nigra from six ALS and three non-degenerated cases with FTIR and micro-X-ray fluorescence (XRF). Heterogeneous pigmented deposits were discovered in spinal cord, brain stem and motor neuron cortex of two ALS cases. The FTIR signature of creatine has been identified in these deposits and in numerous large, non-pigmented deposits in four of the ALS cases. Comparable pigmentation and creatine deposits were not found in controls or in ALS hippocampus and substantia nigra. Ca, K, Fe, Cu and Zn, as determined by XRF, were not correlated with the pigmented deposits; however, there was a higher incidence of hot spots (Ca, Zn, Fe and Cu) in the ALS cases. The identity of the pigmented deposits remains unknown, although the absence of Fe argues against both erythrocytes and neuromelanin. We conclude that elevated creatine deposits may be indicators of dysfunctional oxidative processes in some ALS cases.« less

The Effects of Low-Dose Creatine Supplementation Versus Creatine Loading in Collegiate Football Players

PubMed Central

Deivert, Richard G.; Hagerman, Frederick; Gilders, Roger

2001-01-01

Objective: To compare the effects of low doses of creatine and creatine loading on strength, urinary creatinine concentration, and percentage of body fat. Design and Setting: Division IA collegiate football players took creatine monohydrate for 10 weeks during a sport-specific, periodized, off-season strength and conditioning program. One-repetition maximum (1-RM) squat, urinary creatinine concentrations, and percentage of body fat were analyzed. Subjects: Twenty-five highly trained, Division IA collegiate football players with at least 1 year of college playing experience. Measurements: We tested strength with a 1-RM squat exercise before, during, and after creatine supplementation. Percentage of body fat was measured by hydrostatic weighing before and after supplementation. Urinary creatinine concentration was measured via light spectrophotometer at 0, 1, 3, 7, 14, 21, 28, 35, 42, 48, 56, and 63 days. An analysis of variance with repeated measures was computed to compare means for all variables. Results: Creatine supplementation had no significant group, time, or interaction effects on strength, urinary creatinine concentration, or percentage of body fat. However, significant time effects were found for 1-RM squat and fat-free mass in all groups. Conclusions: Our data suggest that creatine monohydrate in any amount does not have any beneficial ergogenic effects in highly trained collegiate football players. However, a proper resistance training stimulus for 10 weeks can increase strength and fat-free mass in highly trained athletes. PMID:12937451

Separation methods applicable to urinary creatine and creatinine.

PubMed

Smith-Palmer, Truis

2002-12-05

Urinary creatinine has been analyzed for many years as an indicator of glomerular filtration rate. More recently, interest in studying the uptake of creatine as a result of creatine supplementation, a practice increasingly common among bodybuilders and athletes, has lead to a need to measure urinary creatine concentrations. Creatine levels are of the same order of magnitude as creatinine levels when subjects have recently ingested creatine, while somewhat elevated urinary creatine concentrations in non-supplementing subjects can be an indication of a degenerative disease of the muscle. Urinary creatine and creatinine can be analyzed by HPLC using a variety of columns. Detection methods include absorption, fluorescence after post-column derivatization, and mass spectrometry, and some methods have been automated. Capillary zone electrophoresis and micellar electrokinetic capillary chromatography have also been used to analyze urinary creatine and creatinine. Creatine and creatinine have also been analyzed in serum and tissue using HPLC and CE, and many of these separations could also be applicable to urinary analysis.

Lone atrial fibrillation associated with creatine monohydrate supplementation.

PubMed

Kammer, Ryan T

2005-05-01

Atrial fibrillation in young patients without structural heart disease is rare. Therefore, when the arrhythmia is present in this population, reversible causes must be identified and resolved. Thyroid disorders, illicit drug or stimulant use, and acute alcohol intoxication are among these causes. We report the case of a 30-year-old Caucasian man who came to the emergency department in atrial fibrillation with rapid ventricular response. His medical history was unremarkable, except for minor fractures of the fingers and foot. Thyroid-stimulating hormone, magnesium, and potassium levels were within normal limits, urine drug screen was negative, and alcohol use was denied. However, when the patient was questioned about use of herbal products and supplements, the use of creatine monohydrate was revealed. The patient was admitted to the hospital, anticoagulated with unfractionated heparin, and given intravenous diltiazem for rate control and intravenous amiodarone for rate and rhythm control. When discharged less than 24 hours later, he was receiving metoprolol and aspirin, with follow-up plans for echocardiography and nuclear imaging to assess perfusion. Exogenous creatine is used by athletes to theoretically improve exercise performance. Vegetarians may also take creatine to replace what they are not consuming from meat, fish, and other animal products. Previous anecdotal reports have linked creatine to the development of arrhythmia. Clinicians must be diligent when interviewing patients about their drug therapy histories and include questions about their use of herbal products and dietary supplements. In addition, it is important to report adverse effects associated with frequently consumed supplements and herbal products to the Food and Drug Administration and in the literature.

Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder.

PubMed

Cameron, Jessie M; Levandovskiy, Valeriy; Roberts, Wendy; Anagnostou, Evdokia; Scherer, Stephen; Loh, Alvin; Schulze, Andreas

2017-07-31

Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase ( GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase ( GAMT gene), and creatine transporter deficiency ( SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM , GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions). A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM , and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP) or Exome Aggregation Consortium (ExAC) databases). A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF) in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher's exact test). Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis/transport is unlikely to play a part in the pathogenesis of autism spectrum

Creatine supplementation and swim performance: a brief review.

PubMed

Hopwood, Melissa J; Graham, Kenneth; Rooney, Kieron B

2006-03-01

Nutritional supplements are popular among athletes participating in a wide variety of sports. Creatine is one of the most commonly used dietary supplements, as it has been shown to be beneficial in improving performance during repeated bouts of high-intensity anaerobic activity. This review examines the specific effects of creatine supplementation on swimming performance, and considers the effects of creatine supplementation on various measures of power development in this population. Research performed on the effect of creatine supplementation on swimming performance indicates that whilst creatine supplementation is ineffective in improving performance during a single sprint swim, dietary creatine supplementation may benefit repeated interval swim set performance. Considering the relationship between sprint swimming performance and measurements of power, the effect of creatine supplementation on power development in swimmers has also been examined. When measured on a swim bench ergometer, power development does show some improvement following a creatine supplementation regime. How this improvement in power output transfers to performance in the pool is uncertain. Although some evidence exists to suggest a gender effect on the performance improvements seen in swimmers following creatine supplementation, the majority of research indicates that male and female swimmers respond equally to supplementation. A major limitation to previous research is the lack of consideration given to the possible stroke dependant effect of creatine supplementation on swimming performance. The majority of the research conducted to date has involved examination of the freestyle swimming stroke only. The potential for performance improvements in the breaststroke and butterfly swimming strokes is discussed, with regards to the biomechanical differences and differences in efficiency between these strokes and freestyle. Key PointsCreatine supplementation does not improve single sprint

Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans

PubMed Central

Walker, Ann C.; O'Connor-Semmes, Robin L.; Leonard, Michael S.; Miller, Ram R.; Stimpson, Stephen A.; Turner, Scott M.; Ravussin, Eric; Cefalu, William T.; Hellerstein, Marc K.; Evans, William J.

2014-01-01

Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19–30 yr, 70–84 yr), 15 postmenopausal women (51–62 yr, 70–84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA. PMID:24764133

Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans.

PubMed

Clark, Richard V; Walker, Ann C; O'Connor-Semmes, Robin L; Leonard, Michael S; Miller, Ram R; Stimpson, Stephen A; Turner, Scott M; Ravussin, Eric; Cefalu, William T; Hellerstein, Marc K; Evans, William J

2014-06-15

Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19-30 yr, 70-84 yr), 15 postmenopausal women (51-62 yr, 70-84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA. Copyright © 2014 the American Physiological Society.

Thermophysical properties and oxygen transport in (Th x,Pu 1-x)O 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galvin, C. O. T.; Cooper, M. W. D.; Rushton, M. J. D.

Using Molecular Dynamics, this paper investigates the thermophysical properties and oxygen transport of (Th x,Pu 1–x)O 2 (0 ≤ x ≤ 1) between 300–3500 K. Specifically, the superionic transition is investigated and viewed via the thermal dependence of lattice parameter, linear thermal expansion coefficient, enthalpy and specific heat at constant pressure. Oxygen diffusivity and activation enthalpy are also investigated. Below the superionic temperature an increase of oxygen diffusivity for certain compositions of (Th x,Pu 1–x)O 2 compared to the pure end members is predicted. Oxygen defect formation enthalpies are also examined, as they underpin the superionic transition temperature and themore » increase in oxygen diffusivity. The increase in oxygen diffusivity for (Th x,Pu 1–x)O 2 is explained in terms of lower oxygen defect formation enthalpies for (Th x,Pu 1–x)O 2 than PuO 2 and ThO 2, while links are drawn between the superionic transition temperature and oxygen Frenkel disorder.« less

Thermophysical properties and oxygen transport in (Th x,Pu 1-x)O 2

DOE PAGES

Galvin, C. O. T.; Cooper, M. W. D.; Rushton, M. J. D.; ...

2016-10-31

Using Molecular Dynamics, this paper investigates the thermophysical properties and oxygen transport of (Th x,Pu 1–x)O 2 (0 ≤ x ≤ 1) between 300–3500 K. Specifically, the superionic transition is investigated and viewed via the thermal dependence of lattice parameter, linear thermal expansion coefficient, enthalpy and specific heat at constant pressure. Oxygen diffusivity and activation enthalpy are also investigated. Below the superionic temperature an increase of oxygen diffusivity for certain compositions of (Th x,Pu 1–x)O 2 compared to the pure end members is predicted. Oxygen defect formation enthalpies are also examined, as they underpin the superionic transition temperature and themore » increase in oxygen diffusivity. The increase in oxygen diffusivity for (Th x,Pu 1–x)O 2 is explained in terms of lower oxygen defect formation enthalpies for (Th x,Pu 1–x)O 2 than PuO 2 and ThO 2, while links are drawn between the superionic transition temperature and oxygen Frenkel disorder.« less

A simple screening method using ion chromatography for the diagnosis of cerebral creatine deficiency syndromes.

PubMed

Wada, Takahito; Shimbo, Hiroko; Osaka, Hitoshi

2012-08-01

Cerebral creatine deficiency syndromes (CCDS) are caused by genetic defects in L-arginine:glycine amidinotransferase, guanidinoacetate methyltransferase or creatine transporter 1. CCDS are characterized by abnormal concentrations of urinary creatine (CR), guanidinoacetic acid (GA), or creatinine (CN). In this study, we describe a simple HPLC method to determine the concentrations of CR, GA, and CN using a weak-acid ion chromatography column with a UV detector without any derivatization. CR, GA, and CN were separated clearly with the retention times (mean ± SD, n = 3) of 5.54 ± 0.0035 min for CR, 6.41 ± 0.0079 min for GA, and 13.53 ± 0.046 min for CN. This new method should provide a simple screening test for the diagnosis of CCDS.

Creatine Supplementation and Upper Limb Strength Performance: A Systematic Review and Meta-Analysis.

PubMed

Lanhers, Charlotte; Pereira, Bruno; Naughton, Geraldine; Trousselard, Marion; Lesage, François-Xavier; Dutheil, Frédéric

2017-01-01

Creatine is the most widely used supplementation to increase performance in strength; however, the most recent meta-analysis focused specifically on supplementation responses in muscles of the lower limbs without regard to upper limbs. We aimed to systematically review the effect of creatine supplementation on upper limb strength performance. We conducted a systematic review and meta-analyses of all randomized controlled trials comparing creatine supplementation with a placebo, with strength performance measured in exercises shorter than 3 min in duration. The search strategy used the keywords 'creatine', 'supplementation', and 'performance'. Independent variables were age, sex and level of physical activity at baseline, while dependent variables were creatine loading, total dose, duration, time interval between baseline (T0) and the end of the supplementation (T1), and any training during supplementation. We conducted three meta-analyses: at T0 and T1, and on changes between T0 and T1. Each meta-analysis was stratified within upper limb muscle groups. We included 53 studies (563 individuals in the creatine supplementation group and 575 controls). Results did not differ at T0, while, at T1, the effect size (ES) for bench press and chest press were 0.265 (95 % CI 0.132-0.398; p < 0.001) and 0.677 (95 % CI 0.149-1.206; p = 0.012), respectively. Overall, pectoral ES was 0.289 (95 % CI 0.160-0.419; p = 0.000), and global upper limb ES was 0.317 (95 % CI 0.185-0.449; p < 0.001). Meta-analysis of changes between T0 and T1 gave similar results. The meta-regression showed no link with characteristics of population or supplementation, demonstrating the efficacy of creatine independently of all listed conditions. Creatine supplementation is effective in upper limb strength performance for exercise with a duration of less than 3  min, independent of population characteristics, training protocols, and supplementary doses or duration.

The use of creatine supplements in the military.

PubMed

Havenetidis, Konstantinos

2016-08-01

Creatine is considered an effective nutritional ergogenic aid to enhance exercise performance. In spite of the publication of several reviews in the last decade on the topic of exercise performance/sports and creatine there is a need for an update related to the military given the lack of information in this area. The aim of this study was to critically assess original research addressing the use of creatine supplements in the military. A search of the electronic databases PubMed and SPORTDiscus, for the following key words: military personnel, trainees, recruit, soldier, physical fitness, physical conditioning, creatine supplementation, creatine ingestion, nutritional supplements to identify surveys and randomised clinical trials from journal articles and technical reports investigating the effect of creatine supplementation on military populations. Thirty-three out of 90 articles examined the use of creatine as a dietary supplement in military personnel. Twenty-one studies were finally selected on the basis of stated inclusion criteria for military surveys and randomised clinical trials. Most of the surveys (15/17) in the military indicate a high popularity of creatine (average 27%) among supplement users. In contrast, in most of the exercise protocols used (6/9) during randomised clinical trials creatine has produced a non-significant performance-enhancing effect. Creatine is one of the most widely used supplemental compounds in the military. It is not considered a doping infraction or related to any adverse health effects but its long-term usage needs further investigation. Experimental research suggests that creatine supplementation does not enhance physical performance in the military. However, limitations in creatine dosage, military fitness testing and sample group selection might have underestimated the ergogenic properties of creatine. Recent studies also indicate positive effects on various aspects of total force fitness such as cognitive

Genetics Home Reference: X-linked congenital stationary night blindness

MedlinePlus

... Health Conditions X-linked congenital stationary night blindness X-linked congenital stationary night blindness Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked congenital stationary night blindness is a disorder ...

Genetics Home Reference: X-linked lissencephaly with abnormal genitalia

MedlinePlus

... Health Conditions X-linked lissencephaly with abnormal genitalia X-linked lissencephaly with abnormal genitalia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked lissencephaly with abnormal genitalia (XLAG) is a ...

Genetics Home Reference: X-linked sideroblastic anemia and ataxia

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... Health Conditions X-linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare ...

Genetics Home Reference: X-linked intellectual disability, Siderius type

MedlinePlus

... Health Conditions X-linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked intellectual disability, Siderius type is a condition ...

Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes.

PubMed

Clark, Joseph F; Cecil, Kim M

2015-03-01

Primary care pediatricians and a variety of specialist physicians strive to define an accurate diagnosis for children presenting with impairment of expressive speech and delay in achieving developmental milestones. Within the past two decades, a group of disorders featuring this presentation have been identified as cerebral creatine deficiency syndromes (CCDS). Patients with these disorders were initially discerned using proton magnetic resonance spectroscopy of the brain within a magnetic resonance imaging (MRI) examination. The objective of this review is to provide the clinician with an overview of the current information available on identifying and treating these conditions. We explain the salient features of creatine metabolism, synthesis, and transport required for normal development. We propose diagnostic approaches for confirming a CCDS diagnosis. Finally, we describe treatment approaches for managing patients with these conditions.

Genetics Home Reference: X-linked hyper IgM syndrome

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... Home Health Conditions X-linked hyper IgM syndrome X-linked hyper IgM syndrome Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked hyper IgM syndrome is a condition that ...

Coordinated maturational regulation of PHEX and renal phosphate transport inhibitory activity: evidence for the pathophysiological role of PHEX in X-linked hypophosphatemia.

PubMed

Nesbitt, T; Fujiwara, I; Thomas, R; Xiao, Z S; Quarles, L D; Drezner, M K

1999-12-01

The mechanism by which inactivating mutations of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) cause X-linked hypophosphatemia remains unknown. However, recent reports suggest errant PHEX activity in osteoblasts may fail to inactivate a phosphaturic factor produced by these cells. To test this possibility, we examined coordinated maturational expression of PHEX and production of phosphate transport inhibitory activity in osteoblasts from normal and hyp-mice. We assessed the inhibitory activity in conditioned medium by examining the effects on opossum kidney cell phosphate transport and osteoblast PHEX expression by reverse transcriptase-polymerase chain reaction during a 17-day maturational period. Inhibitory activity increased as a function of osteoblast maturational stage, with no activity after 3 days and persistent activity by 6 days of culture. More significantly, equal phosphate transport inhibitory activity in conditioned medium from normal and hyp-mouse osteoblasts (control 1.90 +/- 0.12, normal 1.48 +/- 0.10, hyp 1.45 +/- 0.04 nmol/mg of protein/minute) was observed at 6 days. However, by 10 days hyp-mouse osteoblasts exhibited greater inhibitory activity than controls, and by 17 days the difference in phosphate transport inhibition maximized (control 2.08 +/- 0.09, normal 1.88 +/- 0.06, hyp 1.58 +/- 0.06 nmol/mg of protein/minute). Concurrently, we observed absent PHEX expression in normal osteoblasts after 3 days, limited production at 6 days, and significant production by day 10 of culture, while hyp-mouse osteoblasts exhibited limited PHEX activity secondary to an inactivating mutation. The data suggest that the presence of inactivating PHEX mutations results in the enhanced renal phosphate transport inhibitory activity exhibited by hyp-mouse osteoblasts.

Genetics Home Reference: X-linked dystonia-parkinsonism

MedlinePlus

... X-linked dystonia-parkinsonism syndrome (XDP): clinical and molecular genetic analysis. Brain Pathol. 1992 Oct;2(4):287-95. Review. Citation on PubMed Kaji R, Goto S, Tamiya G, Ando S, Makino S, Lee LV. Molecular dissection and anatomical basis of dystonia: X-linked ...

Effects of creatine supplementation on exercise performance.

PubMed

Demant, T W; Rhodes, E C

1999-07-01

While creatine has been known to man since 1835, when a French scientist reported finding this constitutent of meat, its presence in athletics as a performance enhancer is relatively new. Amid claims of increased power and strength, decreased performance time and increased muscle mass, creatine is being hailed as a true ergogenic aid. Creatinine is synthesised from the amino acids glycine, arginine and methionine in the kidneys, liver and pancreas, and is predominantly found in skeletal muscle, where it exists in 2 forms. Approximately 40% is in the free creatine form (Crfree), while the remaining 60% is in the phosphorylated form, creatine phosphate (CP). The daily turnover rate of approximately 2 g per day is equally met via exogenous intake and endogenous synthesis. Although creatine concentration (Cr) is greater in fast twitch muscle fibres, slow twitch fibres have a greater resynthesis capability due to their increased aerobic capacity. There appears to be no significant difference between males and females in Cr, and training does not appear to effect Cr. The 4 roles in which creatine is involved during performance are temporal energy buffering, spatial energy buffering, proton buffering and glycolysis regulation. Creatine supplementation of 20 g per day for at least 3 days has resulted in significant increases in total Cr for some individuals but not others, suggesting that there are 'responders' and 'nonresponders'. These increases in total concentration among responders is greatest in individuals who have the lowest initial total Cr, such as vegetarians. Increased concentrations of both Crfree and CP are believed to aid performance by providing more short term energy, as well as increase the rate of resynthesis during rest intervals. Creatine supplementation does not appear to aid endurance and incremental type exercises, and may even be detrimental. Studies investigating the effects of creatine supplementation on short term, high intensity exercises have

Genetics Home Reference: X-linked creatine deficiency

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... been identified. The disorder has been estimated to account for between 1 and 2 percent of males with intellectual disability. Related Information What information about a genetic condition can statistics ...

Creatine Supplementation and Lower Limb Strength Performance: A Systematic Review and Meta-Analyses.

PubMed

Lanhers, Charlotte; Pereira, Bruno; Naughton, Geraldine; Trousselard, Marion; Lesage, François-Xavier; Dutheil, Frédéric

2015-09-01

Creatine is the most widely used supplementation to increase strength performance. However, the few meta-analyses are more than 10 years old and suffer from inclusion bias such as the absence of randomization and placebo, the diversity of the inclusion criteria (aerobic/endurance, anaerobic/strength), no evaluation on specific muscles or group of muscles, and the considerable amount of conflicting results within the last decade. The objective of this systematic review was to evaluate meta-analyzed effects of creatine supplementation on lower limb strength performance. We conducted a systematic review and meta-analyses of all randomized controlled trials comparing creatine supplementation with a placebo, with strength performance of the lower limbs measured in exercises lasting less than 3 min. The search strategy used the keywords "creatine supplementation" and "performance". Dependent variables were creatine loading, total dose, duration, the time-intervals between baseline (T0) and the end of the supplementation (T1), as well as any training during supplementation. Independent variables were age, sex, and level of physical activity at baseline. We conducted meta-analyses at T1, and on changes between T0 and T1. Each meta-analysis was stratified within lower limb muscle groups and exercise tests. We included 60 studies (646 individuals in the creatine supplementation group and 651 controls). At T1, the effect size (ES) among stratification for squat and leg press were, respectively, 0.336 (95 % CI 0.047-0.625, p = 0.023) and 0.297 (95 % CI 0.098-0.496, p = 0.003). Overall quadriceps ES was 0.266 (95 % CI 0.150-0.381, p < 0.001). Global lower limb ES was 0.235 (95 % CI 0.125-0.346, p < 0.001). Meta-analysis on changes between T0 and T1 gave similar results. The meta-regression showed no links with characteristics of population or of supplementation, demonstrating the creatine efficacy effects, independent of all listed conditions. Creatine supplementation is

Creatine and the Liver: Metabolism and Possible Interactions.

PubMed

Barcelos, R P; Stefanello, S T; Mauriz, J L; Gonzalez-Gallego, J; Soares, F A A

2016-01-01

The process of creatine synthesis occurs in two steps, catalyzed by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT), which take place mainly in kidney and liver, respectively. This molecule plays an important energy/pH buffer function in tissues, and to guarantee the maintenance of its total body pool, the lost creatine must be replaced from diet or de novo synthesis. Creatine administration is known to decrease the consumption of Sadenosyl methionine and also reduce the homocysteine production in liver, diminishing fat accumulation and resulting in beneficial effects in fatty liver and non-alcoholic liver disease. Different studies have shown that creatine supplementation could supply brain energy, presenting neuroprotective effects against the encephalopathy induced by hyperammonemia in acute liver failure. Creatine is also taken by many athletes for its ergogenic properties. However, little is known about the adverse effects of creatine supplementation, which are barely described in the literature, with reports of mainly hypothetical effects arising from a small number of scientific publications. Antioxidant effects have been found in several studies, although one of the theories regarding the potential for toxicity from creatine supplementation is that it can increase oxidative stress and potentially form carcinogenic compounds.

HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.

PubMed

Salin-Cantegrel, Adèle; Shekarabi, Masoud; Holbert, Sébastien; Dion, Patrick; Rochefort, Daniel; Laganière, Janet; Dacal, Sandra; Hince, Pascale; Karemera, Liliane; Gaspar, Claudia; Lapointe, Jean-Yves; Rouleau, Guy A

2008-09-01

The potassium-chloride co-transporter 3 (KCC3) is mutated in hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC); however, the molecular mechanisms of HMSN/ACC pathogenesis and the exact role of KCC3 in the development of the nervous system remain poorly understood. The functional regulation of this transporter by protein partners is also largely unknown. Using a yeast two-hybrid approach, we discovered that the C-terminal domain (CTD) of KCC3, which is lost in most HMSN/ACC-causing mutations, directly interacts with brain-specific creatine kinase (CK-B), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CK-B was further confirmed by in vitro glutathione S-transferase pull-down assay, followed by sequencing of the pulled-down complexes. In transfected cultured cells, immunofluorescence labeling showed that CK-B co-localizes with wild-type KCC3, whereas the kinase fails to interact with the inactive truncated KCC3. Finally, CK-B's inhibition by DNFB results in reduction of activity of KCC3 in functional assays using Xenopus laevis oocytes. This physical and functional association between the co-transporter and CK-B is, therefore, the first protein-protein interaction identified to be potentially involved in the pathophysiology of HMSN/ACC.

Scientific basis and practical aspects of creatine supplementation for athletes.

PubMed

Volek, Jeff S; Rawson, Eric S

2004-01-01

A large number of studies have been published on creatine supplementation over the last decade. Many studies show that creatine supplementation in conjunction with resistance training augments gains in muscle strength and size. The underlying physiological mechanism(s) to explain this ergogenic effect remain unclear. Increases in muscle fiber hypertrophy and myosin heavy chain expression have been observed with creatine supplementation. Creatine supplementation increases acute weightlifting performance and training volume, which may allow for greater overload and adaptations to training. Creatine supplementation may also induce a cellular swelling in muscle cells, which in turn may affect carbohydrate and protein metabolism. Several studies point to the conclusion that elevated intramuscular creatine can enhance glycogen levels but an effect on protein synthesis/degradation has not been consistently detected. As expected there is a distribution of responses to creatine supplementation that can be largely explained by the degree of creatine uptake into muscle. Thus, there is wide interest in methods to maximize muscle creatine levels. A carbohydrate or carbohydrate/protein-induced insulin response appears to benefit creatine uptake. In summary, the predominance of research indicates that creatine supplementation represents a safe, effective, and legal method to enhance muscle size and strength responses to resistance training.

Genetics Home Reference: alpha thalassemia X-linked intellectual disability syndrome

MedlinePlus

... thalassemia X-linked intellectual disability syndrome Alpha thalassemia X-linked intellectual disability syndrome Printable PDF Open All ... view the expand/collapse boxes. Description Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder ...

Elevated plasma creatinine due to creatine ethyl ester use.

PubMed

Velema, M S; de Ronde, W

2011-02-01

Creatine is a nutritional supplement widely used in sport, physical fitness training and bodybuilding. It is claimed to enhance performance. We describe a case in which serum creatinine is elevated due to the use of creatine ethyl esther. One week after withdrawal, the plasma creatinine had normalised. There are two types of creatine products available: creatine ethyl esther (CEE) and creatine monohydrate (CM). Plasma creatinine is not elevated in all creatine-using subjects. CEE , but not CM, is converted into creatinine in the gastrointestinal tract. As a result the use of CEE may be associated with elevated plasma creatinine levels. Since plasma creatinine is a widely used marker for renal function, the use of CEE may lead to a false assumption of renal failure.

Creatine and Caffeine: Considerations for Concurrent Supplementation.

PubMed

Trexler, Eric T; Smith-Ryan, Abbie E

2015-12-01

Nutritional supplementation is a common practice among athletes, with creatine and caffeine among the most commonly used ergogenic aids. Hundreds of studies have investigated the ergogenic potential of creatine supplementation, with consistent improvements in strength and power reported for exercise bouts of short duration (≤ 30 s) and high intensity. Caffeine has been shown to improve endurance exercise performance, but results are mixed in the context of strength and sprint performance. Further, there is conflicting evidence from studies comparing the ergogenic effects of coffee and caffeine anhydrous supplementation. Previous research has identified independent mechanisms by which creatine and caffeine may improve strength and sprint performance, leading to the formulation of multi-ingredient supplements containing both ingredients. Although scarce, research has suggested that caffeine ingestion may blunt the ergogenic effect of creatine. While a pharmacokinetic interaction is unlikely, authors have suggested that this effect may be explained by opposing effects on muscle relaxation time or gastrointestinal side effects from simultaneous consumption. The current review aims to evaluate the ergogenic potential of creatine and caffeine in the context of high-intensity exercise. Research directly comparing coffee and caffeine anhydrous is discussed, along with previous studies evaluating the concurrent supplementation of creatine and caffeine.

FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

PubMed

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-09-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. © 2016 WILEY PERIODICALS, INC.

FARVATX: FAmily-based Rare Variant Association Test for X-linked genes

PubMed Central

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H.; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-01-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease (COPD). Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. PMID:27325607

Protective effects of some creatine derivatives in brain tissue anoxia.

PubMed

Perasso, Luisa; Lunardi, Gian Luigi; Risso, Federica; Pohvozcheva, Anna V; Leko, Maria V; Gandolfo, Carlo; Florio, Tullio; Cupello, Aroldo; Burov, Sergey V; Balestrino, Maurizio

2008-05-01

Some derivatives more lipophylic than creatine, thus theoretically being capable to better cross the blood-brain barrier, were studied for their protective effect in mouse hippocampal slices. We found that N-amidino-piperidine is harmful to brain tissue, and that phosphocreatine is ineffective. Creatine, creatine-Mg-complex (acetate) and phosphocreatine-Mg-complex (acetate) increased the latency to population spike disappearance during anoxia. Creatine and creatine-Mg-complex (acetate) also increased the latency of anoxic depolarization, while the delay induced by phosphocreatine-Mg-complex (acetate) was of borderline significance (P = 0.056). Phosphocreatine-Mg-complex (acetate) significantly reduced neuronal hyperexcitability during anoxia, an effect that no other compound (including creatine itself) showed. For all parameters except reduced hyperexcitability the effects statistically correlated with tissue levels of creatine or phosphocreatine. Summing up, exogenous phosphocreatine and N-amidino piperidine are not useful for brain protection, while chelates of both creatine and phosphocreatine do replicate some of the known protective effects of creatine. In addition, phosphocreatine-Mg-complex (acetate) also reduced neuronal hyperexcitability during anoxia.

Simultaneous determination of guanidinoacetate, creatine and creatinine in urine and plasma by un-derivatized liquid chromatography-tandem mass spectrometry.

PubMed

Carling, R S; Hogg, S L; Wood, T C; Calvin, J

2008-11-01

Creatine plays an important role in the storage and transmission of phosphate-bound energy. The cerebral creatine deficiency syndromes (CCDS) comprise three inherited defects in creatine biosynthesis and transport. They are characterized by mental retardation, speech and language delay and epilepsy. All three disorders cause low-creatine signal on brain magnetic resonance spectroscopy (MRS); however, MRS may not be readily available and even when it is, biochemical tests are required to determine the underlying disorder. Analysis was performed by liquid chromatography-tandem mass spectrometry in positive ionization mode. Samples were analysed underivatized using a rapid 'dilute and shoot' approach. Chromatographic separation of the three compounds was achieved. Stable isotope internal standards were used for quantification. Creatine, creatinine and guanidinoacetate were measured with a 2.5 minute run time. For guanidinoacetate, the standard curve was linear to at least 5000 mumol/L and for creatine and creatinine it was linear to at least 25 mmol/L. The lower limit of quantitation was 0.4 mumol/L for creatine and guanidinoacetate and 0.8 mumol/L for creatinine. Recoveries ranged from 86% to 106% for the three analytes. Intra- and inter-assay variation for each analyte was <10% in both urine and plasma. A tandem mass spectrometric method has been developed and validated for the underivatized determination of guanidinoacetate, creatine and creatinine in human urine and plasma. Minimal sample preparation coupled with a rapid run time make the method applicable to the routine screening of patients with suspected CCDS.

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake

PubMed Central

Nabuurs, C I; Choe, C U; Veltien, A; Kan, H E; van Loon, L J C; Rodenburg, R J T; Matschke, J; Wieringa, B; Kemp, G J; Isbrandt, D; Heerschap, A

2013-01-01

Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP–phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of l-arginine:glycine amidinotransferase (AGAT−/−), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT−/− mice. Compared with wild-type, the inorganic phosphate/β-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain enzymes were reduced, whereas F1F0-ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT−/− mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT−/− muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT−/− mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests a multifaceted involvement of creatine in muscle energy homeostasis in addition to its role in the phosphocreatine–creatine kinase system. PMID:23129796

X-linked congenital panhypopituitarism.

PubMed

Schimke, R N; Spaulding, J J; Hollowell, J G

1971-05-01

Two half brothers with panhypopituitary dwarfism are reported who have the same mother and different, unrelated fathers. The subject of hereditary panhypopituitarism is reviewed briefly. It is concluded that there are at least two forms of hereditary panhypopituitary dwarfism, one of which may be X-linked.

Plasma creatinine and creatine quantification by capillary electrophoresis diode array detector.

PubMed

Zinellu, Angelo; Caria, Marcello A; Tavera, Claudio; Sotgia, Salvatore; Chessa, Roberto; Deiana, Luca; Carru, Ciriaco

2005-07-15

Traditional clinical assays for nonprotein nitrogen compounds, such as creatine and creatinine, have focused on the use of enzymes or chemical reactions that allow measurement of each analyte separately. Most of these assays are mainly directed to urine quantification, so that their applicability on plasma samples is frequently hard to perform. This work describes a simple free zone capillary electrophoresis method for the simultaneous measurement of creatinine and creatine in human plasma. The effect of analytical parameters such as concentration and pH of Tris-phosphate running buffer and cartridge temperature on resolution, migration times, peak areas, and efficiency was investigated. Good separation was achieved using a 60.2-cm x 75-microm uncoated silica capillary, 75 mmol/L Tris-phosphate buffer, pH 2.25, at 15 degrees C, in less than 8 min. We compared the present method to a validated capillary electrophoresis assay, by measuring plasma creatinine in 120 normal subjects. The obtained data were compared by the Passing-Bablok regression and the Bland-Altman test. Moreover the performance of the developed method was assessed by measuring creatine and creatinine in 16 volunteers prior to and after a moderate physical exercise.

Phenotype-genotype correlations in X linked retinitis pigmentosa.

PubMed Central

Kaplan, J; Pelet, A; Martin, C; Delrieu, O; Aymé, S; Bonneau, D; Briard, M L; Hanauer, A; Larget-Piet, L; Lefrançois, P

1992-01-01

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0). Images PMID:1357178

Sex-specific silencing of X-linked genes by Xist RNA

PubMed Central

Gayen, Srimonta; Maclary, Emily; Hinten, Michael; Kalantry, Sundeep

2016-01-01

X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of XΔTsixY male cells displayed ectopic Xist RNA coating compared with XΔTsixX female cells. This increase reflected the inability of XΔTsixY cells to efficiently silence X-linked genes compared with XΔTsixX cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in XΔTsixX female cells relative to XΔTsixY male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating XΔTsixY and 39,XΔTsix (XΔTsixO) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex-specific differences. Because XΔTsixX female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active XΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing. PMID:26739568

Non-enzymatic cyclization of creatine ethyl ester to creatinine.

PubMed

Giese, Matthew W; Lecher, Carl S

2009-10-16

Creatine ethyl ester was incubated at 37 degrees C in both water and phosphate-buffered saline and the diagnostic methylene resonances in the (1)H NMR spectrum were used to identify the resultant products. It was found that mild aqueous conditions result in the cyclization of creatine ethyl ester to provide inactive creatinine as the exclusive product, and this transformation becomes nearly instantaneous as the pH approaches 7.4. This study demonstrates that mild non-enzymatic conditions are sufficient for the cyclization of creatine ethyl ester into creatinine, and together with previous results obtained under enzymatic conditions suggests that there are no physiological conditions that would result in the production of creatine. It is concluded that creatine ethyl ester is a pronutrient for creatinine rather than creatine under all physiological conditions encountered during transit through the various tissues, thus no ergogenic effect is to be expected from supplementation.

Enzymatic cycling method using creatine kinase to measure creatine by real-time detection.

PubMed

Ueda, Shigeru; Sakasegawa, Shin-Ichi

2016-08-01

We have developed a novel enzymatic cycling method that uses creatine kinase (CK) to measure creatine. The method takes advantage of the reversibility of the CK reaction in which the forward (creatine phosphate forming) and reverse reactions are catalyzed in the presence of an excess amount of ATP and IDP, respectively. Real-time detection was accomplished using ADP-dependent glucokinase (ADP-GK) together with glucose-6-phosphate dehydrogenase. ADP, one of the cycling reaction products, was distinguished from IDP by using the nucleotide selectivity of the ADP-GK. The increasing level of ADP was measured from the level of reduced NADP at 340 nm. The method is appropriate for an assay that requires high sensitivity because the rate of increase in absorbance at 340 nm is proportional to the amount of CK present in the reaction mix. We reasoned that the method with CK in combination with creatinine amidohydrolase could be used to assay creatinine, an important marker of kidney function. Our results confirmed the quantitative capability of the assay. Copyright © 2016 Elsevier Inc. All rights reserved.

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria.

PubMed

Dhayat, Nasser; Simonin, Alexandre; Anderegg, Manuel; Pathare, Ganesh; Lüscher, Benjamin P; Deisl, Christine; Albano, Giuseppe; Mordasini, David; Hediger, Matthias A; Surbek, Daniel V; Vogt, Bruno; Sass, Jörn Oliver; Kloeckener-Gruissem, Barbara; Fuster, Daniel G

2016-05-01

A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome. Copyright © 2016 by the American Society of Nephrology.

Hydrophilic chromatographic determination of carnosine, anserine, balenine, creatine, and creatinine.

PubMed

Mora, Leticia; Sentandreu, Miguel Angel; Toldrá, Fidel

2007-06-13

A new HPLC procedure based on hydrophilic interaction chromatography (HILIC) has been developed for the simultaneous determination of carnosine, anserine, balenine, creatine, and creatinine in meat. This is the first time that HILIC has been directly applied to the study of meat components, having the advantage of not requiring complex cleanup and/or sample derivatization procedures. The chromatographic separation has been developed using a silica column (4.6 x 150 mm, 3 microm), and the proposed methodology is simple, reliable, and fast (<13 min per sample). The method has been validated in terms of linearity, repeatability, reproducibility, and recovery and represents an interesting alternative to methods currently in use for determining the mentioned compounds and other polar substances. The detection limits are 5.64, 8.23, 3.66, 3.99, and 0.06 microg/mL for carnosine, anserine, balenine, creatine, and creatinine, respectively.

Imprinted polymer-modified hanging mercury drop electrode for differential pulse cathodic stripping voltammetric analysis of creatine.

PubMed

Lakshmi, Dhana; Sharma, Piyush S; Prasad, Bhim B

2007-06-15

The molecularly imprinted polymer [poly(p-aminobenzoicacid-co-1,2-dichloroethane)] film casting was made on the surface of a hanging mercury drop electrode by drop-coating method for the selective and sensitive evaluation of creatine in water, blood serum and pharmaceutical samples. The molecular recognition of creatine by the imprinted polymer was found to be specific via non-covalent (electrostatic) imprinting. The creatine binding could easily be detected by differential pulse, cathodic stripping voltammetric signal at optimised operational conditions: accumulation potential -0.01 V (versus Ag/AgCl), polymer deposition time 15s, template accumulation time 60s, pH 7.1 (supporting electrolyte< or =5 x 10(-4)M NaOH), scan rate 10 mV s(-1), pulse amplitude 25 mV. The modified sensor in the present study was found to be highly reproducible and selective with detection limit 0.11 ng mL(-1) of creatine. Cross-reactivity studies revealed no response to the addition of urea, creatinine and phenylalanine; however, some insignificant magnitude of current was observed for tryptophan and histidine in the test samples.

Creatine supplementation and glycemic control: a systematic review.

PubMed

Pinto, Camila Lemos; Botelho, Patrícia Borges; Pimentel, Gustavo Duarte; Campos-Ferraz, Patrícia Lopes; Mota, João Felipe

2016-09-01

The focus of this review is the effects of creatine supplementation with or without exercise on glucose metabolism. A comprehensive examination of the past 16 years of study within the field provided a distillation of key data. Both in animal and human studies, creatine supplementation together with exercise training demonstrated greater beneficial effects on glucose metabolism; creatine supplementation itself demonstrated positive results in only a few of the studies. In the animal studies, the effects of creatine supplementation on glucose metabolism were even more distinct, and caution is needed in extrapolating these data to different species, especially to humans. Regarding human studies, considering the samples characteristics, the findings cannot be extrapolated to patients who have poorer glycemic control, are older, are on a different pharmacological treatment (e.g., exogenous insulin therapy) or are physically inactive. Thus, creatine supplementation is a possible nutritional therapy adjuvant with hypoglycemic effects, particularly when used in conjunction with exercise.

Creatine supplementation and oxidative stress in rat liver

PubMed Central

2013-01-01

Background The objective of this study was to determine the effects of creatine supplementation on liver biomarkers of oxidative stress in exercise-trained rats. Methods Forty 90-day-old adult male Wistar rats were assigned to four groups for the eight-week experiment. Control group (C) rats received a balanced control diet; creatine control group (CCr) rats received a balanced diet supplemented with 2% creatine; trained group (T) rats received a balanced diet and intense exercise training equivalent to the maximal lactate steady state phase; and supplemented-trained (TCr) rats were given a balanced diet supplemented with 2% creatine and subjected to intense exercise training equivalent to the maximal lactate steady state phase. At the end of the experimental period, concentrations of creatine, hydrogen peroxide (H2O2) and thiobarbituric acid reactive substances (TBARS) were measured as well as the enzyme activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-GPx) and catalase (CAT). Liver tissue levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and the GSH/GSSG ratio were also determined. Results Hepatic creatine levels were highest in the CCr and TCr groups with increased concentration of H2O2 observed in the T and TCr animal groups. SOD activity was decreased in the TCr group. GSH-GPx activity was increased in the T and TCr groups while CAT was elevated in the CCr and TCr groups. GSH, GGS and the GSH/GSSG ratio did not differ between all animal subsets. Conclusions Our results demonstrate that creatine supplementation acts in an additive manner to physical training to raise antioxidant enzymes in rat liver. However, because markers of liver oxidative stress were unchanged, this finding may also indicate that training-induced oxidative stress cannot be ameliorated by creatine supplementation. PMID:24325803

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes

PubMed Central

Krasovec, Marc; Filatov, Dmitry A.

2018-01-01

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (πx = 0.016; πaut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex. PMID:29751495

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes.

PubMed

Krasovec, Marc; Nevado, Bruno; Filatov, Dmitry A

2018-05-03

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (π x = 0.016; π aut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex.

Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition.

PubMed

Bassit, R A; Curi, R; Costa Rosa, L F B P

2008-08-01

The effect of creatine supplementation upon plasma levels of pro-inflammatory cytokines: Interleukin (IL) 1 beta and IL-6, Tumor Necrosis Factor alpha (TNFalpha), and Interferon alpha (INF alpha) and Prostaglandin E(2) (PGE(2)) after a half-ironman competition were investigated. Eleven triathletes, each with at least three years experience of participation in this sport were randomly divided between the control and experimental groups. During 5 days prior to competition, the control group (n = 6) was supplemented with carbohydrate (20 g x d(-1)) whereas the experimental group (n = 5) received creatine (20 g x d(-1)) in a double-blind trial. Blood samples were collected 48 h before and 24 and 48 h after competition and were used for the measurement of cytokines and PGE(2). Forty-eight hours prior to competition there was no difference between groups in the plasma concentrations (pg x ml(-1), mean +/- SEM) of IL-6 (7.08 +/- 0.63), TNFalpha (76.50 +/- 5.60), INF alpha (18.32 +/- 1.20), IL-1 beta (23.42 +/- 5.52), and PGE(2) (39.71 +/- 3.8). Twenty-four and 48 h after competition plasma levels of TNFalpha, INF alpha, IL-1 beta and PGE(2) were significantly increased (P < 0.05) in both groups. However, the increases in these were markedly reduced following creatine supplementation. An increase in plasma IL-6 was observed only after 24 h and, in this case, there was no difference between the two groups. Creatine supplementation before a long distance triathlon competition may reduce the inflammatory response induced by this form of strenuous of exercise.

Can creatine supplementation form carcinogenic heterocyclic amines in humans?

PubMed Central

Pereira, Renato Tavares dos Santos; Dörr, Felipe Augusto; Pinto, Ernani; Solis, Marina Yazigi; Artioli, Guilherme Giannini; Fernandes, Alan Lins; Murai, Igor Hisashi; Dantas, Wagner Silva; Seguro, Antônio Carlos; Santinho, Mirela Aparecida Rodrigues; Roschel, Hamilton; Carpentier, Alain; Poortmans, Jacques Remi; Gualano, Bruno

2015-01-01

Abstract Creatine supplementation has been associated with increased cancer risk. In fact, there is evidence indicating that creatine and/or creatinine are important precursors of carcinogenic heterocyclic amines (HCAs). The present study aimed to investigate the acute and chronic effects of low- and high-dose creatine supplementation on the production of HCAs in healthy humans (i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx),  2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)). This was a non-counterbalanced single-blind crossover study divided into two phases, in which low- and high-dose creatine protocols were tested. After acute (1 day) and chronic supplementation (30 days), the HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx were assessed through a newly developed HPLC–MS/MS method. Dietary HCA intake and blood and urinary creatinine were also evaluated. Out of 576 assessments performed (from 149 urine samples), only nine (3 from creatine and 6 from placebo) showed quantifiable levels of HCAs (8-MeIQx: n = 3; 4,8-DiMeIQx: n = 2; PhIP: n = 4). Individual analyses revealed that diet rather than creatine supplementation was the main responsible factor for HCA formation in these cases. This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, did not cause increases in the carcinogenic HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx in healthy subjects. These findings challenge the long-existing notion that creatine supplementation could potentially increase the risk of cancer by stimulating the formation of these mutagens. Key points There is a long-standing concern that creatine supplementation could be associated with cancer, possibly by facilitating the formation of carcinogenic heterocyclic amines (HCAs). This study provides compelling evidence

Can creatine supplementation form carcinogenic heterocyclic amines in humans?

PubMed

Pereira, Renato Tavares dos Santos; Dörr, Felipe Augusto; Pinto, Ernani; Solis, Marina Yazigi; Artioli, Guilherme Giannini; Fernandes, Alan Lins; Murai, Igor Hisashi; Dantas, Wagner Silva; Seguro, Antônio Carlos; Santinho, Mirela Aparecida Rodrigues; Roschel, Hamilton; Carpentier, Alain; Poortmans, Jacques Remi; Gualano, Bruno

2015-09-01

There is a long-standing concern that creatine supplementation could be associated with cancer, possibly by facilitating the formation of carcinogenic heterocyclic amines (HCAs). This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, does not cause a significant increase in HCA formation. HCAs detection was unrelated to creatine supplementation. Diet was likely to be the main factor responsible for HCAs formation after either placebo (n = 6) or creatine supplementation (n = 3). These results directly challenge the recently suggested biological plausibility for the association between creatine use and risk of testicular germ cell cancer. Creatine supplementation has been associated with increased cancer risk. In fact, there is evidence indicating that creatine and/or creatinine are important precursors of carcinogenic heterocyclic amines (HCAs). The present study aimed to investigate the acute and chronic effects of low- and high-dose creatine supplementation on the production of HCAs in healthy humans (i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)). This was a non-counterbalanced single-blind crossover study divided into two phases, in which low- and high-dose creatine protocols were tested. After acute (1 day) and chronic supplementation (30 days), the HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx were assessed through a newly developed HPLC-MS/MS method. Dietary HCA intake and blood and urinary creatinine were also evaluated. Out of 576 assessments performed (from 149 urine samples), only nine (3 from creatine and 6 from placebo) showed quantifiable levels of HCAs (8-MeIQx: n = 3; 4,8-DiMeIQx: n = 2; PhIP: n = 4). Individual analyses revealed that diet rather than creatine supplementation was

Stable isotope dilution microquantification of creatine metabolites in plasma, whole blood and dried blood spots for pharmacological studies in mouse models of creatine deficiency.

PubMed

Tran, C; Yazdanpanah, M; Kyriakopoulou, L; Levandovskiy, V; Zahid, H; Naufer, A; Isbrandt, D; Schulze, A

2014-09-25

To develop an accurate stable isotope dilution assay for simultaneous quantification of creatine metabolites ornithine, arginine, creatine, creatinine, and guanidinoacetate in very small blood sample volumes to study creatine metabolism in mice. Liquid-chromatography (C18) tandem mass spectrometry with butylation was performed in positive ionization mode. Stable isotope dilution assay with external calibration was applied to three different specimen types, plasma, whole blood and dried blood spot (DBS). Analytical separation, sensitivity, accuracy, and linearity of the assay were adequate. The stable isotope dilution assay in plasma revealed no significant bias to gold standard methods for the respective analytes. Compared to plasma, we observed an overestimate of creatine and creatinine (2- to 5-fold and 1.2- to 2-fold, respectively) in whole-blood and DBS, and an underestimate of arginine (2.5-fold) in DBS. Validation of the assay in mouse models of creatine deficiency revealed plasma creatine metabolite pattern in good accordance with those observed in human GAMT and AGAT deficiency. Single dose intraperitoneal application of ornithine in wild-type mice lead to fast ornithine uptake (Tmax ≤ 10 min) and elimination (T1/2=24 min), and a decline of guanidinoacetate. The assay is fast and reliable to study creatine metabolism and pharmacokinetics in mouse models of creatine deficiency. Copyright © 2014 Elsevier B.V. All rights reserved.

Creatine pretreatment protects cortical axons from energy depletion in vitro

PubMed Central

Shen, Hua; Goldberg, Mark P.

2012-01-01

Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6 mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24 h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2 h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency. PMID:22521466

Macular hole in juvenile X-linked retinoschisis.

PubMed

Al-Swaina, Nayef; Nowilaty, Sawsan R

2013-10-01

An 18 year-old male with no antecedent of trauma, systemic syndrome or myopia was referred for surgical treatment of a full thickness macular hole in the left eye. A more careful inspection revealed discrete foveal cystic changes in the fellow eye and subtle peripheral depigmented retinal pigment epithelial changes in both eyes. A spectral-domain optical coherence tomography (SD-OCT) scan confirmed, in addition to the full thickness macular hole in the left eye, microcystic spaces in the nuclear layers of both retinae. The diagnosis of X-linked retinoschisis was confirmed with a full field electroretinogram displaying the typical negative ERG. Macular holes are uncommon in the young and those complicating X-linked retinoschisis are rare. This report highlights the importance of investigating the presence of a macular hole in a young patient and illustrates the clinical and SD-OCT clues beyond the foveal center which led to the correct diagnosis of X-linked juvenile retinoschisis.

Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury.

PubMed

Chamberlain, Kelly A; Chapey, Kristen S; Nanescu, Sonia E; Huang, Jeffrey K

2017-02-08

Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase ( Gamt ) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt -deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination. SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by

Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury

PubMed Central

Nanescu, Sonia E.

2017-01-01

Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase (Gamt) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt-deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination. SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by

X-linked dominant retinitis pigmentosa in an American family

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, R.E.; Daiger, S.P.; Blanton, S.H.

1994-09-01

Retinitis pigmentosa is a genetically heterogeneous disease with autosomal dominant (adRP), autosomal recessive and X-linked forms. At least 3 forms of X-linked retinitis pigmentosa have been reported: RP2 which maps to Xp11.4-p 11.23, RP3 which maps to Xp21.1 and RP6, which maps to Xp21.3-p21.1. The X-linked forms of retinitis pigmentosa are generally considered to be recessive as female carriers are not affected or are much less affected than males. Here we report a five generation American family with X-linked retinitis pigmentosa in which both males and females are significantly affected. The disease locus in this family appears to be distinctmore » from RP2 and RP3. The American family (UTAD054) presents with early-onset retinitis pigmentosa. The family appeared to fit an autosomal dominant pattern; however, linkage testing excluded all known adRP loci. Absence of male-to-male transmission in the pedigree suggested the possibility of X-linked dominant inheritance. Thus we tested six microsatellite markers that map to Xp (DXS987, DXS989, DXS993, DXS999, DXS1003 and DXS1110). Of these, DXS989 showed tight linkage with one allele (199) showing a 100% concordance with disease status. The odds favoring an X-linked dominant mode of inheritance in this family, versus autosomal dominant, are 10{sup 5}:1. In addition, recombinations for DXS999, and dXS1110, the two markers flanking DXS989, were observed in affected individuals. These data map the disease locus in this family to a 9 mb region on the X chromosome between Xp22.11 and Xp21.41. In addition, the recombinant individuals exclude close linkage to RP2 and RP3. The observance of high penetrance in females indicates that this family has X-linked dominant retinitis pigmentosa. We suggest that this mode of inheritance should be considered in other families with dominant retinitis pigmentosa but an absence of male-to-male transmission.« less

Binding-, intracellular transport-, and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus.

PubMed Central

Tsukaguchi, H; Matsubara, H; Taketani, S; Mori, Y; Seido, T; Inada, M

1995-01-01

Nephrogenic diabetes insipidus (NDI) is most often an X-linked disorder in which urine is not concentrated due to renal resistance to arginine vasopressin. We recently identified four vasopressin type 2 receptor gene mutations in unrelated X-linked NDI families, including R143P, delta V278, R202C, and 804insG. All these mutations reduced ligand binding activity to < 10% of the normal without affecting mRNA accumulation. To elucidate whether the receptors are expressed on the cell surface, we analyzed biosynthesis and localization of tagged or untagged receptors stably expressed in Chinese hamster ovary (CHO) cells, using two antibodies directed against distinct termini. Whole-cell and surface labeling studies revealed that the R202C clone had both surface-localized (50-55 kD) and intracellular proteins (40 and 75 kD), similar to the wild-type AVPR2 clone, whereas the R143P and delta V278 clones lacked the surface receptors, despite relatively increased intracellular components. The 804insG mutant cell produced no proteins despite an adequate mRNA level. Immunofluorescence staining confirmed that the R202C mutant reaches the cell surface, whereas the R143P and delta V278 mutants are retained within the cytoplasmic compartment. Thus, R202C, R143P/delta V278, and 804insG result in three distinct phenotypes, that is, a simple binding impairment at the cell surface, blocked intracellular transport, and ineffective biosynthesis or/and accelerated degradation of the receptor, respectively, and therefore are responsible for NDI. This phenotypic classification will help understanding of molecular pathophysiology of this disorder. Images PMID:7560098

Creatine supplementation with specific view to exercise/sports performance: an update

PubMed Central

2012-01-01

Creatine is one of the most popular and widely researched natural supplements. The majority of studies have focused on the effects of creatine monohydrate on performance and health; however, many other forms of creatine exist and are commercially available in the sports nutrition/supplement market. Regardless of the form, supplementation with creatine has regularly shown to increase strength, fat free mass, and muscle morphology with concurrent heavy resistance training more than resistance training alone. Creatine may be of benefit in other modes of exercise such as high-intensity sprints or endurance training. However, it appears that the effects of creatine diminish as the length of time spent exercising increases. Even though not all individuals respond similarly to creatine supplementation, it is generally accepted that its supplementation increases creatine storage and promotes a faster regeneration of adenosine triphosphate between high intensity exercises. These improved outcomes will increase performance and promote greater training adaptations. More recent research suggests that creatine supplementation in amounts of 0.1 g/kg of body weight combined with resistance training improves training adaptations at a cellular and sub-cellular level. Finally, although presently ingesting creatine as an oral supplement is considered safe and ethical, the perception of safety cannot be guaranteed, especially when administered for long period of time to different populations (athletes, sedentary, patient, active, young or elderly). PMID:22817979

Creatine ( methyl-d3) dilution in urine for estimation of total body skeletal muscle mass: accuracy and variability vs. MRI and DXA.

PubMed

Clark, Richard V; Walker, Ann C; Miller, Ram R; O'Connor-Semmes, Robin L; Ravussin, Eric; Cefalu, William T

2018-01-01

A noninvasive method to estimate muscle mass based on creatine ( methyl-d 3 ) (D 3 -creatine) dilution using fasting morning urine was evaluated for accuracy and variability over a 3- to 4-mo period. Healthy older (67- to 80-yr-old) subjects ( n = 14) with muscle wasting secondary to aging and four patients with chronic disease (58-76 yr old) fasted overnight and then received an oral 30-mg dose of D 3 -creatine at 8 AM ( day 1). Urine was collected during 4 h of continued fasting and then at consecutive 4- to 8-h intervals through day 5. Assessment was repeated 3-4 mo later in 13 healthy subjects and 1 patient with congestive heart failure. Deuterated and unlabeled creatine and creatinine were measured using liquid chromatography-tandem mass spectrometry. Total body creatine pool size and muscle mass were calculated from D 3 -creatinine enrichment in urine. Muscle mass was also measured by whole body MRI and 24-h urine creatinine, and lean body mass (LBM) was measured by dual-energy X-ray absorptiometry (DXA). D 3 -creatinine urinary enrichment from day 5 provided muscle mass estimates that correlated with MRI for all subjects ( r = 0.88, P < 0.0001), with less bias [difference from MRI = -3.00 ± 2.75 (SD) kg] than total LBM assessment by DXA, which overestimated muscle mass vs. MRI (+22.5 ± 3.7 kg). However, intraindividual variability was high with the D 3 -creatine dilution method, with intrasubject SD for estimated muscle mass of 2.5 kg vs. MRI (0.5 kg) and DXA (0.8 kg). This study supports further clinical validation of the D 3 -creatine method for estimating muscle mass. NEW & NOTEWORTHY Measurement of creatine ( methyl-d 3 ) (D 3 -creatine) and D 3 -creatinine excretion in fasted morning urine samples may be a simple, less costly alternative to MRI or dual-energy X-ray absorptiometry (DXA) to calculate total body muscle mass. The D 3 -creatine enrichment method provides estimates of muscle mass that correlate well with MRI, and with less

Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas.

PubMed

da Silva, Robin P; Clow, Kathy; Brosnan, John T; Brosnan, Margaret E

2014-02-01

Creatine is an important molecule involved in cellular energy metabolism. Creatine is spontaneously converted to creatinine at a rate of 1·7% per d; creatinine is lost in the urine. Creatine can be obtained from the diet or synthesised from endogenous amino acids via the enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). The liver has high GAMT activity and the kidney has high AGAT activity. Although the pancreas has both AGAT and GAMT activities, its possible role in creatine synthesis has not been characterised. In the present study, we examined the enzymes involved in creatine synthesis in the pancreas as well as the synthesis of guanidinoacetate (GAA) and creatine by isolated pancreatic acini. We found significant AGAT activity and somewhat lower GAMT activity in the pancreas and that pancreatic acini had measurable activities of both AGAT and GAMT and the capacity to synthesise GAA and creatine from amino acids. Creatine supplementation led to a decrease in AGAT activity in the pancreas, though it did not affect its mRNA or protein abundance. This was in contrast with the reduction of AGAT activity and mRNA and protein abundance in the kidney, suggesting that the regulatory mechanisms that control the expression of this enzyme in the pancreas are different from those in the kidney. Dietary creatine increased the concentrations of GAA, creatine and phosphocreatine in the pancreas. Unexpectedly, creatine supplementation decreased the concentrations of S-adenosylmethionine, while those of S-adenosylhomocysteine were not altered significantly.

High-throughput tandem mass spectrometry multiplex analysis for newborn urinary screening of creatine synthesis and transport disorders, Triple H syndrome and OTC deficiency.

PubMed

Auray-Blais, Christiane; Maranda, Bruno; Lavoie, Pamela

2014-09-25

Creatine synthesis and transport disorders, Triple H syndrome and ornithine transcarbamylase deficiency are treatable inborn errors of metabolism. Early screening of patients was found to be beneficial. Mass spectrometry analysis of specific urinary biomarkers might lead to early detection and treatment in the neonatal period. We developed a high-throughput mass spectrometry methodology applicable to newborn screening using dried urine on filter paper for these aforementioned diseases. A high-throughput methodology was devised for the simultaneous analysis of creatine, guanidineacetic acid, orotic acid, uracil, creatinine and respective internal standards, using both positive and negative electrospray ionization modes, depending on the compound. The precision and accuracy varied by <15%. Stability during storage at different temperatures was confirmed for three weeks. The limits of detection and quantification for each biomarker varied from 0.3 to 6.3 μmol/l and from 1.0 to 20.9 μmol/l, respectively. Analyses of urine specimens from affected patients revealed abnormal results. Targeted biomarkers in urine were detected in the first weeks of life. This rapid, simple and robust liquid chromatography/tandem mass spectrometry methodology is an efficient tool applicable to urine screening for inherited disorders by biochemical laboratories. Copyright © 2014 Elsevier B.V. All rights reserved.

[Simultaneous determination of guanidinoacetate, creatine and creatinine by liquid chromatography-tandem mass spectrometry: a diagnostic tool for creatine deficiency syndromes in body fluids and a perspective use on cultured fibroblasts].

PubMed

Van Noolen, Laetitia; Monneret, Denis; Ducros, Véronique; Corne, Christelle; Lunardi, Joël; Faure, Patrice

2013-01-01

Guanidinoacetate (GAA) and creatine (Cr) are creatine deficiency syndromes (CDS) biochemical markers. We describe a liquid chromatography - tandem mass spectrometry method (LC/MSMS) performing simultaneous analysis of GAA, Cr and creatinine (Crn). Study of Cr uptake by fibroblasts for Cr transporter defect diagnosis is also assessed. The three butylated compounds were separated by liquid chromatography and MSMS quantification was achieved by isotopic dilution with electrospray positive ion mode. Linearity was demonstrated from 0 to 600, 675 and 4500 μmol/L and limit of quantification was 0.1, 0.04 and 0.9 μmol/L for GAA, Cr, and Crn respectively. Intra- and inter-assay precision for each analyte was better than 11%, and standard recoveries ranged from 83 to 109%. Reference values in cerebrospinal fluid samples for subjects ≥14 years were also established for GAA and Cr. Five fibroblast cell lines were used for Cr uptake study. Cr uptake by fibroblasts increased with the Cr media concentrations and was significantly inhibited by 3-guanidinopropionate (500 μmol/L), a Cr transporter inhibitor (96h incubation, [Cr media] = 25 μmol/L, p<0.05). A reliable LC/MSMS method for the diagnosis of CDS was developed in different biological fluids. Finally, results of the Cr uptake study reinforce the interest of this technique to diagnose Cr transporter deficiencies.

The CREST-E study of creatine for Huntington disease

PubMed Central

Schifitto, Giovanni; Oakes, David; Bredlau, Amy-Lee; Meyers, Catherine M.; Nahin, Richard; Rosas, Herminia Diana

2017-01-01

Objective: To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies. Results: At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits −0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment. Conclusions: Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD. Clinicaltrials.gov identifier: NCT00712426. Classification of evidence: This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline. PMID:28701493

Creatine Revealed Anticonvulsant Properties on Chemically and Electrically Induced Seizures in Mice.

PubMed

Shafaroodi, Hamed; Shahbek, Farnaz; Faizi, Mehrdad; Ebrahimi, Farzad; Moezi, Leila

2016-01-01

Creatine exerts beneficial effects on a variety of pathologies in which energy metabolism and oxidative stress play an etiological role. Creatine supplements have shown beneficial effects on neurological disorders including Parkinson׳s disease, Huntington›s disease, amyotrophic lateral sclerosis, as well as Alzheimer›s disease and stroke. However, the potential benefits of creatine for patients with convulsive disorders remain poorly defined. While some authors did not suggest any anti- or pro-convulsant roles for creatine treatment, others suggest that creatine may be an anticonvulsant agent. In this study, we investigated the effects of creatine on seizures in mice. Three models were used to explore the role of creatine on seizures in mice including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ, and electroshock models. Acute creatine treatment (10, 20, 40 and 80 mg/Kg) significantly increased the clonic seizure threshold in the intravenous PTZ model. Sub-chronic administration of creatine (10 and 20 mg/Kg) revealed a significant anticonvulsant effect in intravenous PTZ model. Acute creatine administration (10, 20 and 40 mg/Kg) significantly decreased the frequency of clonic seizures in the intraperitoneal PTZ model. Besides, acute creatine (40 and 80 mg/Kg) decreased the incidence of tonic seizures after electroshock. In conclusion, creatine exerts anticonvulsant effects in three seizure models; therefore, it may act as a potential drug to help patients with convulsions. However, further investigations should be done to clarify these results more.

Creatine Revealed Anticonvulsant Properties on Chemically and Electrically Induced Seizures in Mice

PubMed Central

Shafaroodi, Hamed; Shahbek, Farnaz; Faizi, Mehrdad; Ebrahimi, Farzad; Moezi, Leila

2016-01-01

Creatine exerts beneficial effects on a variety of pathologies in which energy metabolism and oxidative stress play an etiological role. Creatine supplements have shown beneficial effects on neurological disorders including Parkinson׳s disease, Huntington›s disease, amyotrophic lateral sclerosis, as well as Alzheimer›s disease and stroke. However, the potential benefits of creatine for patients with convulsive disorders remain poorly defined. While some authors did not suggest any anti- or pro-convulsant roles for creatine treatment, others suggest that creatine may be an anticonvulsant agent. In this study, we investigated the effects of creatine on seizures in mice. Three models were used to explore the role of creatine on seizures in mice including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ, and electroshock models. Acute creatine treatment (10, 20, 40 and 80 mg/Kg) significantly increased the clonic seizure threshold in the intravenous PTZ model. Sub-chronic administration of creatine (10 and 20 mg/Kg) revealed a significant anticonvulsant effect in intravenous PTZ model. Acute creatine administration (10, 20 and 40 mg/Kg) significantly decreased the frequency of clonic seizures in the intraperitoneal PTZ model. Besides, acute creatine (40 and 80 mg/Kg) decreased the incidence of tonic seizures after electroshock. In conclusion, creatine exerts anticonvulsant effects in three seizure models; therefore, it may act as a potential drug to help patients with convulsions. However, further investigations should be done to clarify these results more. PMID:28243281

Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets.

PubMed

Sharkey, Melinda S; Grunseich, Karl; Carpenter, Thomas O

2015-07-01

X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible. Copyright 2015 by the American Academy of Orthopaedic Surgeons.

Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury

PubMed Central

Stevens, Patrick R.; Gawryluk, Jeremy W.; Hui, Liang; Chen, Xuesong; Geiger, Jonathan D.

2015-01-01

HIV-1 infected individuals are living longer but experiencing a prevalence rate of over 50% for HIV-1 associated neurocognitive disorders (HAND) for which no effective treatment is available. Viral and cellular factors secreted by HIV-1 infected cells leads to neuronal injury and HIV-1 Tat continues to be implicated in the pathogenesis of HAND. Here we tested the hypothesis that creatine protected against HIV-1 Tat-induced neuronal injury by preventing mitochondrial bioenergetic crisis and/or redox catastrophe. Creatine blocked HIV-1 Tat1-72-induced increases in neuron cell death and synaptic area loss. Creatine protected against HIV-1 Tat-induced decreases in ATP. Creatine and creatine plus HIV-1 Tat increased cellular levels of creatine, and creatine plus HIV-1 Tat further decreased ratios of phosphocreatine to creatine observed with creatine or HIV-1 Tat treatments alone. Additionally, creatine protected against HIV-1 Tat-induced mitochondrial hypopolarization and HIV-1 Tat-induced mitochondrial permeability transition pore opening. Thus, creatine may be a useful adjunctive therapy against HAND. PMID:25613139

Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury.

PubMed

Stevens, Patrick R; Gawryluk, Jeremy W; Hui, Liang; Chen, Xuesong; Geiger, Jonathan D

2014-01-01

HIV-1 infected individuals live longer but experience a prevalence rate of over 50% for HIV-1 associated neurocognitive disorders (HAND) for which no effective treatment is available. Viral and cellular factors secreted by HIV-1 infected cells lead to neuronal injury and HIV-1 Tat continues to be implicated in the pathogenesis of HAND. Here we tested the hypothesis that creatine protected against HIV-1 Tat-induced neuronal injury by preventing mitochondrial bioenergetic crisis and/or redox catastrophe. Creatine blocked HIV-1 Tat(1-72)-induced increases in neuron cell death and synaptic area loss. Creatine protected against HIV-1 Tat-induced decreases in ATP. Creatine and creatine plus HIV-1 Tat increased cellular levels of creatine, and creatine plus HIV-1 Tat further decreased ratios of phosphocreatine to creatine observed with creatine or HIV-1 Tat treatments alone. Additionally, creatine protected against HIV-1 Tat-induced mitochondrial hypopolarization and HIV-1 Tat-induced mitochondrial permeability transition pore opening. Thus, creatine may be a useful adjunctive therapy against HAND.

Creatine for women in pregnancy for neuroprotection of the fetus.

PubMed

Dickinson, Hayley; Bain, Emily; Wilkinson, Dominic; Middleton, Philippa; Crowther, Caroline A; Walker, David W

2014-12-19

Creatine is an amino acid derivative and, when phosphorylated (phosphocreatine), is involved in replenishing adenosine triphosphate (ATP) via the creatine kinase reaction. Cells obtain creatine from a diet rich in fish, meat, or dairy and by endogenous synthesis from the amino acids arginine, glycine, and methionine in an approximate 50:50 ratio. Animal studies have shown that creatine may provide fetal neuroprotection when given to the mother through her diet in pregnancy. It is important to assess whether maternally administered creatine in human pregnancy (at times of known, suspected, or potential fetal compromise) may offer neuroprotection to the fetus and may accordingly reduce the risk of adverse neurodevelopmental outcomes, such as cerebral palsy and associated impairments and disabilities arising from fetal brain injury. To assess the effects of creatine when used for neuroprotection of the fetus. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2014). We planned to include all published, unpublished, and ongoing randomised trials and quasi-randomised trials. We planned to include studies reported as abstracts only as well as full-text manuscripts. Trials using a cross-over or cluster-randomised design were not eligible for inclusion.We planned to include trials comparing creatine given to women in pregnancy for fetal neuroprotection (regardless of the route, timing, dose, or duration of administration) with placebo, no treatment, or with an alternative agent aimed at providing fetal neuroprotection. We also planned to include comparisons of different regimens for administration of creatine. We identified no completed or ongoing randomised controlled trials. We found no randomised controlled trials for inclusion in this review. As we did not identify any randomised controlled trials for inclusion in this review, we are unable to comment on implications for practice. Although evidence from animal studies has supported a

Creatine Supplementation Associated or Not with Strength Training upon Emotional and Cognitive Measures in Older Women: A Randomized Double-Blind Study

PubMed Central

Alves, Christiano Robles Rodrigues; Merege Filho, Carlos Alberto Abujabra; Benatti, Fabiana Braga; Brucki, Sonia; Pereira, Rosa Maria R.; de Sá Pinto, Ana Lucia; Lima, Fernanda Rodrigues; Roschel, Hamilton; Gualano, Bruno

2013-01-01

Purpose To assess the effects of creatine supplementation, associated or not with strength training, upon emotional and cognitive measures in older woman. Methods This is a 24-week, parallel-group, double-blind, randomized, placebo-controlled trial. The individuals were randomly allocated into one of the following groups (n=14 each): 1) placebo, 2) creatine supplementation, 3) placebo associated with strength training or 4) creatine supplementation associated with strength training. According to their allocation, the participants were given creatine (4 x 5 g/d for 5 days followed by 5 g/d) or placebo (dextrose at the same dosage) and were strength trained or not. Cognitive function, assessed by a comprehensive battery of tests involving memory, selective attention, and inhibitory control, and emotional measures, assessed by the Geriatric Depression Scale, were evaluated at baseline, after 12 and 24 weeks of the intervention. Muscle strength and food intake were evaluated at baseline and after 24 weeks. Results After the 24-week intervention, both training groups (ingesting creatine supplementation and placebo) had significant reductions on the Geriatric Depression Scale scores when compared with the non-trained placebo group (p = 0.001 and p = 0.01, respectively) and the non-trained creatine group (p < 0.001 for both comparison). However, no significant differences were observed between the non-trained placebo and creatine (p = 0.60) groups, or between the trained placebo and creatine groups (p = 0.83). Both trained groups, irrespective of creatine supplementation, had better muscle strength performance than the non-trained groups. Neither strength training nor creatine supplementation altered any parameter of cognitive performance. Food intake remained unchanged. Conclusion Creatine supplementation did not promote any significant change in cognitive function and emotional parameters in apparently healthy older individuals. In addition, strength training per se

Genetics Home Reference: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

MedlinePlus

... Health Conditions IPEX syndrome Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome Printable PDF Open All Close All ... expand/collapse boxes. Description Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome primarily affects males and is ...

Creatine Supplementation Does Not Prevent the Development of Alcoholic Steatosis.

PubMed

Ganesan, Murali; Feng, Dan; Barton, Ryan W; Thomes, Paul G; McVicker, Benita L; Tuma, Dean J; Osna, Natalia A; Kharbanda, Kusum K

2016-11-01

Alcohol-induced reduction in the hepatocellular S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio impairs the activities of many SAM-dependent methyltransferases. These impairments ultimately lead to the generation of several hallmark features of alcoholic liver injury including steatosis. Guanidinoacetate methyltransferase (GAMT) is an important enzyme that catalyzes the final reaction in the creatine biosynthetic process. The liver is a major site for creatine synthesis which places a substantial methylation burden on this organ as GAMT-mediated reactions consume as much as 40% of all the SAM-derived methyl groups. We hypothesized that dietary creatine supplementation could potentially spare SAM, preserve the hepatocellular SAM:SAH ratio, and thereby prevent the development of alcoholic steatosis and other consequences of impaired methylation reactions. For these studies, male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol (EtOH) diet with or without 1% creatine supplementation. At the end of 4 to 5 weeks of feeding, relevant biochemical and histological analyses were performed. We observed that creatine supplementation neither prevented alcoholic steatosis nor attenuated the alcohol-induced impairments in proteasome activity. The lower hepatocellular SAM:SAH ratio seen in the EtOH-fed rats was also not normalized or SAM levels spared when these rats were fed the creatine-supplemented EtOH diet. However, a >10-fold increased level of creatine was observed in the liver, serum, and hearts of rats fed the creatine-supplemented diets. Overall, dietary creatine supplementation did not prevent alcoholic liver injury despite its known efficacy in preventing high-fat-diet-induced steatosis. Betaine, a promethylating agent that maintains the hepatocellular SAM:SAH, still remains our best option for treating alcoholic steatosis. Copyright © 2016 by the Research Society on Alcoholism.

Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

PubMed

Cunha, Mauricio P; Lieberknecht, Vicente; Ramos-Hryb, Ana Belén; Olescowicz, Gislaine; Ludka, Fabiana K; Tasca, Carla I; Gabilan, Nelson H; Rodrigues, Ana Lúcia S

2016-05-01

Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 μM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 μM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.

PubMed

Christie, P T; Harding, B; Nesbit, M A; Whyte, M P; Thakker, R V

2001-08-01

X-linked hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-linked hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-linked hypophosphatemia.

Creatine metabolism in urea cycle defects.

PubMed

Boenzi, Sara; Pastore, Anna; Martinelli, Diego; Goffredo, Bianca Maria; Boiani, Arianna; Rizzo, Cristiano; Dionisi-Vici, Carlo

2012-07-01

Creatine (Cr) and phosphocreatine play an essential role in energy storage and transmission. Maintenance of creatine pool is provided by the diet and by de novo synthesis, which utilizes arginine, glycine and s-adenosylmethionine as substrates. Three primary Cr deficiencies exists: arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency and the defect of Cr transporter SLC6A8. Secondary Cr deficiency is characteristic of ornithine-aminotransferase deficiency, whereas non-uniform Cr abnormalities have anecdotally been reported in patients with urea cycle defects (UCDs), a disease category related to arginine metabolism in which Cr must be acquired by de novo synthesis because of low dietary intake. To evaluate the relationships between ureagenesis and Cr synthesis, we systematically measured plasma Cr in a large series of UCD patients (i.e., OTC, ASS, ASL deficiencies, HHH syndrome and lysinuric protein intolerance). Plasma Cr concentrations in UCDs followed two different trends: patients with OTC and ASS deficiencies and HHH syndrome presented a significant Cr decrease, whereas in ASL deficiency and lysinuric protein intolerance Cr levels were significantly increased (23.5 vs. 82.6 μmol/L; p < 0.0001). This trend distribution appears to be regulated upon cellular arginine availability, highlighting its crucial role for both ureagenesis and Cr synthesis. Although decreased Cr contributes to the neurological symptoms in primary Cr deficiencies, still remains to be explored if an altered Cr metabolism may participate to CNS dysfunction also in patients with UCDs. Since arginine in most UCDs becomes a semi-essential aminoacid, measuring plasma Cr concentrations might be of help to optimize the dose of arginine substitution.

Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration

PubMed Central

Genius, Just; Geiger, Johanna; Bender, Andreas; Möller, Hans-Jürgen; Klopstock, Thomas; Rujescu, Dan

2012-01-01

Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H2O2. In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity. PMID:22347384

In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism

PubMed Central

2012-01-01

Background The discovery of the inherited disorders of creatine (Cr) synthesis and transport in the last few years disclosed the importance of blood Cr supply for the normal functioning of the brain. These putatively rare diseases share a common pathogenetic mechanism (the depletion of brain Cr) and similar phenotypes characterized by mental retardation, language disturbances, seizures and movement disorders. In the effort to improve our knowledge on the mechanisms regulating Cr pool inside the nervous tissue, Cr transport and synthesis and related gene transcripts were explored in primary cultures of rat cerebellar granule cells and astrocytes. Methods Cr uptake and synthesis were explored in vitro by incubating monotypic primary cultures of rat type I astrocytes and cerebellar granule cells with: a) D3-Creatine (D3Cr) and D3Cr plus β-guanidinopropionate (GPA, an inhibitor of Cr transporter), and b) labelled precursors of Guanidinoacetate (GAA) and Cr (Arginine, Arg; Glycine, Gly). Intracellular D3Cr and labelled GAA and Cr were assessed by ESI-MS/MS. Creatine transporter (CT1), L-arginine:glycine amidinotransferase (AGAT), and S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT) gene expression was assessed in the same cells by real time PCR. Results D3Cr signal was extremely high in cells incubated with this isotope (labelled/unlabelled Cr ratio reached about 10 and 122, respectively in cerebellar granule cells and astrocytes) and was reduced by GPA. Labelled Arg and Gly were taken up by the cells and incorporated in GAA, whose concentration paralleled that of these precursors both in the extracellular medium and inside the cells (astrocytes). In contrast, the increase of labelled Cr was relatively much more limited since labelled Cr after precursors' supplementation did not exceed 2,7% (cerebellar granule cells) and 21% (astrocytes) of unlabelled Cr. Finally, AGAT, GAMT and SLC6A8 were expressed in both kind of cells. Conclusions Our results

In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism.

PubMed

Carducci, Claudia; Carducci, Carla; Santagata, Silvia; Adriano, Enrico; Artiola, Cristiana; Thellung, Stefano; Gatta, Elena; Robello, Mauro; Florio, Tullio; Antonozzi, Italo; Leuzzi, Vincenzo; Balestrino, Maurizio

2012-04-26

The discovery of the inherited disorders of creatine (Cr) synthesis and transport in the last few years disclosed the importance of blood Cr supply for the normal functioning of the brain. These putatively rare diseases share a common pathogenetic mechanism (the depletion of brain Cr) and similar phenotypes characterized by mental retardation, language disturbances, seizures and movement disorders. In the effort to improve our knowledge on the mechanisms regulating Cr pool inside the nervous tissue, Cr transport and synthesis and related gene transcripts were explored in primary cultures of rat cerebellar granule cells and astrocytes. Cr uptake and synthesis were explored in vitro by incubating monotypic primary cultures of rat type I astrocytes and cerebellar granule cells with: a) D3-Creatine (D3Cr) and D3Cr plus β-guanidinopropionate (GPA, an inhibitor of Cr transporter), and b) labelled precursors of Guanidinoacetate (GAA) and Cr (Arginine, Arg; Glycine, Gly). Intracellular D3Cr and labelled GAA and Cr were assessed by ESI-MS/MS. Creatine transporter (CT1), L-arginine:glycine amidinotransferase (AGAT), and S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT) gene expression was assessed in the same cells by real time PCR. D3Cr signal was extremely high in cells incubated with this isotope (labelled/unlabelled Cr ratio reached about 10 and 122, respectively in cerebellar granule cells and astrocytes) and was reduced by GPA. Labelled Arg and Gly were taken up by the cells and incorporated in GAA, whose concentration paralleled that of these precursors both in the extracellular medium and inside the cells (astrocytes). In contrast, the increase of labelled Cr was relatively much more limited since labelled Cr after precursors' supplementation did not exceed 2,7% (cerebellar granule cells) and 21% (astrocytes) of unlabelled Cr. Finally, AGAT, GAMT and SLC6A8 were expressed in both kind of cells. Our results confirm that both neurons and astrocytes have

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

PubMed

Schulze, Andreas; Bauman, Margaret; Tsai, Anne Chun-Hui; Reynolds, Ann; Roberts, Wendy; Anagnostou, Evdokia; Cameron, Jessie; Nozzolillo, Alixandra A; Chen, Shiyi; Kyriakopoulou, Lianna; Scherer, Stephen W; Loh, Alvin

2016-01-01

Creatine deficiency may play a role in the neurobiology of autism and may represent a treatable cause of autism. The goal of the study was to ascertain the prevalence of creatine deficiency syndromes (CDSs) in children with autism spectrum disorder (ASD). In a prospective multicenter study, 443 children were investigated after a confirmed diagnosis of ASD. Random spot urine screening for creatine metabolites (creatine, guanidinoacetate, creatinine, and arginine) with liquid chromatography-tandem mass spectrometry and second-tier testing with high-performance liquid chromatography methodology was followed by recall testing in 24-hour urines and confirmatory testing by Sanger-based DNA sequencing of GAMT, GATM, and SLC6A8 genes. Additional diagnostic tests included plasma creatine metabolites and in vivo brain proton magnetic resonance spectroscopy. The creatine metabolites in spot urine in the autism group were compared with 128 healthy controls controlled for age. In 443 subjects with ASD investigated for CDS, we had 0 events (event: 0, 95% confidence interval 0-0.0068), therefore with 95% confidence the prevalence of CDS is <7 in 1000 children with ASD. The autism and control groups did not vary in terms of creatine metabolites (P > .0125) in urine. Our study revealed a very low prevalence of CDS in children with nonsyndromic ASD and no obvious association between creatine metabolites and autism. Unlike our study population, we expect more frequent CDS among children with severe developmental delay, speech impairment, seizures, and movement disorders in addition to impairments in social communication, restricted interests, and repetitive behaviors. Copyright © 2016 by the American Academy of Pediatrics.

Complete inhibition of creatine kinase in isolated perfused rat hearts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fossel, E.T.; Hoefeler, H.

1987-01-01

Transient exposure of an isolated isovolumic perfused rat heart to low concentrations (0.5 mM) of perfusate-born iodoacetamide resulted in complete inhibition of creatine kinase and partial inhibition of glyceraldehyde-3-phosphate dehydrogenase in the heart. At low levels of developed pressure, hearts maintained mechanical function, ATP, and creatine phosphate levels at control values. However, iodoacetamide-inhibited hearts were unable to maintain control values of end diastolic pressure or peak systolic pressure as work load increased. Global ischemia resulted in loss of all ATP without loss of creatine phosphate, indicating lack of active creatine kinase. These results indicate that isovolumic perfused rat hearts aremore » able to maintain normal function and normal levels of high-energy phosphates without active creatine kinase at low levels of developed pressure. /sup 31/P-NMR of the heart was carried out.« less

Creatine Synthesis: An Undergraduate Organic Chemistry Laboratory Experiment

ERIC Educational Resources Information Center

Smith, Andri L.; Tan, Paula

2006-01-01

Students in introductory chemistry classes typically appreciate seeing the connection between course content and the "real world". For this reason, we have developed a synthesis of creatine monohydrate--a popular supplement used in sports requiring short bursts of energy--for introductory organic chemistry laboratory courses. Creatine monohydrate…

Genetics Home Reference: X-linked spondyloepiphyseal dysplasia tarda

MedlinePlus

... Educational Resources (6 links) Cincinnati Children's Hospital: Coxa Vera Disease InfoSearch: Spondyloepiphyseal dysplasia tarda X-linked Johns ... Free article on PubMed Central Savarirayan R, Thompson E, Gécz J. Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). ...

Chromatographic separation and continuously referenced, on-line monitoring of creatine kinase isoenzymes by use of an immobilized-enzyme microreactor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Denton, M.S.; Bostick, W.D.; Dinsmore, S.R.

1978-08-01

We describe a new concept in continuously referenced monitoring of the isoenzyme activities of creatine kinase (EC 2.7.3.2) after liquid-chromatographic separation. After separation on a diethylaminoethyl-Sephacel column, the three isoenzymes of creatine kinase undergo a series of coupled enzyme reactions, ultimately resulting in the formation of ultraviolet-detectable NADPH. A major advantage of this detection system is the immobilized-enzyme microreactor (2 x 17 mm), which may be removed and stored refrigerated when not in use. A split-stream configuration allows self-blanking of endogenous ultraviolet-absorbing constituents in authentic sera samples, which would otherwise make definitive diagnosis and quantitation difficult or impossible. This detectionmore » system is applicable to the automated analysis of creatine kinase isoenzymes in the clinical laboratory.« less

Chromatographic separation and continuously referenced, on-line monitoring of creatine kinase isoenzymes by use of an immobilized-enzyme microreactor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Denton, M.S.; Bostick, W.D.; Dinsmore, S.R.

1978-08-01

We describe a new concept in continuously referenced monitoring of the isoenzyme activities of creatine kinase (EC 2.7.3.2) after liquid-chromatographic separation. After separation on a diethylaminoethyl-Sephacel column, the three isoenzymes of creatine kinase undergo a series of upled enzyme reactions, ultimately resulting in the formation of ultraviolet-detectable NADPH. A major advantage of this detection system is the immobilized-enzyme microreactor (2 x 17 mm), which may be removed and stored refrigerated when not in use. A split-stream configuration allows self-blanking of endogenous ultraviolet-absorbing constituents in authentic sera samples, which would otherwise make definitive diagnosis and quantitation difficult or impossible. This detectionmore » system is applicable to the automated analysis of creatine kinase isoenzymes in the clinical laboratory. 5 figures; 42 references.« less

Creatine co-ingestion with carbohydrate or cinnamon extract provides no added benefit to anaerobic performance.

PubMed

Islam, Hashim; Yorgason, Nick J; Hazell, Tom J

2016-09-01

The insulin response following carbohydrate ingestion enhances creatine transport into muscle. Cinnamon extract is promoted to have insulin-like effects, therefore this study examined if creatine co-ingestion with carbohydrates or cinnamon extract improved anaerobic capacity, muscular strength, and muscular endurance. Active young males (n = 25; 23.7 ± 2.5 y) were stratified into 3 groups: (1) creatine only (CRE); (2) creatine+ 70 g carbohydrate (CHO); or (3) creatine+ 500 mg cinnamon extract (CIN), based on anaerobic capacity (peak power·kg(-1)) and muscular strength at baseline. Three weeks of supplementation consisted of a 5 d loading phase (20 g/d) and a 16 d maintenance phase (5 g/d). Pre- and post-supplementation measures included a 30-s Wingate and a 30-s maximal running test (on a self-propelled treadmill) for anaerobic capacity. Muscular strength was measured as the one-repetition maximum 1-RM for chest, back, quadriceps, hamstrings, and leg press. Additional sets of the number of repetitions performed at 60% 1-RM until fatigue measured muscular endurance. All three groups significantly improved Wingate relative peak power (CRE: 15.4% P = .004; CHO: 14.6% P = .004; CIN: 15.7%, P = .003), and muscular strength for chest (CRE: 6.6% P < .001; CHO: 6.7% P < .001; CIN: 6.4% P < .001), back (CRE: 5.8% P < .001; CHO: 6.4% P < .001; CIN: 8.1% P < .001), and leg press (CRE: 11.7% P = .013; CHO: 10.0% P = .007; CIN: 17.3% P < .001). Only the CRE (10.4%, P = .021) and CIN (15.5%, P < .001) group improved total muscular endurance. No differences existed between groups post-supplementation. These findings demonstrate that three different methods of creatine ingestion lead to similar changes in anaerobic power, strength, and endurance.

Qualitative in vitro NMR analysis of creatine ethyl ester pronutrient in human plasma.

PubMed

Giese, M W; Lecher, C S

2009-10-01

There are a number of forms of creatine available that attempt to improve the solubility and permeability, with the anticipation this will result in an improved pharmacokinetic profile and ultimately an enhanced ergogenic response. Previous research has shown that the different salt forms can improve solubility resulting in slightly altered pharmacokinetic profiles, however specific data exploring the conversion of esterified derivatives to creatine is lacking. The purpose of this study was to examine the assertion that creatine ethyl ester undergoes enzymatic conversion to creatine in human tissues. The IN VITRO response of creatine ethyl ester to incubation in human plasma was examined by H-NMR analysis. Lyophilized human plasma was reconstituted in D2O and phosphate-buffered saline and 1.5 mg of the analyte was added. Following incubation at 37 degrees C for 4 h and subsequent protein precipitation, the supernatant was analyzed by NMR, utilizing the diagnostic chemical shift of the methylene signal to determine the species present in solution, I.E. creatine ethyl ester, creatine, or creatinine. Both creatine and creatinine were run in parallel as control experiments and each assay was run in triplicate. As expected both creatine and creatinine remained unchanged. However, conversion of creatine ethyl ester to creatine by the esterases in human plasma was not observed to any detectable extent and the only species detected after the incubation period was creatinine. While not a definitive characterization of the IN VIVO behavior, these results strongly warrant a complete IN VIVO pharmacokinetic analysis of creatine ethyl ester since it appears these "pronutrients" may actually provide large exogenous sources of pharmacologically inactive creatinine rather than ergogenic creatine.

siRNAs from an X-linked satellite repeat promote X-chromosome recognition in Drosophila melanogaster.

PubMed

Menon, Debashish U; Coarfa, Cristian; Xiao, Weimin; Gunaratne, Preethi H; Meller, Victoria H

2014-11-18

Highly differentiated sex chromosomes create a lethal imbalance in gene expression in one sex. To accommodate hemizygosity of the X chromosome in male fruit flies, expression of X-linked genes increases twofold. This is achieved by the male- specific lethal (MSL) complex, which modifies chromatin to increase expression. Mutations that disrupt the X localization of this complex decrease the expression of X-linked genes and reduce male survival. The mechanism that restricts the MSL complex to X chromatin is not understood. We recently reported that the siRNA pathway contributes to localization of the MSL complex, raising questions about the source of the siRNAs involved. The X-linked 1.688 g/cm(3) satellite related repeats (1.688(X) repeats) are restricted to the X chromosome and produce small RNA, making them an attractive candidate. We tested RNA from these repeats for a role in dosage compensation and found that ectopic expression of single-stranded RNAs from 1.688(X) repeats enhanced the male lethality of mutants with defective X recognition. In contrast, expression of double-stranded hairpin RNA from a 1.688(X) repeat generated abundant siRNA and dramatically increased male survival. Consistent with improved survival, X localization of the MSL complex was largely restored in these males. The striking distribution of 1.688(X) repeats, which are nearly exclusive to the X chromosome, suggests that these are cis-acting elements contributing to identification of X chromatin.

Proton transfer pathways, energy landscape, and kinetics in creatine-water systems.

PubMed

Ivchenko, Olga; Whittleston, Chris S; Carr, Joanne M; Imhof, Petra; Goerke, Steffen; Bachert, Peter; Wales, David J

2014-02-27

We study the exchange processes of the metabolite creatine, which is present in both tumorous and normal tissues and has NH2 and NH groups that can transfer protons to water. Creatine produces chemical exchange saturation transfer (CEST) contrast in magnetic resonance imaging (MRI). The proton transfer pathway from zwitterionic creatine to water is examined using a kinetic transition network constructed from the discrete path sampling approach and an approximate quantum-chemical energy function, employing the self-consistent-charge density-functional tight-binding (SCC-DFTB) method. The resulting potential energy surface is visualized by constructing disconnectivity graphs. The energy landscape consists of two distinct regions corresponding to the zwitterionic creatine structures and deprotonated creatine. The activation energy that characterizes the proton transfer from the creatine NH2 group to water was determined from an Arrhenius fit of rate constants as a function of temperature, obtained from harmonic transition state theory. The result is in reasonable agreement with values obtained in water exchange spectroscopy (WEX) experiments.

Genetics Home Reference: X-linked agammaglobulinemia

MedlinePlus

... Sep;104(3):221-30. Citation on PubMed Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr ... Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

Severe manifestations in carrier females in X linked retinitis pigmentosa.

PubMed Central

Souied, E; Segues, B; Ghazi, I; Rozet, J M; Chatelin, S; Gerber, S; Perrault, I; Michel-Awad, A; Briard, M L; Plessis, G; Dufier, J L; Munnich, A; Kaplan, J

1997-01-01

Retinitis pigmentosa (RP) is a group of progressive hereditary disorders of the retina in which various modes of inheritance have been described. Here, we report on X linked RP in nine families with constant and severe expression in carrier females. In our series, however, the phenotype was milder and delayed in carrier females compared to hemizygous males. This form of X linked RP could be regarded therefore as partially dominant. The disease gene maps to chromosome Xp2.1 in the genetic interval encompassing the RP3 locus (Zmax=13.71 at the DXS1100 locus). Single strand conformation polymorphism and direct sequence analysis of the retinitis pigmentosa GTPase regulator (RPGR) gene, which accounts for RP3, failed to detect any mutation in our families. Future advances in the identification of X linked RP genes will hopefully help to elucidate the molecular basis of this X linked dominant RP. Images PMID:9350809

Making connections : intermodal links in the public transportation system

DOT National Transportation Integrated Search

2007-09-01

Since at least 1991, federal transportation policy has sought to encourage intermodal connections the links that allow passengers to switch from one mode of public transportation to another. The intermodal terminal is a key building block for dev...

Molecular and clinical studies of X-linked deafness among Pakistani families.

PubMed

Waryah, Ali M; Ahmed, Zubair M; Bhinder, Munir A; Binder, Munir A; Choo, Daniel I; Sisk, Robert A; Shahzad, Mohsin; Khan, Shaheen N; Friedman, Thomas B; Riazuddin, Sheikh; Riazuddin, Saima

2011-07-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling and molecular epidemiology of hearing loss among Pakistanis.

Molecular and Clinical Studies of X-linked Deafness Among Pakistani Families

PubMed Central

Waryah, Ali M.; Ahmed, Zubair M.; Choo, Daniel I.; Sisk, Robert A.; Binder, Munir A.; Shahzad, Mohsin; Khan, Shaheen N.; Friedman, Thomas B.; Riazuddin, Sheikh; Riazuddin, Saima

2011-01-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132, PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild to profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling, and molecular epidemiology of hearing loss among Pakistanis. PMID:21633365

Contribution of creatine to protein homeostasis in athletes after endurance and sprint running.

PubMed

Tang, Fu-Chun; Chan, Chun-Chen; Kuo, Po-Ling

2014-02-01

Few studies have focused on the metabolic changes induced by creatine supplementation. This study investigated the effects of creatine supplementation on plasma and urinary metabolite changes of athletes after endurance and sprint running. Twelve male athletes (20.3 ± 1.4 y) performed two identical (65-70 % maximum heart rate reserved) 60 min running exercises (endurance trial) before and after creatine supplementation (12 g creatine monohydrate/day for 15 days), followed by a 5-day washout period. Subsequently, they performed two identical 100 m sprint running exercises (power trial) before and after 15 days of creatine supplementation in accordance with the supplementary protocol of the endurance trial. Body composition measurements were performed during the entire study. Plasma samples were examined for the concentrations of glucose, lactate, branched-chain amino acids (BCAAs), free-tryptophan (f-TRP), glutamine, alanine, hypoxanthine, and uric acid. Urinary samples were examined for the concentrations of hydroxyproline, 3-methylhistidine, urea nitrogen, and creatinine. Creatine supplementation significantly increased body weights of the athletes of endurance trial. Plasma lactate concentration and ratio of f-TRP/BCAAs after recovery from endurance running were significantly decreased with creatine supplementation. Plasma purine metabolites (the sum of hypoxanthine and uric acid), glutamine, urinary 3-methylhistidine, and urea nitrogen concentrations tended to decrease before running in trials with creatine supplements. After running, urinary hydroxyproline concentration significantly increased in the power trial with creatine supplements. The findings suggest that creatine supplementation tended to decrease muscle glycogen and protein degradation, especially after endurance exercise. However, creatine supplementation might induce collagen proteolysis in athletes after sprint running.

X linked mental retardation: a clinical guide.

PubMed

Raymond, F L

2006-03-01

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.

Study of renal and hepatic toxicity in rats supplemented with creatine.

PubMed

Baracho, Nilo Cesar do Vale; Castro, Letícia Pereira de; Borges, Niara da Cunha; Laira, Patrícia Benício

2015-05-01

To evaluate the renal and hepatic function, through biochemical analysis after 14 days of creatine supplementation in physically inactive rats. Twenty four male, adult, Wistar rats were used which were kept in individual metabolic cages and were distributed into four groups, and received the following treatments by gavage:1) CONTROL: distilled water; 2)Creatine 0.5g/Kg/day; 3) Creatine 1g/Kg/day; 4) Creatine 2g/Kg/day. Their urinary outputs as well as food and water intake were daily measured. At the end of the experiment, the animals were euthanized and serum samples were stored for biochemical analysis. Creatine supplementation at the doses given produced no significant changes in plasma levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin, total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, glucose, creatinine, urea, and creatinine clearance, compared to control group (p> 0.05) Similarly, water and food intake, as well as urinary output, did not show significant changes among the four groups studied. At the doses used, oral creatine supplementation did not result in renal and/or hepatic toxicity.

Radioimmunoassay measurement of creatine kinase bb in the serum of schizophrenic patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lerner, M.H.; Friedhoff, A.J.

1980-03-03

Brain type creatine kinase (BB) isoenzyme was measured using a highly sensitive and specific radioimmunoassay procedure in two schizophrenic populations. The data would indicate that in the schizophrenic populations examined there is insufficient tissue disruption to cause abnormal build-up of brain creatine kinase levels. However the possibility of a rapid removal of creatine kinase BB from the circulation exists. The elevated creatine kinase reported in acute schizophrenics is most likely not of brain origin.

Effect of creatine supplementation and drop-set resistance training in untrained aging adults.

PubMed

Johannsmeyer, Sarah; Candow, Darren G; Brahms, C Markus; Michel, Deborah; Zello, Gordon A

2016-10-01

To investigate the effects of creatine supplementation and drop-set resistance training in untrained aging adults. Participants were randomized to one of two groups: Creatine (CR: n=14, 7 females, 7 males; 58.0±3.0yrs, 0.1g/kg/day of creatine+0.1g/kg/day of maltodextrin) or Placebo (PLA: n=17, 7 females, 10 males; age: 57.6±5.0yrs, 0.2g/kg/day of maltodextrin) during 12weeks of drop-set resistance training (3days/week; 2 sets of leg press, chest press, hack squat and lat pull-down exercises performed to muscle fatigue at 80% baseline 1-repetition maximum [1-RM] immediately followed by repetitions to muscle fatigue at 30% baseline 1-RM). Prior to and following training and supplementation, assessments were made for body composition, muscle strength, muscle endurance, tasks of functionality, muscle protein catabolism and diet. Drop-set resistance training improved muscle mass, muscle strength, muscle endurance and tasks of functionality (p<0.05). The addition of creatine to drop-set resistance training significantly increased body mass (p=0.002) and muscle mass (p=0.007) compared to placebo. Males on creatine increased muscle strength (lat pull-down only) to a greater extent than females on creatine (p=0.005). Creatine enabled males to resistance train at a greater capacity over time compared to males on placebo (p=0.049) and females on creatine (p=0.012). Males on creatine (p=0.019) and females on placebo (p=0.014) decreased 3-MH compared to females on creatine. The addition of creatine to drop-set resistance training augments the gains in muscle mass from resistance training alone. Creatine is more effective in untrained aging males compared to untrained aging females. Copyright © 2016 Elsevier Inc. All rights reserved.

A Simulation of X-Linked Inheritance.

ERIC Educational Resources Information Center

Harrell, Pamela Esprivalo

1997-01-01

Describes how to lead students through a classroom-based simulation to teach a variety of concepts such as X-linked traits, sex determination, and sex anomalies. The simulation utilizes inexpensive materials such as plastic eggs that twist apart to represent human eggs and sperm. (AIM)

Creatine supplementation increases glycogen storage but not GLUT-4 expression in human skeletal muscle.

PubMed

van Loon, Luc J C; Murphy, Robyn; Oosterlaar, Audrey M; Cameron-Smith, David; Hargreaves, Mark; Wagenmakers, Anton J M; Snow, Rodney

2004-01-01

It has been speculated that creatine supplementation affects muscle glucose metabolism in humans by increasing muscle glycogen storage and up-regulating GLUT-4 protein expression. In the present study, we assessed the effects of creatine loading and prolonged supplementation on muscle glycogen storage and GLUT-4 mRNA and protein content in humans. A total of 20 subjects participated in a 6-week supplementation period during which creatine or a placebo was ingested. Muscle biopsies were taken before and after 5 days of creatine loading (20 g.day(-1)) and after 6 weeks of continued supplementation (2 g.day(-1)). Fasting plasma insulin concentrations, muscle creatine, glycogen and GLUT-4 protein content as well as GLUT-4, glycogen synthase-1 (GS-1) and glycogenin-1 (Gln-1) mRNA expression were determined. Creatine loading significantly increased total creatine, free creatine and creatine phosphate content with a concomitant 18 +/- 5% increase in muscle glycogen content (P<0.05). The subsequent use of a 2 g.day(-1) maintenance dose for 37 days did not maintain total creatine, creatine phosphate and glycogen content at the elevated levels. The initial increase in muscle glycogen accumulation could not be explained by an increase in fasting plasma insulin concentration, muscle GLUT-4 mRNA and/or protein content. In addition, neither muscle GS-1 nor Gln-1 mRNA expression was affected. We conclude that creatine ingestion itself stimulates muscle glycogen storage, but does not affect muscle GLUT-4 expression.

Escape of X-linked miRNA genes from meiotic sex chromosome inactivation

PubMed Central

Sosa, Enrique; Flores, Luis; Yan, Wei; McCarrey, John R.

2015-01-01

Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis. PMID:26395485

Effects on Energy Metabolism of Two Guanidine Molecules, (Boc)2 -Creatine and Metformin.

PubMed

Garbati, Patrizia; Ravera, Silvia; Scarfì, Sonia; Salis, Annalisa; Rosano, Camillo; Poggi, Alessandro; Damonte, Gianluca; Millo, Enrico; Balestrino, Maurizio

2017-09-01

Several enzymes are involved in the energy production, becoming a possible target for new anti-cancer drugs. In this paper, we used biochemical and in silico studies to evaluate the effects of two guanidine molecules, (Boc) 2 -creatine and metformin, on creatine kinase, an enzyme involved in the regulation of intracellular energy levels. Our results show that both drugs inhibit creatine kinase activity; however, (Boc) 2 -creatine displays a competitive inhibition, while metformin acts with a non-competitive mechanism. Moreover, (Boc) 2 -creatine is able to inhibit the activity of hexokinase with a non-competitive mechanism. Considering that creatine kinase and hexokinase are involved in energy metabolism, we evaluated the effects of (Boc) 2 -creatine and metformin on the ATP/AMP ratio and on cellular proliferation in healthy fibroblasts, human breast cancer cells (MDA-MB-468), a human neuroblastoma cell line (SH-SY5Y), a human Hodgkin lymphoma cell line (KMH2). We found that healthy fibroblasts were only partially affected by (Boc) 2 -creatine, while both ATP/AMP ratio and viability of the three cancer cell lines were significantly decreased. By inhibiting both creatine kinase and hexokinase, (Boc) 2 -creatine appears as a promising new agent in anticancer treatment. Further research is needed to understand what types of cancer cells are most suitable to treatment by this new compound. J. Cell. Biochem. 118: 2700-2711, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Protective effect of creatine against inhibition by methylglyoxal of mitochondrial respiration of cardiac cells.

PubMed Central

Roy, Soumya Sinha; Biswas, Swati; Ray, Manju; Ray, Subhankar

2003-01-01

Previous publications from our laboratory have shown that methylglyoxal inhibits mitochondrial respiration of malignant and cardiac cells, but it has no effect on mitochondrial respiration of other normal cells [Biswas, Ray, Misra, Dutta and Ray (1997) Biochem. J. 323, 343-348; Ray, Biswas and Ray (1997) Mol. Cell. Biochem. 171, 95-103]. However, this inhibitory effect of methylglyoxal is not significant in cardiac tissue slices. Moreover, post-mitochondrial supernatant (PMS) of cardiac cells could almost completely protect the mitochondrial respiration against the inhibitory effect of methylglyoxal. A systematic search indicated that creatine present in cardiac cells is responsible for this protective effect. Glutathione has also some protective effect. However, creatine phosphate, creatinine, urea, glutathione disulphide and beta-mercaptoethanol have no protective effect. The inhibitory and protective effects of methylglyoxal and creatine respectively on cardiac mitochondrial respiration were studied with various concentrations of both methylglyoxal and creatine. Interestingly, neither creatine nor glutathione have any protective effect on the inhibition by methylglyoxal on the mitochondrial respiration of Ehrlich ascites carcinoma cells. The creatine and glutathione contents of several PMS, which were tested for the possible protective effect, were measured. The activities of two important enzymes, namely glyoxalase I and creatine kinase, which act upon glutathione plus methylglyoxal and creatine respectively, were also measured in different PMS. Whether mitochondrial creatine kinase had any role in the protective effect of creatine had also been investigated using 1-fluoro-2,4-dinitrobenzene, an inhibitor of creatine kinase. The differential effect of creatine on mitochondria of cardiac and malignant cells has been discussed with reference to the therapeutic potential of methylglyoxal. PMID:12605598

Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease.

PubMed

Horn, Morten A; Erichsen, Martina M; Wolff, Anette S B; Månsson, Jan-Eric; Husebye, Eystein S; Tallaksen, Chantal M E; Skjeldal, Ola H

2013-09-01

X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 1·5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. © 2013 John Wiley & Sons Ltd.

Effects of oxygen stoichiometry on the scaling behaviors of YBa2Cu3O(x) grain boundary weak-links

NASA Technical Reports Server (NTRS)

Wu, K. H.; Fu, C. M.; Jeng, W. J.; Juang, J. Y.; Uen, T. M.; Gou, Y. S.

1995-01-01

The effects of oxygen stoichiometry on the transport properties of the pulsed laser deposited YBa2Cu3O(x) bicrystalline grain boundary weak-link junctions were studied. It is found that not only the cross boundary resistive transition foot structure can be manipulated repeatedly with oxygen annealing processes but the junction behaviors are also altered in accordance. In the fully oxygenated state i.e with x = 7.0 in YBa2Cu3O(x) stoichiometry, the junction critical current exhibits a power of 2 scaling behavior with temperature. In contrast, when annealed in the conditions of oxygen-deficient state (e.g with x = 6.9 in YBa2Cu3O(x) stoichiometry) the junction critical current switches to a linear temperature dependence behavior. The results are tentatively attributed to the modification of the structure in the boundary area upon oxygen annealing, which, in turn, will affect the effective dimension of the geometrically constrained weak-link bridges. The detailed discussion on the responsible physical mechanisms as well as the implications of the present results on device applications will be given.

MULTIMODAL IMAGING OF MOSAIC RETINOPATHY IN CARRIERS OF HEREDITARY X-LINKED RECESSIVE DISEASES.

PubMed

Wu, An-Lun; Wang, Jung-Pan; Tseng, Yun-Ju; Liu, Laura; Kang, Yu-Chuan; Chen, Kuan-Jen; Chao, An-Ning; Yeh, Lung-Kun; Chen, Tun-Lu; Hwang, Yih-Shiou; Wu, Wei-Chi; Lai, Chi-Chun; Wang, Nan-Kai

2018-05-01

To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.

Dietary guanidinoacetic acid increases brain creatine levels in healthy men.

PubMed

Ostojic, Sergej M; Ostojic, Jelena; Drid, Patrik; Vranes, Milan; Jovanov, Pavle

2017-01-01

Guanidinoacetic acid (GAA) is an experimental dietary additive that might act as a creatine source in tissues with high-energy requirements. In this case study, we evaluated brain levels of creatine in white matter, gray matter, cerebellum, and thalamus during 8 wk oral GAA administration in five healthy men and monitored the prevalence and severity of side effects of the intervention. Volunteers were supplemented daily with 36 mg/kg body weight (BW) of GAA for the first 4 wk of the intervention; afterward GAA dosage was titrated ≤60 mg/kg BW of GAA daily. At baseline, 4, and 8 wk, the participants underwent brain magnetic resonance spectroscopy, clinical chemistry studies, and open-ended questionnaire for side-effect prevalence and severity. Brain creatine levels increased in similar fashion in cerebellum, and white and gray matter after GAA supplementation, with an initial increase of 10.7% reported after 4 wk, and additional upsurge (7.7%) from the weeks 4 to 8 follow-up (P < 0.05). Thalamus creatine levels decreased after 4 wk for 6.5% (P = 0.02), and increased nonsignificantly after 8 wk for 8% (P = 0.09). GAA induced an increase in N-acetylaspartate levels at 8-wk follow-up in all brain areas evaluated (P < 0.05). No participants reported any neurologic adverse event (e.g., seizures, tingling, convulsions) during the intervention. Supplemental GAA led to a region-dependent increase of the creatine pool in the human brain. This might be relevant for restoring cellular bioenergetics in disorders characterized by low brain creatine and functional enzymatic machinery for creatine synthesis, including neurodegenerative diseases, brain tumors, or cerebrovascular disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetics Home Reference: X-linked lymphoproliferative disease

MedlinePlus

... infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, ... severe susceptibility to EBV infection severe susceptibility to infectious mononucleosis X-linked lymphoproliferative syndrome XLP Related Information How ...

Effect of low-dose, short-duration creatine supplementation on anaerobic exercise performance.

PubMed

Hoffman, Jay R; Stout, Jeffrey R; Falvo, Michael J; Kang, Jie; Ratamess, Nicholas A

2005-05-01

To examine the efficacy of a low-dose, short-duration creatine monohydrate supplement, 40 physically active men were randomly assigned to either a placebo or creatine supplementation group (6 g of creatine monohydrate per day). Testing occurred before and at the end of 6 days of supplementation. During each testing session, subjects performed three 15-second Wingate anaerobic power tests. No significant (p > 0.05) group or time differences were observed in body mass, peak power, mean power, or total work. In addition, no significant (p > 0.05) differences were observed in peak power, mean power, or total work. However, the change in the rate of fatigue of total work was significantly (p < 0.05) lower in the creatine supplementation group than in the placebo group, indicating a reduced fatigue rate in subjects supplementing with creatine compared with the placebo. Although the results of this study demonstrated reduced fatigue rates in patients during high-intensity sprint intervals, further research is necessary in examining the efficacy of low-dose, short-term creatine supplementation.

The effects of pre versus post workout supplementation of creatine monohydrate on body composition and strength

PubMed Central

2013-01-01

Background Chronic supplementation with creatine monohydrate has been shown to promote increases in total intramuscular creatine, phosphocreatine, skeletal muscle mass, lean body mass and muscle fiber size. Furthermore, there is robust evidence that muscular strength and power will also increase after supplementing with creatine. However, it is not known if the timing of creatine supplementation will affect the adaptive response to exercise. Thus, the purpose of this investigation was to determine the difference between pre versus post exercise supplementation of creatine on measures of body composition and strength. Methods Nineteen healthy recreational male bodybuilders (mean ± SD; age: 23.1 ± 2.9; height: 166.0 ± 23.2 cm; weight: 80.18 ± 10.43 kg) participated in this study. Subjects were randomly assigned to one of the following groups: PRE-SUPP or POST-SUPP workout supplementation of creatine (5 grams). The PRE-SUPP group consumed 5 grams of creatine immediately before exercise. On the other hand, the POST-SUPP group consumed 5 grams immediately after exercise. Subjects trained on average five days per week for four weeks. Subjects consumed the supplement on the two non-training days at their convenience. Subjects performed a periodized, split-routine, bodybuilding workout five days per week (Chest-shoulders-triceps; Back-biceps, Legs, etc.). Body composition (Bod Pod®) and 1-RM bench press (BP) were determined. Diet logs were collected and analyzed (one random day per week; four total days analyzed). Results 2x2 ANOVA results - There was a significant time effect for fat-free mass (FFM) (F = 19.9; p = 0.001) and BP (F = 18.9; p < 0.001), however, fat mass (FM) and body weight did not reach significance. While there were trends, no significant interactions were found. However, using magnitude-based inference, supplementation with creatine post workout is possibly more beneficial in comparison to pre workout supplementation

The effects of pre versus post workout supplementation of creatine monohydrate on body composition and strength.

PubMed

Antonio, Jose; Ciccone, Victoria

2013-01-01

Chronic supplementation with creatine monohydrate has been shown to promote increases in total intramuscular creatine, phosphocreatine, skeletal muscle mass, lean body mass and muscle fiber size. Furthermore, there is robust evidence that muscular strength and power will also increase after supplementing with creatine. However, it is not known if the timing of creatine supplementation will affect the adaptive response to exercise. Thus, the purpose of this investigation was to determine the difference between pre versus post exercise supplementation of creatine on measures of body composition and strength. Nineteen healthy recreational male bodybuilders (mean ± SD; age: 23.1 ± 2.9; height: 166.0 ± 23.2 cm; weight: 80.18 ± 10.43 kg) participated in this study. Subjects were randomly assigned to one of the following groups: PRE-SUPP or POST-SUPP workout supplementation of creatine (5 grams). The PRE-SUPP group consumed 5 grams of creatine immediately before exercise. On the other hand, the POST-SUPP group consumed 5 grams immediately after exercise. Subjects trained on average five days per week for four weeks. Subjects consumed the supplement on the two non-training days at their convenience. Subjects performed a periodized, split-routine, bodybuilding workout five days per week (Chest-shoulders-triceps; Back-biceps, Legs, etc.). Body composition (Bod Pod®) and 1-RM bench press (BP) were determined. Diet logs were collected and analyzed (one random day per week; four total days analyzed). 2x2 ANOVA results - There was a significant time effect for fat-free mass (FFM) (F = 19.9; p = 0.001) and BP (F = 18.9; p < 0.001), however, fat mass (FM) and body weight did not reach significance. While there were trends, no significant interactions were found. However, using magnitude-based inference, supplementation with creatine post workout is possibly more beneficial in comparison to pre workout supplementation with regards to FFM, FM

Meta-Analysis of Creatine for Neuroprotection Against Parkinson's Disease.

PubMed

Attia; Ahmed, Hussien; Gadelkarim, Mohamed; Morsi, Mahmoud; Awad, Kamal; Elnenny, Mohamed; Ghanem, Esraa; El-Jaafary, Shaimaa; Negida, Ahmed

2017-01-01

Creatine is an antioxidant agent that showed neuroprotective effects in animal models of Parkinson's disease (PD). Creatine was selected by the National Institute of Neurological Disorders and Stroke as a possible disease modifying agent for Parkinson's disease. Therefore, many clinical trials evaluated the efficacy of creatine for patients with PD. The aim of this systematic review and meta-analysis is to synthesize evidence from published randomized controlled trials (RCTs) about the efficacy of Creatine for patients with PD. We followed PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for PubMed, EBSCO, web of science and Ovid Midline was carried out. We included RCTs comparing creatine with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, and UPDRS III were pooled as mean difference (MD) between two groups from baseline to the endpoint. Statistical heterogeneity was assessed by visual inspection of the forest plot and measured by chi-square and I square tests. Three RCTs (n=1935) were included in this study. The overall effect did not favor either of the two groups in terms of: UPDRS total score (MD 1.07, 95% CI [3.38 to 1.25], UPDRS III (MD 0.62, 95% CI [2.27 to 1.02]), UPDRS II (MD 0.03, 95% CI [0.81 to 0.86], or UPDRS I (MD 0.03, 95% CI [0.33 to 0.28]). Current evidence does not support the use of creatine for neuroprotection against PD. Future well-designed, randomized controlled trials are needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Caffeine and Creatine Content of Dietary Supplements Consumed by Brazilian Soccer Players.

PubMed

Inácio, Suelen Galante; de Oliveira, Gustavo Vieira; Alvares, Thiago Silveira

2016-08-01

Caffeine and creatine are ingredients in the most popular dietary supplements consumed by soccer players. However, some products may not contain the disclosed amounts of the ingredients listed on the label, compromising the safe usage and the effectiveness of these supplements. Therefore, the aim of this study was to evaluate the content of caffeine and creatine in dietary supplements consumed by Brazilian soccer players. The results obtained were compared with the caffeine content listed on the product label. Two batches of the supplement brands consumed by ≥ 50% of the players were considered for analysis. The quantification of caffeine and creatine in the supplements was determined by a high-performance liquid chromatography system with UV detector. Nine supplements of caffeine and 7 supplements of creatine met the inclusion criteria for analysis. Eight brands of caffeine and five brands of creatine showed significantly different values (p < .05) as compared with the values stated on the label. There were no significant differences between the two batches of supplements analyzed, except for one caffeine supplement. It can be concluded that caffeine and creatine dietary supplements consumed by Brazilian soccer players present inaccurate values listed on the label, although most presented no difference among batches. To ensure consumer safety and product efficacy, accurate information on caffeine and creatine content should be provided on all dietary supplement labels.

Caffeine, creatine, GRIN2A and Parkinson's disease progression.

PubMed

Simon, David K; Wu, Cai; Tilley, Barbara C; Lohmann, Katja; Klein, Christine; Payami, Haydeh; Wills, Anne-Marie; Aminoff, Michael J; Bainbridge, Jacquelyn; Dewey, Richard; Hauser, Robert A; Schaake, Susen; Schneider, Jay S; Sharma, Saloni; Singer, Carlos; Tanner, Caroline M; Truong, Daniel; Wei, Peng; Wong, Pei Shieen; Yang, Tianzhong

2017-04-15

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring.

PubMed

Sartini, S; Lattanzi, D; Ambrogini, P; Di Palma, M; Galati, C; Savelli, D; Polidori, E; Calcabrini, C; Rocchi, M B L; Sestili, P; Cuppini, R

2016-01-15

Creatine supplementation has been shown to protect neurons from oxidative damage due to its antioxidant and ergogenic functions. These features have led to the hypothesis of creatine supplementation use during pregnancy as prophylactic treatment to prevent CNS damage, such as hypoxic-ischemic encephalopathy. Unfortunately, very little is known on the effects of creatine supplementation during neuron differentiation, while in vitro studies revealed an influence on neuron excitability, leaving the possibility of creatine supplementation during the CNS development an open question. Using a multiple approach, we studied the hippocampal neuron morphological and functional development in neonatal rats born by dams supplemented with 1% creatine in drinking water during pregnancy. CA1 pyramidal neurons of supplemented newborn rats showed enhanced dendritic tree development, increased LTP maintenance, larger evoked-synaptic responses, and higher intrinsic excitability in comparison to controls. Moreover, a faster repolarizing phase of action potential with the appearance of a hyperpolarization were recorded in neurons of the creatine-treated group. Consistently, CA1 neurons of creatine exposed pups exhibited a higher maximum firing frequency than controls. In summary, we found that creatine supplementation during pregnancy positively affects morphological and electrophysiological development of CA1 neurons in offspring rats, increasing neuronal excitability. Altogether, these findings emphasize the need to evaluate the benefits and the safety of maternal intake of creatine in humans. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease.

PubMed

Fuld, J P; Kilduff, L P; Neder, J A; Pitsiladis, Y; Lean, M E J; Ward, S A; Cotton, M M

2005-07-01

Skeletal muscle wasting and dysfunction are strong independent predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). Creatine nutritional supplementation produces increased muscle mass and exercise performance in health. A controlled study was performed to look for similar effects in 38 patients with COPD. Thirty eight patients with COPD (mean (SD) forced expiratory volume in 1 second (FEV(1)) 46 (15)% predicted) were randomised to receive placebo (glucose polymer 40.7 g) or creatine (creatine monohydrate 5.7 g, glucose 35 g) supplements in a double blind trial. After 2 weeks loading (one dose three times daily), patients participated in an outpatient pulmonary rehabilitation programme combined with maintenance (once daily) supplementation. Pulmonary function, body composition, and exercise performance (peripheral muscle strength and endurance, shuttle walking, cycle ergometry) took place at baseline (n = 38), post loading (n = 36), and post rehabilitation (n = 25). No difference was found in whole body exercise performance between the groups: for example, incremental shuttle walk distance mean -23.1 m (95% CI -71.7 to 25.5) post loading and -21.5 m (95% CI -90.6 to 47.7) post rehabilitation. Creatine increased fat-free mass by 1.09 kg (95% CI 0.43 to 1.74) post loading and 1.62 kg (95% CI 0.47 to 2.77) post rehabilitation. Peripheral muscle performance improved: knee extensor strength 4.2 N.m (95% CI 1.4 to 7.1) and endurance 411.1 J (95% CI 129.9 to 692.4) post loading, knee extensor strength 7.3 N.m (95% CI 0.69 to 13.92) and endurance 854.3 J (95% CI 131.3 to 1577.4) post rehabilitation. Creatine improved health status between baseline and post rehabilitation (St George's Respiratory Questionnaire total score -7.7 (95% CI -14.9 to -0.5)). Creatine supplementation led to increases in fat-free mass, peripheral muscle strength and endurance, health status, but not exercise capacity. Creatine may constitute a new ergogenic treatment

Effect of age, diet, and tissue type on PCr response to creatine supplementation.

PubMed

Solis, Marina Yazigi; Artioli, Guilherme Giannini; Otaduy, Maria Concepción García; Leite, Claudia da Costa; Arruda, Walquiria; Veiga, Raquel Ramos; Gualano, Bruno

2017-08-01

Creatine/phosphorylcreatine (PCr) responses to creatine supplementation may be modulated by age, diet, and tissue, but studies assessing this possibility are lacking. Therefore we aimed to determine whether PCr responses vary as a function of age, diet, and tissue. Fifteen children, 17 omnivorous and 14 vegetarian adults, and 18 elderly individuals ("elderly") participated in this study. Participants were given placebo and subsequently creatine (0.3 g·kg -1 ·day -1 ) for 7 days in a single-blind fashion. PCr was measured through phosphorus magnetic resonance spectroscopy ( 31 P-MRS) in muscle and brain. Creatine supplementation increased muscle PCr in children ( P < 0.0003) and elderly ( P < 0.001), whereas the increase in omnivores did not reach statistically significant difference ( P = 0.3348). Elderly had greater PCr increases than children and omnivores ( P < 0.0001 for both), whereas children experienced greater PCr increases than omnivores ( P = 0.0022). In relation to diet, vegetarians ( P < 0.0001), but not omnivores, had significant increases in muscle PCr content. Brain PCr content was not affected by creatine supplementation in any group, and delta changes in brain PCr (-0.7 to +3.9%) were inferior to those in muscle PCr content (+10.3 to +27.6%; P < 0.0001 for all comparisons). PCr responses to a standardized creatine protocol (0.3 g·kg -1 ·day -1 for 7 days) may be affected by age, diet, and tissue. Whereas creatine supplementation was able to increase muscle PCr in all groups, although to different extents, brain PCr was shown to be unresponsive overall. These findings demonstrate the need to tailor creatine protocols to optimize creatine/PCr accumulation both in muscle and in brain, enabling a better appreciation of the pleiotropic properties of creatine. NEW & NOTEWORTHY A standardized creatine supplementation protocol (0.3 g·kg -1 ·day -1 for 7 days) effectively increased muscle, but not brain, phosphorylcreatine. Older participants

X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria

PubMed Central

Brancaleoni, V.; Balwani, M.; Granata, F.; Graziadei, G.; Missineo, P.; Fiorentino, V.; Fustinoni, S.; Cappellini, M.D.; Naik, H.; Desnick, R.J.; Di Pierro, E.

2015-01-01

X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromsomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP. PMID:25615817

Linkage localization of X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergoffen, J.; Trofatter, J.; Haines, J.L.

1993-02-01

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived frommore » work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.« less

Creatine maintains intestinal homeostasis and protects against colitis.

PubMed

Turer, Emre; McAlpine, William; Wang, Kuan-Wen; Lu, Tianshi; Li, Xiaohong; Tang, Miao; Zhan, Xiaoming; Wang, Tao; Zhan, Xiaowei; Bu, Chun-Hui; Murray, Anne R; Beutler, Bruce

2017-02-14

Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N -ethyl- N -nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted ( Gatm c/c ) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatm c/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatm c/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

Creatine maintains intestinal homeostasis and protects against colitis

PubMed Central

Turer, Emre; McAlpine, William; Wang, Kuan-wen; Lu, Tianshi; Li, Xiaohong; Tang, Miao; Zhan, Xiaoming; Wang, Tao; Zhan, Xiaowei; Bu, Chun-Hui; Murray, Anne R.; Beutler, Bruce

2017-01-01

Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury. PMID:28137860

X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pegoraro, E.; Hoffman, E.P.; Carelli, V.

1996-02-02

Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model ofmore » mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.« less

Creatine supplementation in the aging population: effects on skeletal muscle, bone and brain.

PubMed

Gualano, Bruno; Rawson, Eric S; Candow, Darren G; Chilibeck, Philip D

2016-08-01

This narrative review aims to summarize the recent findings on the adjuvant application of creatine supplementation in the management of age-related deficits in skeletal muscle, bone and brain metabolism in older individuals. Most studies suggest that creatine supplementation can improve lean mass and muscle function in older populations. Importantly, creatine in conjunction with resistance training can result in greater adaptations in skeletal muscle than training alone. The beneficial effect of creatine upon lean mass and muscle function appears to be applicable to older individuals regardless of sex, fitness or health status, although studies with very old (>90 years old) and severely frail individuals remain scarce. Furthermore, there is evidence that creatine may affect the bone remodeling process; however, the effects of creatine on bone accretion are inconsistent. Additional human clinical trials are needed using larger sample sizes, longer durations of resistance training (>52 weeks), and further evaluation of bone mineral, bone geometry and microarchitecture properties. Finally, a number of studies suggest that creatine supplementation improves cognitive processing under resting and various stressed conditions. However, few data are available on older adults, and the findings are discordant. Future studies should focus on older adults and possibly frail elders or those who have already experienced an age-associated cognitive decline.

Folic Acid and Creatine as Therapeutic Approaches to Lower Blood Arsenic: A Randomized Controlled Trial

PubMed Central

Peters, Brandilyn A.; Hall, Megan N.; Liu, Xinhua; Parvez, Faruque; Sanchez, Tiffany R.; van Geen, Alexander; Mey, Jacob L.; Siddique, Abu B.; Shahriar, Hasan; Uddin, Mohammad Nasir; Islam, Tariqul; Balac, Olgica; Ilievski, Vesna; Factor-Litvak, Pam; Graziano, Joseph H.

2015-01-01

Peters BA, Hall MN, Liu X, Parvez F, Sanchez TR, van Geen A, Mey JL, Siddique AB, Shahriar H, Uddin MN, Islam T, Balac O, Ilievski V, Factor-Litvak P, Graziano JH, Gamble MV. 2015. Folic acid and creatine as therapeutic approaches to lower blood arsenic: a randomized controlled trial. Environ Health Perspect 123:1294–1301; http://dx.doi.org/10.1289/ehp.1409396 PMID:25978852

Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: a randomized trial.

PubMed

Hass, Chris J; Collins, Mitchell A; Juncos, Jorge L

2007-01-01

Persons with Parkinson disease (PD) exhibit decreased muscular fitness including decreased muscle mass, muscle strength, bioenergetic capabilities and increased fatigability. This purpose of this investigation was to evaluate the therapeutic effects of resistance training with and without creatine supplementation in patients with mild to moderate PD. Twenty patients with idiopathic PD were randomized to receive creatine monohydrate supplementation plus resistance training (CRE) or placebo (lactose monohydrate) plus resistance training (PLA), using a double-blind procedure. Creatine and placebo supplementation consisted of 20 g/d for the first 5 days and 5 g/d thereafter. Both groups participated in progressive resistance training (24 sessions, 2 times per week, 1 set of 8-12 repetitions, 9 exercises). Participants performed 1-repetition maximum (1-RM) for chest press, leg extension, and biceps curl. Muscular endurance was evaluated for chest press and leg extension as the number of repetitions to failure using 60% of baseline 1-RM. Functional performance was evaluated as the time to perform 3 consecutive chair rises. Statistical analyses (ANOVA) revealed significant Group x Time interactions for chest press strength and biceps curl strength, and post hoc testing revealed that the improvement was significantly greater for CRE. Chair rise performance significantly improved only for CRE (12%, P=.03). Both PLA and CRE significantly improved 1-RM for leg extension (PLA: 16%; CRE: 18%). Muscular endurance improved significantly for both groups. These findings demonstrate that creatine supplementation can enhance the benefits of resistance training in patients with PD.

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility.

PubMed

Lu, Xuemei; Shapiro, Joshua A; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-08-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

[No X-chromosome linked juvenile foveal retinoschisis].

PubMed

Pérez Alvarez, M J; Clement Fernández, F

2002-08-01

To describe the clinical characteristics of two cases of juvenile foveal retinoschisis in women with an atypical hereditary pattern, no X-chromosome linked. An autosomal recessive inheritance is proposed. Two generations of a family (5 members) in which only two sisters were evaluated. The complete examination of these two cases includes retinography, fluorescein angiography, automated perimetry, color vision testing, electroretinogram, electrooculogram and visually evoked potentials. Comparing our cases with the classic form of X-linked juvenile retinoschisis, they are less severely affected. The best visual acuity and the less disturbed or even normal electroretinogram confirm this fact. We emphasise the existence of isolated plaques of retinal pigment epithelium atrophy with perivascular pigment clumps without foveal schisis in one patient, which could represent an evolved form of this entity. The hereditary foveal juvenile retinoschisis in women suggests an autosomal inheritance (autosomal recessive in our cases) and presents less severe involvement (Arch Soc Esp Oftalmol 2002; 77: 443-448).

Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats

PubMed Central

Allen, Patricia J.; D'Anci, Kristen E.; Kanarek, Robin B.; Renshaw, Perry F.

2013-01-01

The potential role of metabolic impairments in the pathophysiology of depression is motivating researchers to evaluate the treatment efficacy of creatine, a naturally occurring energetic and neuroprotective compound found in brain and muscle tissues. Growing evidence is demonstrating the benefit of oral creatine supplements for reducing depressive symptoms in humans and animals. A novel question is whether dietary creatine, when combined with antidepressant drug therapy, would be more effective than either compound alone. To answer this question, four studies were conducted to investigate the behavioral effects of combined creatine and low-dose fluoxetine treatment using the forced swim test in male and female rats. Sprague-Dawley rats were fed powdered rodent chow supplemented with 0%, 2% or 4% w/w creatine monohydrate for 5 weeks. Rats were injected with fluoxetine (5.0 or 10.0 mg/kg) or saline according to a sub-acute dosing schedule. Female rats maintained on a 4% creatine diet displayed antidepressant-like effects compared to non-supplemented females prior to fluoxetine treatment. In contrast, creatine did not alter behavior reliably in males. Following drug treatment and a second forced swim trial, the antidepressant-like profile of creatine remained significant only in females co-administered 5.0 mg/kg fluoxetine. Moreover, in females only, supplementation with 4% creatine produced a more robust antidepressant-like behavioral profile compared to either dose of fluoxetine alone. Estrous cycle data indicated that ovarian hormones influenced the antidepressant-like effects of creatine. Addressing the issue of sex differences in response to treatment may affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. PMID:22429992

Creatine supplementation with methylglyoxal: a potent therapy for cancer in experimental models.

PubMed

Pal, Aparajita; Roy, Anirban; Ray, Manju

2016-08-01

The anti-cancer effect of methylglyoxal (MG) is now well established in the literature. The main aim of this study was to investigate the effect of creatine as a supplement in combination with MG both in vitro and in vivo. In case of the in vitro studies, two different cell lines, namely MCF-7 (human breast cancer cell line) and C2C12 (mouse myoblast cell line) were chosen. MG in combination with creatine showed enhanced apoptosis as well as higher cytotoxicity in the breast cancer MCF-7 cell line, compared to MG alone. Pre-treatment of well-differentiated C2C12 myotubes with cancerogenic 3-methylcholanthrene (3MC) induced a dedifferentiation of these myotubes towards cancerous cells (that mimic the effect of 3MC observed in solid fibro-sarcoma animal models) and subsequent exposure of these induced cancer cells with MG proved to be cytotoxic. Thus, creatine plus ascorbic acid enhanced the anti-cancer effects of MG. In contrast, when normal C2C12 muscle cells or myotubes (mouse normal myoblast cell line) were treated with MG or MG plus creatine and ascorbic acid, no detrimental effects were seen. This indicated that cytotoxic effects of MG are specifically limited towards cancer cells and are further enhanced when MG is used in combination with creatine and ascorbic acid. For the in vivo studies, tumors were induced by injecting Sarcoma-180 cells (2 × 10(6) cells/mouse) in the left hind leg. After 7 days of tumor inoculation, treatments were started with MG (20 mg/kg body wt/day, via the intravenous route), with or without creatine (150 mg/kg body wt/day, fed orally) and ascorbic acid (50 mg/kg body wt/day, fed orally) and continued for 10 consecutive days. Significant regression of tumor size was observed when Sarcoma-180 tumor-bearing mice were treated with MG and even more so with the aforesaid combination. The creatine-supplemented group demonstrated better overall survival in comparison with tumor-bearing mice without creatine. In conclusion, it may be

Purification and characterization of creatine kinase isozymes from the nurse shark Ginglymostoma cirratum.

PubMed

Gray, K A; Grossman, S H; Summers, D D

1986-01-01

Creatine kinase from nurse shark brain and muscle has been purified to apparent homogeneity. In contrast to creatine kinases from most other vertebrate species, the muscle isozyme and the brain isozyme from nurse shark migrate closely in electrophoresis and, unusually, the muscle isozyme is anodal to the brain isozyme. The isoelectric points are 5.3 and 6.2 for the muscle and brain isozymes, respectively. The purified brain preparation also contains a second active protein with pI 6.0. The amino acid content of the muscle isozyme is compared with other isozymes of creatine kinase using the Metzger Difference Index as an estimation of compositional relatedness. All comparisons show a high degree of compositional similarity including arginine kinase from lobster muscle. The muscle isozyme is marginally more resistant to temperature inactivation than the brain isozyme; the muscle protein does not exhibit unusual stability towards high concentrations of urea. Kinetic analysis of the muscle isozyme reveals Michaelis constants of 1.6 mM MgATP, 12 mM creatine, 1.2 mM MgADP and 50 mM creatine phosphate. Dissociation constants for the same substrate from the binary and ternary enzyme-substrate complex do not differ significantly, indicating limited cooperatively in substrate binding. Enzyme activity is inhibited by small planar anions, most severely by nitrate. Shark muscle creatine kinase hybridizes in vitro with rabbit muscle or monkey brain creatine kinase; shark brain isozyme hybridizes with monkey brain or rabbit brain creatine kinase. Shark muscle and shark brain isozymes, under a wide range of conditions, failed to produce a detectable hybrid.

Concentrations in beef and lamb of taurine, carnosine, coenzyme Q(10), and creatine.

PubMed

Purchas, R W; Rutherfurd, S M; Pearce, P D; Vather, R; Wilkinson, B H P

2004-03-01

Levels of taurine, carnosine, coenzyme Q(10), and creatine were measured in beef liver and several muscles of beef and lamb and in cooked and uncooked meat. The amino acid taurine has numerous biological functions, the dipeptide carnosine is a buffer as well as an antioxidant, coenzyme Q(10) is also an antioxidant present within mitochondria, and creatine along with creatine phosphate is involved with energy metabolism in muscle. Large differences were shown for all compounds between beef cheek muscle (predominantly red fibres) and beef semitendinosus muscle (mainly white fibres), with cheek muscle containing 9.9 times as much taurine, and 3.2 times as much coenzyme Q(10), but only 65% as much creatine and 9% as much carnosine. Levels in lamb relative to beef semitendinosus muscles were higher for taurine but slightly lower for carnosine, coenzyme Q(10) and creatine. Values for all the compounds varied significantly between eight lamb muscles, possibly due in part to differences in the proportion of muscle fibre types. Slow cooking (90 min at 70 °C) of lamb longissimus and semimembranosus muscles led to significant reductions in the content of taurine, carnosine, and creatine (P<0.001), but a slight increase in coenzyme Q(10). There was also a four-fold increase in creatinine, presumably due to its formation from creatine. It is concluded that biologically, and possibly nutritionally, significant levels of taurine, carnosine, coenzyme Q(10), and creatine are present in beef and lamb, but that these levels vary between muscles, between animals, and with cooking.

URINARY CREATINE AT REST AND AFTER REPEATED SPRINTS IN ATHLETES: A PILOT STUDY

PubMed Central

Nasrallah, F.; Feki, M.; Chamari, K.; Omar, S.; Alouane-Trabelsi, L.; Ben Mansour, A.; Kaabachi, N.

2014-01-01

Creatine plays a key role in muscle function and its evaluation is important in athletes. In this study, urinary creatine concentration was measured in order to highlight its possible significance in monitoring sprinters. The study included 51 sprinters and 25 age- and sex-matched untrained subjects as a control group. Body composition was measured and dietary intake estimated. Urine samples were collected before and after standardized physical exercise. Creatine was assessed by gas chromatography mass spectrometry. Basal urinary creatine (UC) was significantly lower in sprinters than controls (34±30 vs. 74±3 µmol/mmol creatinine, p < 0.05). UC was inversely correlated with body mass (r = −0.34, p < 0.01) and lean mass (r = −0.30, p < 0.05), and positively correlated with fat mass (r = 0.32, p < 0.05). After acute exercise, urinary creatine significantly decreased in both athletes and controls. UC is low in sprinters at rest and further decreases after exercise, most likely due to a high uptake and use of creatine by muscles, as muscle mass and physical activity are supposed to be greater in athletes than untrained subjects. Further studies are needed to test the value of urinary creatine as a non-invasive marker of physical condition and as a parameter for managing Cr supplementation in athletes. PMID:24917689

Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene.

PubMed

Dlamini, Nomazulu; Josifova, Dragana J; Paine, Simon M L; Wraige, Elizabeth; Pitt, Matthew; Murphy, Amanda J; King, Andrew; Buk, Stefan; Smith, Frances; Abbs, Stephen; Sewry, Caroline; Jacques, Thomas S; Jungbluth, Heinz

2013-05-01

Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A>T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development. Copyright © 2013 Elsevier B.V. All rights reserved.

Age dependence of myosin heavy chain transitions induced by creatine depletion in rat skeletal muscle

NASA Technical Reports Server (NTRS)

Adams, Gregory R.; Baldwin, Kenneth M.

1995-01-01

This study was designed to test the hypothesis that myosin heavy chain (MHC) plasticity resulting from creatine depletion is an age-dependent process. At weaning (age 28 days), rat pups were placed on either standard rat chow (normal diet juvenile group) or the same chow supplemented with 1% wt/wt of the creatine analogue beta-guanidinopropionic acid (creatine depletion juvenile (CDJ) group). Two groups of adult rats (age approximately 8 wk) were placed on the same diet regimens (normal diet adult and creatine depletion adult (CDA) groups). After 40 days (CDJ and normal diet juvenile groups) and 60 days (CDA and normal diet adult groups), animals were killed and several skeletal muscles were removed for analysis of creatine content or MHC ditribution. In the CDJ group, creatine depletion (78%) was accompanied by significant shifts toward expression of slower MHC isoforms in two slow and three fast skeletal muscles. In contrast, creatine depletion in adult animals did not result in similar shifts toward slow MHC isoform expression in either muscle type. The results of this study indicate that there is a differential effect of creatine depletion on MHC tranitions that appears to be age dependent. These results strongly suggest that investigators contemplating experimental designs involving the use of the creatine analogue beta-guanidinopropionic acid should consider the age of the animals to be used.

Determination of total creatine kinase activity in blood serum using an amperometric biosensor based on glucose oxidase and hexokinase.

PubMed

Kucherenko, I S; Soldatkin, O O; Lagarde, F; Jaffrezic-Renault, N; Dzyadevych, S V; Soldatkin, A P

2015-11-01

Creatine kinase (CK: adenosine-5-triphosphate-creatine phosphotransferase) is an important enzyme of muscle cells; the presence of a large amount of the enzyme in blood serum is a biomarker of muscular injuries, such as acute myocardial infarction. This work describes a bi-enzyme (glucose oxidase and hexokinase based) biosensor for rapid and convenient determination of CK activity by measuring the rate of ATP production by this enzyme. Simultaneously the biosensor determines glucose concentration in the sample. Platinum disk electrodes were used as amperometric transducers. Glucose oxidase and hexokinase were co-immobilized via cross-linking with BSA by glutaraldehyde and served as a biorecognition element of the biosensor. The biosensor work at different concentrations of CK substrates (ADP and creatine phosphate) was investigated; optimal concentration of ADP was 1mM, and creatine phosphate - 10 mM. The reproducibility of the biosensor responses to glucose, ATP and CK during a day was tested (relative standard deviation of 15 responses to glucose was 2%, to ATP - 6%, to CK - 7-18% depending on concentration of the CK). Total time of CK analysis was 10 min. The measurements of creatine kinase in blood serum samples were carried out (at 20-fold sample dilution). Twentyfold dilution of serum samples was chosen as optimal for CK determination. The biosensor could distinguish healthy and ill people and evaluate the level of CK increase. Thus, the biosensor can be used as a test-system for CK analysis in blood serum or serve as a component of multibiosensors for determination of important blood substances. Determination of activity of other kinases by the developed biosensor is also possible for research purposes. Copyright © 2015 Elsevier B.V. All rights reserved.

Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease

PubMed Central

Fuld, J; Kilduff, L; Neder, J; Pitsiladis, Y; Lean, M; Ward, S; Cotton, M

2005-01-01

Background: Skeletal muscle wasting and dysfunction are strong independent predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). Creatine nutritional supplementation produces increased muscle mass and exercise performance in health. A controlled study was performed to look for similar effects in 38 patients with COPD. Methods: Thirty eight patients with COPD (mean (SD) forced expiratory volume in 1 second (FEV1) 46 (15)% predicted) were randomised to receive placebo (glucose polymer 40.7 g) or creatine (creatine monohydrate 5.7 g, glucose 35 g) supplements in a double blind trial. After 2 weeks loading (one dose three times daily), patients participated in an outpatient pulmonary rehabilitation programme combined with maintenance (once daily) supplementation. Pulmonary function, body composition, and exercise performance (peripheral muscle strength and endurance, shuttle walking, cycle ergometry) took place at baseline (n = 38), post loading (n = 36), and post rehabilitation (n = 25). Results: No difference was found in whole body exercise performance between the groups: for example, incremental shuttle walk distance mean –23.1 m (95% CI –71.7 to 25.5) post loading and –21.5 m (95% CI –90.6 to 47.7) post rehabilitation. Creatine increased fat-free mass by 1.09 kg (95% CI 0.43 to 1.74) post loading and 1.62 kg (95% CI 0.47 to 2.77) post rehabilitation. Peripheral muscle performance improved: knee extensor strength 4.2 N.m (95% CI 1.4 to 7.1) and endurance 411.1 J (95% CI 129.9 to 692.4) post loading, knee extensor strength 7.3 N.m (95% CI 0.69 to 13.92) and endurance 854.3 J (95% CI 131.3 to 1577.4) post rehabilitation. Creatine improved health status between baseline and post rehabilitation (St George's Respiratory Questionnaire total score –7.7 (95% CI –14.9 to –0.5)). Conclusions: Creatine supplementation led to increases in fat-free mass, peripheral muscle strength and endurance, health status, but not exercise

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility

PubMed Central

Lu, Xuemei; Shapiro, Joshua A.; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J.; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-01-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible. PMID:20511493

Low dose creatine supplementation enhances sprint phase of 400 meters swimming performance.

PubMed

Anomasiri, Wilai; Sanguanrungsirikul, Sompol; Saichandee, Pisut

2004-09-01

This study demonstrated the effect of low dose creatine supplement (10 g. per day) on the sprinting time in the last 50 meters of 400 meters swimming competition, as well as the effect on exertion. Nineteen swimmers in the experimental group received creatine monohydrate 5 g with orange solution 15 g, twice per day for 7 days and nineteen swimmers in the control group received the same quantity of orange solution. The results showed that the swimmers who received creatine supplement lessened the sprinting time in the last 50 meters of 400 meters swimming competition than the control group. (p<0.05). The results of Wingate test (anaerobic power, anaerobic capacity and fatigue index) compared between pre and post supplementation. There was significant difference at p<0.05 in the control group from training effect whereas there was significant difference at p<0.000 from training effect and creatine supplement in the experiment group. Therefore, the creatine supplement in amateur swimmers in the present study enhanced the physical performance up to the maximum capacity.

Genetics Home Reference: X-linked cardiac valvular dysplasia

MedlinePlus

... inflammation of the inner lining of the heart (endocarditis), abnormal blood clots, or sudden death. X-linked ... Johns Hopkins Medicine: Mitral Valve Prolapse MedlinePlus Encyclopedia: Endocarditis MedlinePlus Encyclopedia: Mitral Valve Prolapse General Information from ...

The CREST-E study of creatine for Huntington disease: A randomized controlled trial.

PubMed

Hersch, Steven M; Schifitto, Giovanni; Oakes, David; Bredlau, Amy-Lee; Meyers, Catherine M; Nahin, Richard; Rosas, Herminia Diana

2017-08-08

To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease. We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies. At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits -0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment. Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD. NCT00712426. This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The arginine-creatine pathway is disturbed in children and adolescents with renal transplants.

PubMed

Andrade, Fernando; Rodríguez-Soriano, Juan; Prieto, José Angel; Elorz, Javier; Aguirre, Mireia; Ariceta, Gema; Martin, Sergio; Sanjurjo, Pablo; Aldámiz-Echevarría, Luis

2008-08-01

Cardiovascular disease is an important cause of morbidity in recipients of renal transplants. The aim of the present study was to analyze the status of the arginine-creatine pathway in such patients, given the relationship between the arginine metabolism and both renal function and the methionine-homocysteine cycle. Twenty-nine children and adolescents (median age 13, range 6-18 years), who had received a renal allograft 14.5-82.0 months before, were recruited for the study. On immunosuppressive therapy, all patients evidenced an adequate level of renal function. Plasma concentrations of homocysteine and glycine were significantly higher, whereas urinary excretions of guanidinoacetate and creatine were significantly lower than controls. Urinary excretions of guanidinoacetate and creatine correlated positively with creatinine clearance. Urinary excretion of creatine was negatively correlated with plasma concentration of homocysteine. The demonstration of disturbances in the arginine-creatine pathway in patients with well-functioning renal transplants and in absence of chronic renal failure represents a novel finding. We speculate that the low urinary excretion of guanidinoacetate and creatine is probably related to the nephrotoxic effect of immunosuppressive therapy and to defective methylation associated with the presence of hyperhomocysteinemia.

Clinical and genetic features in autosomal recessive and X-linked Alport syndrome.

PubMed

Wang, Yanyan; Sivakumar, Vanessa; Mohammad, Mardhiah; Colville, Deb; Storey, Helen; Flinter, Frances; Dagher, Hayat; Savige, Judy

2014-03-01

This study determined the family history and clinical features that suggested autosomal recessive rather than X-linked Alport syndrome. All patients had the diagnosis of Alport syndrome and the mode of inheritance confirmed by genetic testing, and underwent examination at a single centre. Patients comprised 9 males and 6 females with autosomal recessive Alport syndrome, and 18 males and 22 females with X-linked disease. Fourteen (93 %) individuals with autosomal recessive Alport syndrome developed early end-stage renal failure, all 15 had hearing loss, and most had lenticonus (12, 80 %), and a central (13, 87 %) or peripheral (13, 87 %) retinopathy. These features occurred as often as in males with X-linked disease. Females with autosomal recessive inheritance were less likely to have an affected family member in another generation (p = 0.01) than females with X-linked disease. They were more likely to have renal failure (p = 0.003), hearing loss (p = 0.02) and lenticonus (p < 0.001). Fifty percent had a central retinopathy compared with 18 % with X-linked disease (p = 0.14), but peripheral retinopathy prevalence was not different (p = 0.64). Nonsense mutations accounted for 67 % (8/12) of these disease-causing mutations. Autosomal recessive inheritance is increased in females with Alport syndrome and early onset renal failure, hearing loss, lenticonus, and, possibly, central retinopathy.

Locating inefficient links in a large-scale transportation network

NASA Astrophysics Data System (ADS)

Sun, Li; Liu, Like; Xu, Zhongzhi; Jie, Yang; Wei, Dong; Wang, Pu

2015-02-01

Based on data from geographical information system (GIS) and daily commuting origin destination (OD) matrices, we estimated the distribution of traffic flow in the San Francisco road network and studied Braess's paradox in a large-scale transportation network with realistic travel demand. We measured the variation of total travel time Δ T when a road segment is closed, and found that | Δ T | follows a power-law distribution if Δ T < 0 or Δ T > 0. This implies that most roads have a negligible effect on the efficiency of the road network, while the failure of a few crucial links would result in severe travel delays, and closure of a few inefficient links would counter-intuitively reduce travel costs considerably. Generating three theoretical networks, we discovered that the heterogeneously distributed travel demand may be the origin of the observed power-law distributions of | Δ T | . Finally, a genetic algorithm was used to pinpoint inefficient link clusters in the road network. We found that closing specific road clusters would further improve the transportation efficiency.

Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

PubMed

Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

2012-01-01

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

Dietary creatine supplementation lowers hepatic triacylglycerol by increasing lipoprotein secretion in rats fed high-fat diet.

PubMed

da Silva, Robin P; Leonard, Kelly-Ann; Jacobs, René L

2017-12-01

Recent studies have shown that dietary creatine supplementation can prevent lipid accumulation in the liver. Creatine is a small molecule that plays a large role in energy metabolism, but since the enzyme creatine kinase is not present in the liver, the classical role in energy metabolism does not hold in this tissue. Fat accumulation in the liver can lead to the development of nonalcoholic fatty liver disease (NAFLD), a progressive disease that is prevalent in humans. We have previously reported that creatine can directly influence lipid metabolism in cell culture to promote lipid secretion and oxidation. Our goal in the current study was to determine whether similar mechanisms that occur in cell culture were present in vivo. We also sought to determine whether dietary creatine supplementation could be effective in reversing steatosis. Sprague-Dawley rats were fed a high-fat diet or a high-fat diet supplemented with creatine for 5 weeks. We found that rats supplemented with creatine had significantly improved rates of lipoprotein secretion and alterations in mitochondrial function that were consistent with greater oxidative capacity. We also find that introducing creatine into a high-fat diet halted hepatic lipid accumulation in rats with fatty liver. Our results support our previous report that liver cells in culture with creatine secrete and oxidize more oleic acid, demonstrating that dietary creatine can effectively change hepatic lipid metabolism by increasing lipoprotein secretion and oxidation in vivo. Our data suggest that creatine might be an effective therapy for NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

X-linked mental retardation associated with macro-orchidism.

PubMed Central

Turner, G; Eastman, C; Casey, J; McLeay, A; Procopis, P; Turner, B

1975-01-01

Two families are described with an X-linked form of mental retardation in whom the affected males were found to have bilateral enlargement of the testes. No conclusive evidence of any endocrinological disturbance was found. Images PMID:1240971

Does long-term creatine supplementation impair kidney function in resistance-trained individuals consuming a high-protein diet?

PubMed Central

2013-01-01

Background The aim of this study was to determine the effects of creatine supplementation on kidney function in resistance-trained individuals ingesting a high-protein diet. Methods A randomized, double-blind, placebo-controlled trial was performed. The participants were randomly allocated to receive either creatine (20 g/d for 5 d followed by 5 g/d throughout the trial) or placebo for 12 weeks. All of the participants were engaged in resistance training and consumed a high-protein diet (i.e., ≥ 1.2 g/Kg/d). Subjects were assessed at baseline (Pre) and after 12 weeks (Post). Glomerular filtration rate was measured by 51Cr-EDTA clearance. Additionally, blood samples and a 24-h urine collection were obtained for other kidney function assessments. Results No significant differences were observed for 51Cr-EDTA clearance throughout the trial (Creatine: Pre 101.42 ± 13.11, Post 108.78 ± 14.41 mL/min/1.73m2; Placebo: Pre 103.29 ± 17.64, Post 106.68 ± 16.05 mL/min/1.73m2; group x time interaction: F = 0.21, p = 0.64). Creatinine clearance, serum and urinary urea, electrolytes, proteinuria, and albuminuria remained virtually unchanged. Conclusions A 12-week creatine supplementation protocol did not affect kidney function in resistance-trained healthy individuals consuming a high-protein diet; thus reinforcing the safety of this dietary supplement. Trial registration ClinicalTrials.gov NCT01817673 PMID:23680457

Editorial: X-chromosome-linked Kallmann's syndrome: Pathology at the molecular level

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prager, D.; Braunstein, G.D.

Kallmann's syndrome or olfactogenital dysplasia refers to a disorder characterized by hypogonadotropic hypogonadism and anosmia or hyposmia which can occur sporadically or in a familial setting. Originally described in 1856, the first familial cases were reported by Kallmann et al., in 1944. Based on segregation analysis of multiple families, three modes of transmission have been documented: X-linked, autosomal dominant with variable penetrance, and autosomal recessive. Kallmann's syndrome occurs in less than 1 in 10,000 male births, with a 5-fold excess of affected males to females, suggesting that the X-linked form is the most frequent. By genetic linkage analysis the X-linkedmore » form of Kallmann's syndrome was localized to Xp22.3. This was confirmed by the description of patients with contiguous gene syndromes due to deletions of various portions of the distal short arm of the X-chromosome. Such patients present with complex phenotypes characterized by a combination of Kallmann's syndrome with X-linked icthyosis due to steroid sulfatase deficiency, chondrodysplasia punctata, short stature, and mental retardation. DNA analysis has identified and mapped the genes responsible for these disorders. 10 refs., 1 fig., 1 tab.« less

Nuclear Overhauser effect studies on the conformation of magnesium adenosine 5'-triphosphate bound to rabbit muscle creatine kinase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosevear, P.R.; Powers, V.M.; Dowhan, D.

1987-08-25

Nuclear Overhauser effects were used to determine interproton distances on MgATP bound to rabbit muscle creatine kinase. The internuclear distances were used in a distance geometry program that objectively determines both the conformation of the bound MgATP and its uniqueness. Two classes of structures were found that satisfied the measured interproton distances. Both classes had the same anti glycosidic torsional angle (X = 78 +/- 10/sup 0/) but differed in their ribose ring puckers (O1'-endo or C4'-exo). The uniqueness of the glycosidic torsional angle is consistent with the preference of creatine kinase for adenine nucleotides. One of these conformations ofmore » MgATP bound to creatine kinase is indistinguishable from the conformation found for Co(NH/sub 3/)/sub 4/ ATP bound to the catalytic subunit of protein kinase, which also has a high specificity for adenine nucleotides. Distance geometry calculations also suggest that upper limit distances, when low enough (less than or equal to 3.4 A), can be used instead of measured distances to define, within experimental error, the glycosidic torsional angle of bound nucleotides. However, this approach does not permit an evaluation of the ribose ring pucker.« less

The Effects of Creatine Supplementation on Explosive Performance and Optimal Individual Postactivation Potentiation Time.

PubMed

Wang, Chia-Chi; Yang, Ming-Ta; Lu, Kang-Hao; Chan, Kuei-Hui

2016-03-04

Creatine plays an important role in muscle energy metabolism. Postactivation potentiation (PAP) is a phenomenon that can acutely increase muscle power, but it is an individualized process that is influenced by muscle fatigue. This study examined the effects of creatine supplementation on explosive performance and the optimal individual PAP time during a set of complex training bouts. Thirty explosive athletes performed tests of back squat for one repetition maximum (1RM) strength and complex training bouts for determining the individual optimal timing of PAP, height and peak power of a counter movement jump before and after the supplementation. Subjects were assigned to a creatine or placebo group and then consumed 20 g of creatine or carboxymethyl cellulose per day for six days. After the supplementation, the 1RM strength in the creatine group significantly increased (p < 0.05). The optimal individual PAP time in the creatine group was also significant earlier than the pre-supplementation and post-supplementation of the placebo group (p < 0.05). There was no significant difference in jump performance between the groups. This study demonstrates that creatine supplementation improves maximal muscle strength and the optimal individual PAP time of complex training but has no effect on explosive performance.

The Effects of Creatine Supplementation on Explosive Performance and Optimal Individual Postactivation Potentiation Time

PubMed Central

Wang, Chia-Chi; Yang, Ming-Ta; Lu, Kang-Hao; Chan, Kuei-Hui

2016-01-01

Creatine plays an important role in muscle energy metabolism. Postactivation potentiation (PAP) is a phenomenon that can acutely increase muscle power, but it is an individualized process that is influenced by muscle fatigue. This study examined the effects of creatine supplementation on explosive performance and the optimal individual PAP time during a set of complex training bouts. Thirty explosive athletes performed tests of back squat for one repetition maximum (1RM) strength and complex training bouts for determining the individual optimal timing of PAP, height and peak power of a counter movement jump before and after the supplementation. Subjects were assigned to a creatine or placebo group and then consumed 20 g of creatine or carboxymethyl cellulose per day for six days. After the supplementation, the 1RM strength in the creatine group significantly increased (p < 0.05). The optimal individual PAP time in the creatine group was also significant earlier than the pre-supplementation and post-supplementation of the placebo group (p < 0.05). There was no significant difference in jump performance between the groups. This study demonstrates that creatine supplementation improves maximal muscle strength and the optimal individual PAP time of complex training but has no effect on explosive performance. PMID:26959056

Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity.

PubMed

Kazak, Lawrence; Chouchani, Edward T; Lu, Gina Z; Jedrychowski, Mark P; Bare, Curtis J; Mina, Amir I; Kumari, Manju; Zhang, Song; Vuckovic, Ivan; Laznik-Bogoslavski, Dina; Dzeja, Petras; Banks, Alexander S; Rosen, Evan D; Spiegelman, Bruce M

2017-10-03

Diet-induced thermogenesis is an important homeostatic mechanism that limits weight gain in response to caloric excess and contributes to the relative stability of body weight in most individuals. We previously demonstrated that creatine enhances energy expenditure through stimulation of mitochondrial ATP turnover, but the physiological role and importance of creatine energetics in adipose tissue have not been explored. Here, we have inactivated the first and rate-limiting enzyme of creatine biosynthesis, glycine amidinotransferase (GATM), selectively in fat (Adipo-Gatm KO). Adipo-Gatm KO mice are prone to diet-induced obesity due to the suppression of elevated energy expenditure that occurs in response to high-calorie feeding. This is paralleled by a blunted capacity for β3-adrenergic activation of metabolic rate, which is rescued by dietary creatine supplementation. These results provide strong in vivo genetic support for a role of GATM and creatine metabolism in energy expenditure, diet-induced thermogenesis, and defense against diet-induced obesity. Published by Elsevier Inc.

Creatine phosphokinase levels in children with severe developmental disturbances.

PubMed

Cohen, D J; Johnson, W; Caparulo, B K; Young, J G

1976-06-01

Serum creatine phosphokinase (CPK) levels were studied in individuals: 40 psychotic children suffering from childhood autism, atypical personality development, and childhood schizophrenia; five children with childhood aphasia; 22 children with severe personality disorders; 29 normal children and normal siblings of psychotic children; and 14 normal parents of psychotic children. Creatine phosphokinase levels from the entire population of adults and children were normally disturbed, and the mean CPK levels for the eight diagnostic groups were within normal limits. Those 22 children with personality disorders had significantly higher CPK levels than the other diagnostic groups. This relatively higher level of CPK may be related to vulnerability to later development of schizophrenic spectrum disorders. There was no apparent relationship between CPK levels and motor activity, nor was there any change in the level of CPK during a trial of psychoactive medication. Creatine phosphokinase levels remained relatively stable on test-retest determination.

Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment

PubMed Central

Hastrup, Hanne; Karlin, Arthur; Javitch, Jonathan A.

2001-01-01

There is evidence both for and against Na+- and Cl−-dependent neurotransmitter transporters forming oligomers. We found that cross-linking the human dopamine transporter (DAT), which is heterologously expressed in human embryonic kidney 293 cells, either with copper phenanthroline (CuP) or the bifunctional reagent bis-(2-methanethiosulfonatoethyl)amine hydrochloride (bis-EA) increased the apparent molecular mass determined with nonreducing SDS/PAGE from ≈85 to ≈195 kDa. After cross-linking, but not before, coexpressed, differentially epitope-tagged DAT molecules, solubilized in Triton X-100, were coimmunoprecipitated. Thus, the 195-kDa complex was a homodimer. Cross-linking of DAT did not affect tyramine uptake. Replacement of Cys-306 with Ala prevented cross-linking. Replacement of all of the non-disulfide-bonded cysteines in the extracellular and membrane domains, except for Cys-306, did not prevent cross-linking. We conclude that the cross-link is between Cys-306 at the extracellular end of TM6 in each of the two DATs. The motif GVXXGVXXA occurs at the intracellular end of TM6 in DAT and is found in a number of other neurotransmitter transporters. This sequence was originally found at the dimerization interface in glycophorin A, and it promotes dimerization in model systems. Mutation of either glycine disrupted DAT expression and function. The intracellular end of TM6, like the extracellular end, is likely to be part of the dimerization interface. PMID:11526230

Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment.

PubMed

Hastrup, H; Karlin, A; Javitch, J A

2001-08-28

There is evidence both for and against Na(+)- and Cl(-)-dependent neurotransmitter transporters forming oligomers. We found that cross-linking the human dopamine transporter (DAT), which is heterologously expressed in human embryonic kidney 293 cells, either with copper phenanthroline (CuP) or the bifunctional reagent bis-(2-methanethiosulfonatoethyl)amine hydrochloride (bis-EA) increased the apparent molecular mass determined with nonreducing SDS/PAGE from approximately 85 to approximately 195 kDa. After cross-linking, but not before, coexpressed, differentially epitope-tagged DAT molecules, solubilized in Triton X-100, were coimmunoprecipitated. Thus, the 195-kDa complex was a homodimer. Cross-linking of DAT did not affect tyramine uptake. Replacement of Cys-306 with Ala prevented cross-linking. Replacement of all of the non-disulfide-bonded cysteines in the extracellular and membrane domains, except for Cys-306, did not prevent cross-linking. We conclude that the cross-link is between Cys-306 at the extracellular end of TM6 in each of the two DATs. The motif GVXXGVXXA occurs at the intracellular end of TM6 in DAT and is found in a number of other neurotransmitter transporters. This sequence was originally found at the dimerization interface in glycophorin A, and it promotes dimerization in model systems. Mutation of either glycine disrupted DAT expression and function. The intracellular end of TM6, like the extracellular end, is likely to be part of the dimerization interface.

Reduced creatine kinase release with statin use at the time of myocardial infarction.

PubMed

Bybee, Kevin A; Kopecky, Stephen L; Williams, Brent A; Murphy, Joseph G; Scott Wright, R

2004-09-01

Statin pre-treatment has been shown to reduce myocardial infarct size in animal models. We evaluated peak creatine kinase levels in humans based on concomitant or very early statin initiation following myocardial infarction. We identified 66 consecutive patients who received a statin within 24 h of admission to our coronary care unit for myocardial infarction. Each statin patient was matched with three patients who had not received statin therapy (n=198). Statin patients were subgrouped into those receiving statin therapy at the time of infarction (n=44) and those initiated on statin therapy within 24 h of infarction (n=22). Peak total creatine kinase concentrations were compared between groups. A linear regression model was developed to test for differences in peak creatine kinase after adjusting for differences between groups. Patients receiving statin therapy within 24 h of admission had significantly smaller median peak creatine kinase concentrations compared to those not receiving a statin (416 IU/l [258, 992] vs. 699 IU/l [339, 1728]; p=0.020). Subgroup analysis revealed that the lower peak creatine kinase concentrations within the statin group were a result of lower creatine kinase concentrations in those patients on a statin at the time of myocardial infarction (399 IU/l [255, 869] vs. 678 IU/l [276, 1870]; p<0.05). This difference retained statistical significance after adjustment for differences between groups. Statin therapy at the time of myocardial infarction is associated with lower peak creatine kinase concentrations. This suggests that statins may exhibit protective effects in the setting of myocardial ischemia and/or infarction in humans.

Exploratory studies of the potential anti-cancer effects of creatine.

PubMed

Campos-Ferraz, P L; Gualano, B; das Neves, W; Andrade, I T; Hangai, I; Pereira, R T S; Bezerra, R N; Deminice, R; Seelaender, M; Lancha, A H

2016-08-01

Two experiments were performed, in which male Wistar Walker 256 tumor-bearing rats were inoculated with 4 × 10(7) tumor cells subcutaneously and received either creatine (300 mg/kg body weight/day; CR) or placebo (water; PL) supplementation via intragastric gavage. In experiment 1, 50 rats were given PL (n = 22) or CR (n = 22) and a non-supplemented, non-inoculated group served as control CT (n = 6), for 40 days, and the survival rate and tumor mass were assessed. In experiment 2, 25 rats were given CR or PL for 15 days and sacrificed for biochemical analysis. Again, a non-supplemented, non-inoculated group served as control (CT; n = 6). Tumor and muscle creatine kinase (CK) activity and total creatine content, acidosis, inflammatory cytokines, and antioxidant capacity were assessed. Tumor growth was significantly reduced by approximately 30 % in CR when compared with PL (p = 0.03), although the survival rate was not significantly different between CR and PL (p = 0.65). Tumor creatine content tended to be higher in CR than PL (p = 0.096). Tumor CK activity in the cytosolic fraction was higher in CR than PL (p < 0.0001). Blood pCO2 was higher in CT and CR than PL (p = 0.0007 and p = 0.004, respectively). HCO3 was augmented in CT compared to PL (p = 0.03) and CR (p = 0.001). Plasma IL-6 was lower and IL-10 level was higher in CR than PL (p = 0.03 and p = 0.0007, respectively) and TNF-alpha featured a tendency of decrease in CR compared to PL (p = 0.08). Additionally, total antioxidant capacity tended to be lower in CT than PL (p = 0.07). Creatine supplementation was able to slow tumor growth without affecting the overall survival rate, probably due to the re-establishment of the CK-creatine system in cancer cells, leading to attenuation in acidosis, inflammation, and oxidative stress. These findings support the role of creatine as a putative anti-cancer agent as well as help in expanding our knowledge on its potential mechanisms

Creatine metabolism and safety profiles after six-week oral guanidinoacetic acid administration in healthy humans.

PubMed

Ostojic, Sergej M; Niess, Barbara; Stojanovic, Marko; Obrenovic, Milos

2013-01-01

Guanidinoacetic acid (GAA) is a natural precursor of creatine, yet the potential use of GAA as a nutritional additive for restoring creatine availability in humans has been limited by unclear efficacy and safety after exogenous GAA administration. The present study evaluated the effects of orally administered GAA on serum and urinary GAA, creatine and creatinine concentration, and on the occurrence of adverse events in healthy humans. Twenty-four healthy volunteers were randomized in a double-blind design to receive either GAA (2.4 grams daily) or placebo (PLA) by oral administration for 6 weeks. www.clinicaltrials.gov, identification number NCT01133899. Serum creatine and creatinine increased significantly from before to after administration in GAA-supplemented participants (P < 0.05). The proportion of participants who reported minor side effects was 58.3% in the GAA group and 45.5% in the placebo group (P = 0.68). A few participants experienced serum creatine levels above 70 µmol/L. Exogenous GAA is metabolized to creatine, resulting in a significant increase of fasting serum creatine after intervention. GAA had an acceptable side-effects profile with a low incidence of biochemical abnormalities.

Creatine Metabolism and Safety Profiles after Six-Week Oral Guanidinoacetic Acid Administration in Healthy Humans

PubMed Central

Ostojic, Sergej M.; Niess, Barbara; Stojanovic, Marko; Obrenovic, Milos

2013-01-01

Objectives; Guanidinoacetic acid (GAA) is a natural precursor of creatine, yet the potential use of GAA as a nutritional additive for restoring creatine availability in humans has been limited by unclear efficacy and safety after exogenous GAA administration. The present study evaluated the effects of orally administered GAA on serum and urinary GAA, creatine and creatinine concentration, and on the occurrence of adverse events in healthy humans. Methods and Results; Twenty-four healthy volunteers were randomized in a double-blind design to receive either GAA (2.4 grams daily) or placebo (PLA) by oral administration for 6 weeks. Clinical trial registration: www.clinicaltrials.gov, identification number NCT01133899. Serum creatine and creatinine increased significantly from before to after administration in GAA-supplemented participants (P < 0.05). The proportion of participants who reported minor side effects was 58.3% in the GAA group and 45.5% in the placebo group (P = 0.68). A few participants experienced serum creatine levels above 70 µmol/L. Conclusion; Exogenous GAA is metabolized to creatine, resulting in a significant increase of fasting serum creatine after intervention. GAA had an acceptable side-effects profile with a low incidence of biochemical abnormalities. PMID:23329885

Effects of creatine supplementation along with resistance training on urinary formaldehyde and serum enzymes in wrestlers.

PubMed

Nasseri, Azadeh; Jafari, Afshar

2016-04-01

Formaldehyde is a cytotoxic agent produced from creatine through a metabolic pathway, and in this regard, it has been claimed that creatine supplementation could be cytotoxic. Even though the cytotoxic effects of creatine supplementation have been widely studied, yet little is known about how resistance training can alter these toxic effects. This study aimed to determine the effects of short-term creatine supplementation plus resistance training on the level of urinary formaldehyde and concentrations of serum enzymes in young male wrestlers. In a double-blind design twenty-one subjects were randomized into creatine supplementation (Cr), creatine supplementation plus resistance training (Cr + T) and placebo plus resistance training (Pl + T) groups. Participants ingested creatine (0.3 g/kg/day) or placebo for 7 days. The training protocol consisted of 3 sessions in one week, each session including three sets of 6-9 repetitions at 80-85% of one-repetition maximum for whole-body exercise. Urine and blood samples were collected at baseline and at the end of the supplementation. Creatine supplementation significantly increased the excretion rate of urinary formaldehyde in the Cr and Cr + T groups by 63.4% and 30.4%, respectively (P<0.05), indicating that resistance training could partially lower this rate by 17.7%. No significant differences were detected in the levels of serum enzymes across time and groups (P>0.05). These findings indicate that resistance training may lower the increase of urinary formaldehyde excretion induced by creatine supplementation, suggesting that creatine consumption could be relatively less toxic when combined with resistance training.

The multifocal electroretinogram in X-linked juvenile retinoschisis.

PubMed

Huang, Shizhou; Wu, Dezheng; Jiang, Futian; Luo, Guangwei; Liang, Jiongji; Wen, Feng; Yu, Minzhong; Long, Shixian; Wu, Lezheng

2003-05-01

To measure and compare the multifocal electroretinography in normal control and X-linked juvenile retinoschisis, 13 cases (13 right eyes) of normal control and nine cases (17 eyes) of X-linked juvenile retinoschisis were measured with VERIS Science 4.0. Four cases (eight eyes) out of the nine retinoschisis cases were tested with Ganzfeld ERG at the same day. The results showed statistically significant difference of average response densities and latencies in six ring retinal regions between the normal control and retinoschisis. The trace array and 3-D topography of multifocal ERG showed multi-area amplitude decrease with absence or reduction of central peak amplitude in patients with retinoschisis. The P1/N1 ratio of multifocal ERG average response densities in six ring retinal regions was different from the b/a ratio of Ganzfeld ERG. The multifocal ERG and Ganzfeld ERG each had its advantage in the diagnosis of retinoschisis.

Characterization of transport phenomena in porous transport layers using X-ray microtomography

NASA Astrophysics Data System (ADS)

Hasanpour, S.; Hoorfar, M.; Phillion, A. B.

2017-06-01

Among different methods available for estimating the transport properties of porous transport layers (PTLs) of polymer electrolyte membrane fuel cells, X-ray micro computed tomography (X-μCT) imaging in combination with image-based numerical simulation has been recognized as a viable tool. In this study, four commercially-available single-layer and dual-layer PTLs are analyzed using this method in order to compare and contrast transport properties between different PTLs, as well as the variability within a single sheet. Complete transport property datasets are created for each PTL. The simulation predictions indicate that PTLs with high porosity show considerable variability in permeability and effective diffusivity, while PTLs with low porosity do not. Furthermore, it is seen that the Tomadakis-Sotirchos (TS) analytical expressions for porous media match the image-based simulations when porosity is relatively low but predict higher permeability and effective diffusivity for porosity values greater than 80%. Finally, the simulations show that cracks within MPL of dual-layer PTLs have a significant effect on the overall permeability and effective diffusivity of the PTLs. This must be considered when estimating the transport properties of dual-layer PTLs. These findings can be used to improve macro-scale models of product and reactant transport within fuel cells, and ultimately, fuel cell efficiency.

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family

PubMed Central

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-01

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children. PMID:26823236

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family.

PubMed

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursey, Terry G; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-29

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children.

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers.

PubMed

Lourenço, Charles Marques; Simão, Gustavo Novelino; Santos, Antonio Carlos; Marques, Wilson

2012-07-01

X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

Effect of free creatine therapy on cisplatin-induced renal damage.

PubMed

Genc, Gurkan; Okuyucu, Ali; Meydan, Bilge Can; Yavuz, Oguzhan; Nisbet, Ozlem; Hokelek, Murat; Bedir, Abdulkerim; Ozkaya, Ozan

2014-08-01

Abstract Cisplatin is one of the commonly used anticancer drugs and nephrotoxicity limits its use. The aim of this study is to investigate the possible protective effect of creatine supplementation on cisplatin-induced nephrotoxicity. Sixty male Sprague-Dawley rats were divided into three groups: Group I: Cisplatin (n=20) (7 mg/kg cisplatin intraperitoneal (i.p.) single dose), group II: Cisplatin+creatine monohydrate (n=20) (7 mg/kg cisplatin i.p. single dose and 300 mg/kg creatine p.o. daily for 30 days starting on first day of cisplatin injection), group III: Control group (n=20) (Serum physiologic, 2.5 mL/kg i.p.). Sacrifications were performed at first week and 30th day. Blood urea nitrogen (BUN) and serum creatinine levels, histopathological evaluation, mitochondrial deoxyribonucleic acid (mtDNA) common deletion rates, and body weights of rats were evaluated. A significant decrease in body weight, higher values of kidney function tests, histopathological scores, and mtDNA deletion ratios were observed in group I compared to control group at days 7 and 30 (p<0.05). In group II, there was a slight decrease in body weight at same days (p=0.931 and 0.084, respectively). Kidney function tests, histopathological scores, and mtDNA common deletion ratios were statistically better in group II than group I at 7th and 30th day (p<0.05). Although creatine significantly reversed kidney functions and pathological findings, this improvement was not sufficient to reach normal control group's results at days 7 and 30. In conclusion, the present study demonstrates that creatine administration is a promising adjuvant protective drug for reducing nephrotoxic effect of cisplatin.

Muscle-Tendon Unit Properties during Eccentric Exercise Correlate with the Creatine Kinase Response

PubMed Central

Hicks, Kirsty M.; Onambele-Pearson, Gladys L.; Winwood, Keith; Morse, Christopher I.

2017-01-01

Aim: The aim of this paper was to determine whether; (1) patella tendon stiffness, (2) the magnitude of vastus lateralis fascicle lengthening, and (3) eccentric torque correlate with markers of exercise induced muscle damage. Method: Combining dynamometry and ultrasonography, patella tendon properties and vastus lateralis architectural properties were measured pre and during the first of six sets of 12 maximal voluntary eccentric knee extensions. Maximal isometric torque loss and creatine kinase activity were measured pre-damage (−48 h), 48, 96, and 168 h post-damage as markers of exercise-induced muscle damage. Results: A significant increase in creatine kinase (883 ± 667 UL) and a significant reduction in maximal isometric torque loss (21%) was reported post-eccentric contractions. Change in creatine kinase from pre to peak significantly correlated with the relative change in vastus lateralis fascicle length during eccentric contractions (r = 0.53, p = 0.02) and with eccentric torque (r = 0.50, p = 0.02). Additionally, creatine kinase tended to correlate with estimated patella tendon lengthening during eccentric contractions (p < 0.10). However, creatine kinase did not correlate with resting measures of patella tendon properties or vastus lateralis properties. Similarly, torque loss did not correlate with any patella tendon or vastus lateralis properties at rest or during eccentric contractions. Conclusion: The current study demonstrates that the extent of fascicle strain during eccentric contractions correlates with the magnitude of the creatine kinase response. Although at rest, there is no relationship between patella tendon properties and markers of muscle damage; during eccentric contractions however, the patella tendon may play a role in the creatine kinase response following EIMD. PMID:28974931

Creatine as a booster for human brain function. How might it work?

PubMed

Rae, Caroline D; Bröer, Stefan

2015-10-01

Creatine, a naturally occurring nitrogenous organic acid found in animal tissues, has been found to play key roles in the brain including buffering energy supply, improving mitochondrial efficiency, directly acting as an anti-oxidant and acting as a neuroprotectant. Much of the evidence for these roles has been established in vitro or in pre-clinical studies. Here, we examine the roles of creatine and explore the current status of translation of this research into use in humans and the clinic. Some further possibilities for use of creatine in humans are also discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Method of empirical dependences in estimation and prediction of activity of creatine kinase isoenzymes in cerebral ischemia

NASA Astrophysics Data System (ADS)

Sergeeva, Tatiana F.; Moshkova, Albina N.; Erlykina, Elena I.; Khvatova, Elena M.

2016-04-01

Creatine kinase is a key enzyme of energy metabolism in the brain. There are known cytoplasmic and mitochondrial creatine kinase isoenzymes. Mitochondrial creatine kinase exists as a mixture of two oligomeric forms - dimer and octamer. The aim of investigation was to study catalytic properties of cytoplasmic and mitochondrial creatine kinase and using of the method of empirical dependences for the possible prediction of the activity of these enzymes in cerebral ischemia. Ischemia was revealed to be accompanied with the changes of the activity of creatine kinase isoenzymes and oligomeric state of mitochondrial isoform. There were made the models of multiple regression that permit to study the activity of creatine kinase system in cerebral ischemia using a calculating method. Therefore, the mathematical method of empirical dependences can be applied for estimation and prediction of the functional state of the brain by the activity of creatine kinase isoenzymes in cerebral ischemia.

Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia.

PubMed

Kasper, Burkhard S; Kurzbuch, Katrin; Chang, Bernard S; Pauli, Elisabeth; Hamer, Hajo M; Winkler, Jürgen; Hehr, Ute

2013-06-01

Periventricular nodular heterotopia (PNH) is a developmental disorder of the central nervous system, characterized by heterotopic nodules of gray matter resulting from disturbed neuronal migration. The most common form of bilateral PNH is X-linked dominant inherited, caused by mutations in the Filamin A gene (FLNA) and associated with a wide variety of other clinical findings including congenital heart disease. The typical patient with FLNA-associated PNH is female and presents with difficult to treat seizures. In contrast, hemizygous FLNA loss of function mutations in males are reported to be perinatally lethal. In X-linked dominant traits like FLNA-associated PNH the causal mutation is commonly inherited from the mother. Here, we present an exceptional family with paternal transmission of classic bilateral FLNA-associated PNH from a mildly affected father with somatic and germline mosaicism for a c.5686G>A FLNA splice mutation to both daughters with strikingly variable clinical manifestation and PNH extent in cerebral MR imaging. Our observations emphasize the importance to consider in genetic counseling and risk assessment the rare genetic constellation of paternal transmission for families with X-linked dominant inherited FLNA-associated PNH. Copyright © 2013 Wiley Periodicals, Inc.

Neovascular glaucoma in a patient with X-linked juvenile retinoschisis.

PubMed

Zuo, Chengguo; Chen, Changzheng; Xing, Yiqiao; Du, Lei

2005-09-01

To report the rubeosis iridis and neovascular glaucoma findings in one patient of X-linked juvenile retinoschisis(XLRS). Color fundus photography, fluorescein angiography (FFA), OCT and B-scan were performed in a patient with X-linked juvenile retinoschisis complicated with neovascular glaucoma. Color fundus photography, fluorescein angiography (FFA), OCT and B-scan unveiled a rare condition of XLRS complicated with neovascular glaucoma. XLRS may complicate with neovascular glaucoma. It is necessary to test OCT, FFA, ERG and carefully examine the fundus of the follow eye when it comes to uncertain neovascular glaucoma of youth and child. And only in this way, can we exclude XLRS.

Genotypic analysis of X-linked retinoschisis in Western Australia.

PubMed

Lamey, Tina; Laurin, Sarina; Chelva, Enid; De Roach, John

2010-01-01

X-linked Retinoschisis is a leading cause of juvenile macular degeneration. Four Western Australian families affected by X-Linked Retinoschisis were analysed using DNA and clinical information from the Australian Inherited Retinal Disease (IRD) Register and DNA Bank. By direct sequencing of the RS1 gene, three genetic variants were identified; 52+1G > T, 289T > G and 416delA. 289T > G has not been previously reported and is likely to cause a substitution of a membrane binding residue (W92G) in the functional discoidin domain. All clinically diagnosed individuals showed typical electronegative ERGs. The 52+1G > T obligate carrier also recorded a bilaterally abnormal rod ERG and mildly abnormal photopic responses. mfERG trace arrays showed reduced response densities in the paramacular region extending futher temporally for each eye.

Pyoderma Gangrenosum–Like Ulcer in a Patient With X-Linked Agammaglobulinemia

PubMed Central

Murray, Patrick R.; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B.; Ecker, David J.; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L.

2011-01-01

Background Pyoderma gangrenosum–like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient’s culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. Observation An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when sub-cultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. Conclusions This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum–like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum–like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy. PMID:20479300

Transcription map of Xq27: candidates for several X-linked diseases.

PubMed

Zucchi, I; Jones, J; Affer, M; Montagna, C; Redolfi, E; Susani, L; Vezzoni, P; Parvari, R; Schlessinger, D; Whyte, M P; Mumm, S

1999-04-15

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found. Copyright 1999 Academic Press.

Simultaneous Assay of Isotopic Enrichment and Concentration of Guanidinoacetate and Creatine by Gas Chromatography-Mass Spectrometry

PubMed Central

Kasumov, Takhar; Gruca, Lourdes L.; Dasarathy, Srinivasan; Kalhan, Satish C.

2012-01-01

A gas chromatographic-mass spectrometric (GC-MS) method for the simultaneous measurement of isotopic enrichment and concentration of guanidinoacetic acid and creatine in plasma sample for kinetic studies is reported. The method, based on preparation of the bis(trifluoromethyl)-pyrimidine methyl ester derivatives of guanidinoacetic acid and creatine, is robust and sensitive. The lowest measurable m1 and m3 enrichment for guanidinoacetic acid and creatine, respectively, was 0.3%. The calibration curves for measurements of concentration were linear over a range of 0.5-250 μM guanidinoacetic acid and 2-500 μM for creatine. The method was reliable for inter-assay and intra-assay precision, accuracy and linearity. The technique was applied in a healthy adult to determine in vivo fractional synthesis rate of creatine using primed- constant rate infusion of [1-13C]glycine. It was found that isotopic enrichment of guanidinoacetic acid reached plateau by 30 min of infusion of [1-13C]glycine, indicating either a small pool size or a rapid turnover rate or both, of guanidinoacetic acid. In contrast, tracer appearance in creatin was slow (slope: 0.00097), suggesting a large pool size and a slow rate of synthesis of creatine. This method can be used to estimate rate of synthesis of creatine in-vivo in human and animal studies. PMID:19646413

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

PubMed

Jonsson, Kenneth B; Zahradnik, Richard; Larsson, Tobias; White, Kenneth E; Sugimoto, Toshitsugu; Imanishi, Yasuo; Yamamoto, Takehisa; Hampson, Geeta; Koshiyama, Hiroyuki; Ljunggren, Osten; Oba, Koichi; Yang, In Myung; Miyauchi, Akimitsu; Econs, Michael J; Lavigne, Jeffrey; Jüppner, Harald

2003-04-24

Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic

Unusual phenotypic expression of an XLRS1 mutation in X-linked juvenile retinoschisis.

PubMed

Dodds, Jodi A; Srivastava, Anand K; Holden, Kenton R

2006-04-01

X-linked juvenile retinoschisis is a rare progressive vitreoretinal degenerative process that appears in early childhood, results in decreased visual acuity and blindness (if severe), and is caused by various mutations within the XLRS1 gene at Xp22.2. We report an affected family of Western European ancestry with X-linked juvenile retinoschisis. The family was found to carry a 304C-->T substitution in exon 4 of the XLRS1 gene, resulting in an Arg102Trp amino acid substitution. Two of the four available clinical cases in this family were found to carry the mutation. All available mothers of affected males were found to be unaffected carriers of the mutation, a typical feature of X-linked diseases. Two new female carriers, sisters of affected males, were identified and counseled accordingly. Questionnaires on visual functioning were given to the affected family members to examine the psychologic and sociologic impact of X-linked juvenile retinoschisis, which documented an associated stigma even when affected with a "mild" phenotype.

Expression pattern of X-linked genes in sex chromosome aneuploid bovine cells.

PubMed

Basrur, Parvathi K; Farazmand, Ali; Stranzinger, Gerald; Graphodatskaya, Daria; Reyes, Ed R; King, W Allan

2004-01-01

Expression of the X-inactive specific transcript (XIST) gene is a prerequisite step for dosage compensation in mammals, accomplished by silencing one of the two X chromosomes in normal female diploid cells or all X chromosomes in excess of one in sex chromosome aneuploids. Our previous studies showing that XIST expression does not eventuate the inactivation of X-linked genes in fetal bovine testis had suggested that XIST expression may not be an indicator of X inactivation in this species. In this study, we used a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) approach on cultures of bovine cells with varying sex chromosome constitution (XY, XX, XXY and XXX) to test whether the levels of XIST expressed conform to the number of late replicating (inactive) X chromosomes displayed by proliferating cells in these cultures. Expression patterns of four X-linked genes, including hypoxanthine phosphorybosyl transferase (HPRT), glucose-6-phosphate dehydrogenase (G6PD), zinc finger protein locus on the X (ZFX). and 'selected mouse cDNA on the X' (SMCX), in all these cells were also tested. Results showed that XIST expression was significantly higher (p < 0.05) in XXX cells compared to XX and XXY cells and that G6PD. HPRT, and SMCX loci are subject to X inactivation. The significantly higher levels of ZFX expressed in XXX cells compared to XX and XXY cells (p < 0.05) confirmed that this bovine locus, as human ZFX, escapes X inactivation. However, the levels of XIST and ZFX expressed were not proportional to the X chromosome load in these cells suggesting that X-linked loci escaping inactivation may be regulated at transcription (or post-transcription) level by mechanisms that prevent gene-specific product accumulation beyond certain levels in sex chromosome aneuploids.

Can the use of creatine supplementation attenuate muscle loss in cachexia and wasting?

PubMed

Sakkas, Giorgos K; Schambelan, Morris; Mulligan, Kathleen

2009-11-01

Weight loss and low BMI due to an underlying illness have been associated with increased mortality, reduced functional capacity, and diminished quality of life. There is a need for well tolerated, long-term approaches to maintain body weight in patients with cachexia or wasting. The purpose of this review is to highlight the scientific and clinical evidence derived from the recent literature investigating the rationale for and potential medical use of creatine supplementation in patients with cachexia or wasting. Some studies have demonstrated that supplementation with creatine can increase creatine reserves in skeletal muscle and increase muscle mass and performance in various disease states that affect muscle size and function. The mechanisms underlying these effects are not clear. It has been suggested that creatine supplementation may increase intramuscular phosphocreatine stores and promote more rapid recovery of adenosine triphosphate levels following exercise, thus allowing users to exercise for longer periods or at higher intensity levels. Other hypothesized mechanisms include attenuation of proinflammatory cytokines, stimulation of satellite cell proliferation and upregulation of genes that promote protein synthesis and cell repair. Creatine is a generally well tolerated, low-cost, over-the-counter nutritional supplement that shows potential in improving lean body mass and functionality in patients with wasting diseases. However, placebo-controlled studies have shown variable effects, with improvements in some and not in others. Additional studies with longer follow-up are required to identify the populations that might benefit most from creatine supplementation.

Effects of oxygen stoichiometry on the scaling behaviors of YBa{sub 2}Cu{sub 3}O{sub x} grain boundary weak-links

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, K.H.; Fu, C.M.; Jeng, W.J.

1994-12-31

The effects of oxygen stoichiometry on the transport properties of the pulsed laser deposited YBa{sub 2}Cu{sub 3}O{sub x} bicrystalline grain boundary weak-link junctions were studied. It is found that not only the cross boundary resistive transition foot structure can be manipulated repeatedly with oxygen annealling processes but the junction behaviors are also altered in accordance. In the fully oxygenated state i.e. with x=7.0 in YBa{sub 2}Cu{sub 3}O{sub x} stoichiometry, the junction critical current exhibits a power of 2 scaling behavior with temperature. In contrast, when annealed in the conditions of oxygen-deficient state (e.g. with x=6.9 in YBa{sub 2}Cu{sub 3}O{sub x}more » stoichiometry) the junction critical current switches to a linear temperature dependence behavior. The results are tentatively attributed to the modification of the structure in the boundary area upon oxygen annealing, which, in turn, will affect the effective dimension of the geometrically constrained weak-link bridges. The detailed discussion on the responsible physical mechanisms as well as the implications of the present results on device applications will be given.« less

Estimation of skeletal muscle mass from body creatine content

NASA Technical Reports Server (NTRS)

Pace, N.; Rahlmann, D. F.

1982-01-01

Procedures have been developed for studying the effect of changes in gravitational loading on skeletal muscle mass through measurements of the body creatine content. These procedures were developed for studies of gravitational scale effects in a four-species model, comprising the hamster, rat, guinea pig, and rabbit, which provides a sufficient range of body size for assessment of allometric parameters. Since intracellular muscle creatine concentration varies among species, and with age within a given species, the concentration values for metabolically mature individuals of these four species were established. The creatine content of the carcass, skin, viscera, smooth muscle, and skeletal muscle was determined for each species. In addition, the skeletal muscle mass of the major body components was determined, as well as the total and fat-free masses of the body and carcass, and the percent skeletal muscle in each. It is concluded that these procedures are particularly useful for studying the effect of gravitational loading on the skeletal muscle content of the animal carcass, which is the principal weight-bearing organ of the body.

X-linked cardiomyopathy is heterogeneous

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilson, M.J.; Sillence, D.O.; Mulley, J.C.

Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of amore » large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.« less

X-Linked Intellectual Disability: Unique Vulnerability of the Male Genome

ERIC Educational Resources Information Center

Stevenson, Roger E.; Schwartz, Charles E.

2009-01-01

X-linked intellectual disability (XLID) accounts for approximately 16% of males with intellectual disability (ID). This is, in part, related to the fact that males have a single X chromosome. Progress in the clinical and molecular characterization of XLID has outpaced progress in the delineation of ID due to genes on the other 22 chromosomes.…

Silencing of X-Linked MicroRNAs by Meiotic Sex Chromosome Inactivation

PubMed Central

Royo, Hélène; Seitz, Hervé; ElInati, Elias; Peters, Antoine H. F. M.; Stadler, Michael B.; Turner, James M. A.

2015-01-01

During the pachytene stage of meiosis in male mammals, the X and Y chromosomes are transcriptionally silenced by Meiotic Sex Chromosome Inactivation (MSCI). MSCI is conserved in therian mammals and is essential for normal male fertility. Transcriptomics approaches have demonstrated that in mice, most or all protein-coding genes on the X chromosome are subject to MSCI. However, it is unclear whether X-linked non-coding RNAs behave in a similar manner. The X chromosome is enriched in microRNA (miRNA) genes, with many exhibiting testis-biased expression. Importantly, high expression levels of X-linked miRNAs (X-miRNAs) have been reported in pachytene spermatocytes, indicating that these genes may escape MSCI, and perhaps play a role in the XY-silencing process. Here we use RNA FISH to examine X-miRNA expression in the male germ line. We find that, like protein-coding X-genes, X-miRNAs are expressed prior to prophase I and are thereafter silenced during pachynema. X-miRNA silencing does not occur in mouse models with defective MSCI. Furthermore, X-miRNAs are expressed at pachynema when present as autosomally integrated transgenes. Thus, we conclude that silencing of X-miRNAs during pachynema in wild type males is MSCI-dependent. Importantly, misexpression of X-miRNAs during pachynema causes spermatogenic defects. We propose that MSCI represents a chromosomal mechanism by which X-miRNAs, and other potential X-encoded repressors, can be silenced, thereby regulating genes with critical late spermatogenic functions. PMID:26509798

Improved radioimmunoassay for creatine kinase isoenzymes in plasma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ritter, C.S.; Mumm, S.R.; Roberts, R.

1981-11-01

We describe convenient and relatively rapid procedures for purifying creatine kinase isoenzymes MM, BB, and MB, and their use in an improved radioimmunoassay for creatine kinase isoenzymes in plasma. The modifications include use of: (a) BB with a specific activity of 400 kU/G, which can be labeled with a specific radioactivity of 20 Ci/g; (b) albumin-free purified MB as inhibitor; (c) antiserum to MB creatine kinase; and (d) a second-antibody technique that necessitates only a 15-min incubation. The radioimmunoassay for MB has a sensitivity of 0.2 ..mu..g/L (80 mU/L) and a CV of <5%. Plasma MB average 22 (SD 12)more » ..mu..g/L in 200 normal subjects; 24 (SD 12) ..mu..g/L in 200 patients with chest pain without infarction; and 23 (SD 7) ..mu..g/L in 43 patients with renal disease, whether measured before or after dialysis. Peak values for plasma MB averaged 191 (SD 86) ..mu..g/L in 325 patients with documented myocardial infarction; BB was negligible. Extensive clinical experience indicates the radioimmunoassay to be suitably rapid, highly sensitive, and reliable as a diagnostic assay for MB on plasma.« less

Does muscle creatine phosphokinase have access to the total pool of phosphocreatine plus creatine?

PubMed

Hochachka, P W; Mossey, M K

1998-03-01

Two fundamental assumptions underlie currently accepted dogma on creatine phosphokinase (CPK) function in phosphagen-containing cells: 1) CPK always operates near equilibrium and 2) CPK has access to, and reacts with, the entire pool of phosphocreatine (PCr) and creatine (Cr). We tested the latter assumption in fish fast-twitch or white muscle (WM) by introducing [14C]Cr into the WM pool in vivo. To avoid complications arising from working with muscles formed from a mixture of fast and slow fibers, it was advantageous to work with fish WM because it is uniformly fast twitch and is anatomically separated from other fiber types. According to current theory, at steady state after [14C]Cr administration, the specific activities of PCr and Cr should be the same under essentially all conditions. In contrast, we found that, in various metabolic states between rest and recovery from exercise, the specific activity of PCr greatly exceeds that of Cr. The data imply that a significant fraction of Cr is not free to rapidly exchange with exogenously added [14C]Cr. Releasing of this unlabeled or "cold" Cr on acid extraction accounts for lowered specific activities. This unexpected and provocative result is not consistent with traditional models of phosphagen function.

Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cherryson, A.K.; Yeung, L.; Kennerson, M.L.

1994-09-01

Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We havemore » identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).« less

Creatine Supplementation and Skeletal Muscle Metabolism for Building Muscle Mass- Review of the Potential Mechanisms of Action.

PubMed

Farshidfar, Farnaz; Pinder, Mark A; Myrie, Semone B

2017-01-01

Creatine, a very popular supplement among athletic populations, is of growing interest for clinical applications. Since over 90% of creatine is stored in skeletal muscle, the effect of creatine supplementation on muscle metabolism is a widely studied area. While numerous studies over the past few decades have shown that creatine supplementation has many favorable effects on skeletal muscle physiology and metabolism, including enhancing muscle mass (growth/hypertrophy); the underlying mechanisms are poorly understood. This report reviews studies addressing the mechanisms of action of creatine supplementation on skeletal muscle growth/hypertrophy. Early research proposed that the osmotic effect of creatine supplementation serves as a cellular stressor (osmosensing) that acts as an anabolic stimulus for protein synthesis signal pathways. Other reports indicated that creatine directly affects muscle protein synthesis via modulations of components in the mammalian target of rapamycin (mTOR) pathway. Creatine may also directly affect the myogenic process (formation of muscle tissue), by altering secretions of myokines, such as myostatin and insulin-like growth factor-1, and expressions of myogenic regulatory factors, resulting in enhanced satellite cells mitotic activities and differentiation into myofiber. Overall, there is still no clear understanding of the mechanisms of action regarding how creatine affects muscle mass/growth, but current evidence suggests it may exert its effects through multiple approaches, with converging impacts on protein synthesis and myogenesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

PubMed

Lefebvre, Mathilde; Dufernez, Fabienne; Bruel, Ange-Line; Gonzales, Marie; Aral, Bernard; Saint-Onge, Judith; Gigot, Nadège; Desir, Julie; Daelemans, Caroline; Jossic, Frédérique; Schmitt, Sébastien; Mangione, Raphaele; Pelluard, Fanny; Vincent-Delorme, Catherine; Labaune, Jean-Marc; Bigi, Nicole; D'Olne, Dominique; Delezoide, Anne-Lise; Toutain, Annick; Blesson, Sophie; Cormier-Daire, Valérie; Thevenon, Julien; El Chehadeh, Salima; Masurel-Paulet, Alice; Joyé, Nicole; Vibert-Guigue, Claude; Rigonnot, Luc; Rousseau, Thierry; Vabres, Pierre; Hervé, Philippe; Lamazière, Antonin; Rivière, Jean-Baptiste; Faivre, Laurence; Laurent, Nicole; Thauvin-Robinet, Christel

2015-07-01

Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations. © 2015 John Wiley & Sons, Ltd.

Genetics Home Reference: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia

MedlinePlus

... Share: Email Facebook Twitter Home Health Conditions XMEN X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ... Javascript to view the expand/collapse boxes. Description X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ...

Development of Ratiometric Fluorescent Biosensors for the Determination of Creatine and Creatinine in Urine.

PubMed

Duong, Hong Dinh; Rhee, Jong Il

2017-11-08

In this study, the oxazine 170 perchlorate (O17)-ethylcellulose (EC) membrane was successfully exploited for the fabrication of creatine- and creatinine-sensing membranes. The sensing membrane exhibited a double layer of O17-EC membrane and a layer of enzyme(s) entrapped in the EC and polyurethane hydrogel (PU) matrix. The sensing principle of the membranes was based on the hydrolytic catalysis of urea, creatine, and creatinine by the enzymes. The reaction end product, ammonia, reacted with O17-EC membrane, resulting in the change in fluorescence intensities at two emission wavelengths ( λ em = 565 and 625 nm). Data collected from the ratio of fluorescence intensities at λ em = 565 and 625 nm were proportional to the concentrations of creatine or creatinine. Creatine- and creatinine-sensing membranes were very sensitive to creatine and creatinine at the concentration range of 0.1-1.0 mM, with a limit of detection (LOD) of 0.015 and 0.0325 mM, respectively. Furthermore, these sensing membranes showed good features in terms of response time, reversibility, and long-term stability. The interference study demonstrated that some components such as amino acids and salts had some negative effects on the analytical performance of the membranes. Thus, the simple and sensitive ratiometric fluorescent sensors provide a simple and comprehensive method for the determination of creatine and creatinine concentrations in urine.

Development of Ratiometric Fluorescent Biosensors for the Determination of Creatine and Creatinine in Urine

PubMed Central

Duong, Hong Dinh; Rhee, Jong Il

2017-01-01

In this study, the oxazine 170 perchlorate (O17)-ethylcellulose (EC) membrane was successfully exploited for the fabrication of creatine- and creatinine-sensing membranes. The sensing membrane exhibited a double layer of O17-EC membrane and a layer of enzyme(s) entrapped in the EC and polyurethane hydrogel (PU) matrix. The sensing principle of the membranes was based on the hydrolytic catalysis of urea, creatine, and creatinine by the enzymes. The reaction end product, ammonia, reacted with O17-EC membrane, resulting in the change in fluorescence intensities at two emission wavelengths (λem = 565 and 625 nm). Data collected from the ratio of fluorescence intensities at λem = 565 and 625 nm were proportional to the concentrations of creatine or creatinine. Creatine- and creatinine-sensing membranes were very sensitive to creatine and creatinine at the concentration range of 0.1–1.0 mM, with a limit of detection (LOD) of 0.015 and 0.0325 mM, respectively. Furthermore, these sensing membranes showed good features in terms of response time, reversibility, and long-term stability. The interference study demonstrated that some components such as amino acids and salts had some negative effects on the analytical performance of the membranes. Thus, the simple and sensitive ratiometric fluorescent sensors provide a simple and comprehensive method for the determination of creatine and creatinine concentrations in urine. PMID:29117119

Creatine Supplementation Increases Total Body Water in Soccer Players: a Deuterium Oxide Dilution Study.

PubMed

Deminice, R; Rosa, F T; Pfrimer, K; Ferrioli, E; Jordao, A A; Freitas, E

2016-02-01

This study aimed to evaluate changes in total body water (TBW) in soccer athletes using a deuterium oxide dilution method and bioelectrical impedance (BIA) formulas after 7 days of creatine supplementation. In a double-blind controlled manner, 13 healthy (under-20) soccer players were divided randomly in 2 supplementation groups: Placebo (Pla, n=6) and creatine supplementation (CR, n=7). Before and after the supplementation period (0.3 g/kg/d during 7 days), TBW was determined by deuterium oxide dilution and BIA methods. 7 days of creatine supplementation lead to a large increase in TBW (2.3±1.0 L) determined by deuterium oxide dilution, and a small but significant increase in total body weight (1.0±0.4 kg) in Cr group compared to Pla. The Pla group did not experience any significant changes in TBW or body weight. Although 5 of 6 BIA equations were sensitive to determine TBW changes induced by creatine supplementation, the Kushner et al. 16 method presented the best concordance levels when compared to deuterium dilution method. In conclusion, 7-days of creatine supplementation increased TBW determined by deuterium oxide dilution or BIA formulas. BIA can be useful to determine TBW changes promoted by creatine supplementation in soccer athletes, with special concern for formula choice. © Georg Thieme Verlag KG Stuttgart · New York.

NcoI and TaqI RFLPs for human M creatine kinase (CKM)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perryman, M.B.; Hejtmancik, J.F.; Ashizawa, Tetsuo

1988-09-12

Probe pHMCKUT contains a 135 bp cDNA fragment inserted into pGEM 3. The probe corresponds to nucleotides 1,201 to 1,336 located in the 3{prime} untranslated region of human M creatine kinase. The probe is specific for human M creatine kinase and does not hybridize to human B cretine kinase sequences. NcoI identifies a two allele polymorphism of a band at either 2.5 kb or 3.6 kb. TaqI identifies a two allele polymorphism at either 3.8 kb or 4.5 kb. Human M creatine has been localized to chromosome 19q. Autosomal co-dominant inheritance was shown in six informative Caucasian families.

Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.

PubMed Central

Stöckler, S.; Isbrandt, D.; Hanefeld, F.; Schmidt, B.; von Figura, K.

1996-01-01

In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three of the transcripts encode truncated polypeptides that lack a residue known to be critical for catalytic activity of GAMT. Deficiency of GAMT is the first inborn error of creatine metabolism. It causes a severe developmental delay and extrapyramidal symptoms in early infancy and is treatable by oral substitution with creatine. Images Figure 2 PMID:8651275

Creatine and the Male Adolescent Athlete

ERIC Educational Resources Information Center

Schumaker, Shauna; Eyers, Christina; Cappaert, Thomas

2012-01-01

As the level of competition in youth sports increases, so does athletes' vulnerability to experimenting with performance-enhancing aids (PEAs) at alarmingly young ages. One of the more commonly used PEAs is a supplement called creatine, which has the ability to generate muscular energy, allowing athletes to train at higher intensities for longer…

Molecular genetic analysis of patients with sporadic and X-linked infantile nystagmus

PubMed Central

Zhao, Hui; Huang, Xiu-Feng; Zheng, Zhi-Li; Deng, Wen-Li; Lei, Xin-Lan; Xing, Dong-Jun; Ye, Liang; Xu, Su-Zhong; Chen, Jie; Zhang, Fang; Yu, Xin-Ping; Jin, Zi-Bing

2016-01-01

Objectives Infantile nystagmus (IN) is a genetically heterogeneous condition characterised by involuntary rhythmic oscillations of the eyes accompanied by different degrees of vision impairment. Two genes have been identified as mainly causing IN: FRMD7 and GPR143. The aim of our study was to identify the genetic basis of both sporadic IN and X-linked IN. Design Prospective analysis. Patients Twenty Chinese patients, including 15 sporadic IN cases and 5 from X-linked IN families, were recruited and underwent molecular genetic analysis. We first performed PCR-based DNA sequencing of the entire coding region and the splice junctions of the FRMD7 and GPR143 genes in participants. Mutational analysis and co-segregation confirmation were then performed. Setting All clinical examinations and genetic experiments were performed in the Eye Hospital of Wenzhou Medical University. Results Two mutations in the FRMD7 gene, including one novel nonsense mutation (c.1090C>T, p.Q364X) and one reported missense mutation (c.781C>G, p.R261G), were identified in two of the five (40%) X-linked IN families. However, none of putative mutations were identified in FRMD7 or GPR143 in any of the sporadic cases. Conclusions The results suggest that mutations in FRMD7 appeared to be the major genetic cause of X-linked IN, but not of sporadic IN. Our findings provide further insights into FRMD7 mutations, which could be helpful for future genetic diagnosis and genetic counselling of Chinese patients with nystagmus. PMID:27036142

Evaluation of Intravascular Hemolysis With Erythrocyte Creatine in Patients With Aortic Stenosis.

PubMed

Sugiura, Tetsuro; Okumiya, Toshika; Kubo, Toru; Takeuchi, Hiroaki; Matsumura, Yoshihisa

2016-07-27

Chronic intravascular hemolysis has been identified in patients with cardiac valve prostheses, but only a few case reports have evaluated intravascular hemolysis in patients with native valvular heart disease. To detect intravascular hemolysis in patients with aortic stenosis, erythrocyte creatine was evaluated with hemodynamic indices obtained by echocardiography.Erythrocyte creatine, a marker of erythrocyte age, was assayed in 30 patients with aortic stenosis and 10 aged matched healthy volunteers. Peak flow velocity of the aortic valve was determined by continuous-wave Doppler echocardiography. Twenty of 30 patients with aortic stenosis had high erythrocyte creatine levels (> 1.8 µmol/g Hb) and erythrocyte creatine was significantly higher as compared with control subjects (1.98 ± 0.49 versus 1.52 ± 0.19 µmol/g Hb, P = 0.007). Peak transvalvular pressure gradient ranged from 46 to 142 mmHg and peak flow velocity ranged from 3.40 to 5.95 m/second. Patients with aortic stenosis had a significantly lower erythrocyte count (387 ± 40 versus 436 ± 42 × 10(4) µL, P = 0.002) and hemoglobin (119 ± 11 versus 135 ± 11 g/L, P < 0.001) as compared with control subjects. Erythrocyte creatine had a fair correlation with peak flow velocity (r = 0.55, P = 0.002).In conclusion, intravascular hemolysis due to destruction of erythrocytes was detected in patients with moderate to severe aortic stenosis and the severity of intravascular hemolysis was related to valvular flow velocity of the aortic valve.

75 FR 17769 - In the Matter of Certain Products Advertised as Containing Creatine Ethyl Ester; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-07

... Advertised as Containing Creatine Ethyl Ester; Notice of Commission Issuance of a Limited Exclusion Order Against the Products Advertised as Containing Creatine Ethyl Ester of Respondents Found in Default... importation of certain products advertised as containing creatine ethyl ester by reason of false advertising...

X-linked intellectual disability update 2017.

PubMed

Neri, Giovanni; Schwartz, Charles E; Lubs, Herbert A; Stevenson, Roger E

2018-04-25

The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function. © 2018 Wiley Periodicals, Inc.

Evaluation of pharmacological induction of fatty acid beta-oxidation in X-linked adrenoleukodystrophy.

PubMed

McGuinness, M C; Zhang, H P; Smith, K D

2001-01-01

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder associated with elevated levels of saturated unbranched very-long-chain fatty acids (VLCFA; C > 22:0) in plasma and tissues, and reduced VLCFA beta-oxidation in fibroblasts, white blood cells, and amniocytes from X-ALD patients. The X-ALD gene (ABCD1) at Xq28 encodes the adrenoleukodystrophy protein (ALDP) that is related to the peroxisomal ATP-binding cassette (ABCD) transmembrane half-transporter proteins. The function of ALDP is unknown and its role in VLCFA accumulation unresolved. Previously, our laboratory has shown that sodium 4-phenylbutyrate (4PBA) treatment of X-ALD fibroblasts results in increased peroxisomal VLCFA beta-oxidation activity and increased expression of the X-ALD-related protein, ALDRP, encoded by the ABCD2 gene. In this study, the effect of various pharmacological agents on VLCFA beta-oxidation in ALD mouse fibroblasts is tested. 4PBA, styrylacetate and benzyloxyacetate (structurally related to 4PBA), and trichostatin A (functionally related to 4PBA) increase both VLCFA (peroxisomal) and long-chain fatty acid [LCFA (peroxisomal and mitochondrial)] beta-oxidation. Isobutyrate, zaprinast, hydroxyurea, and 5-azacytidine had no effect on VLCFA or LCFA beta-oxidation. Lovastatin had no effect on fatty acid beta-oxidation under normal tissue culture conditions but did result in an increase in both VLCFA and LCFA beta-oxidation when ALD mouse fibroblasts were cultured in the absence of cholesterol. The effect of trichostatin A on peroxisomal VLCFA beta-oxidation is shown to be independent of an increase in ALDRP expression, suggesting that correction of the biochemical abnormality in X-ALD is not dependent on pharmacological induction of a redundant gene (ABCD2). These studies contribute to a better understanding of the role of ALDP in VLCFA accumulation and may lead to the development of more effective pharmacological therapies. Copyright 2001 Academic Press.

A family study of congenital X linked sideroblastic anaemia.

PubMed Central

Holmes, J; May, A; Geddes, D; Jacobs, A

1990-01-01

We report on the cytogenetic findings in a family study of pyridoxine responsive, X linked sideroblastic anaemia. An increase in the number of X chromosomes was observed in a small proportion of metaphases prepared from five female members, but these findings did not strictly correlate with the carrier status of the condition. No consistent cytogenetic abnormality could be identified or associated with this rare familial condition. The diagnosis and counselling of carriers of this condition is discussed. Images PMID:2308152

Serum creatine kinase isoenzymes in children with osteogenesis imperfecta.

PubMed

D'Eufemia, P; Finocchiaro, R; Zambrano, A; Lodato, V; Celli, L; Finocchiaro, S; Persiani, P; Turchetti, A; Celli, M

2017-01-01

This study evaluates serum creatine kinase isoenzyme activity in children with osteogenesis imperfecta to determine its usefulness as a biochemical marker during treatment with bisphosphonate. The changes of creatine kinase (CK) isoenzyme activity during and after discontinuation therapy were observed. These results could be useful in addressing over-treatment risk prevention. The brain isoenzyme of creatine kinase (CKbb) is highly expressed in mature osteoclasts during osteoclastogenesis, thus plays an important role in bone resorption. We previously identified high serum CKbb levels in 18 children with osteogenesis imperfect (OI) type 1 treated for 1 year with bisphosphonate (neridronate). In the present study, serum CK isoenzymes were evaluated in the same children with continuous versus discontinued neridronate treatment over a further 2-year follow-up period. This study included 18 children with OI type 1, 12 with continued (group A) and 6 with ceased (group B) neridronate treatment. Auxological data, serum biochemical markers of bone metabolism, bone mineral density z-score, and serum total CK and isoenzyme activities were determined in both groups. Serum CKbb was progressively and significantly increased in group A (p < 0.004) but rapidly decreased to undetectable levels in group B. In both groups, the cardiac muscle creatine kinase isoenzyme (CKmb) showed a marked decrease, while serum C-terminal telopeptide (CTx) levels were almost unchanged. This study provides evidence of the cumulative effect of neridronate administration in increasing serum CKbb levels and the reversible effect after its discontinuation. This approach could be employed for verifying the usefulness of serum CKbb as a biochemical marker in patients receiving prolonged bisphosphonate treatment. Moreover, the decreased serum CKmb levels suggest a systemic effect of these drugs.

Use of topical dorzolamide for patients with X-linked juvenile retinoschisis: case report.

PubMed

Bastos, André Luís Carvalho de Moura; Freitas, Bruno de Paula; Villas Boas, Oscar; Ramiro, Alexandre Campelo

2008-01-01

X-linked juvenile retinoschisis (XLRS) is a recessively inherited vitreoretinal degeneration characterized by macular pathology and splitting of the neuroretinal layers that is associated with alterations in the XLRS1 gene. There have been no therapeutic interventions known to be effective for patients with X-linked juvenile retinoschisis, but some studies are trying to determine the importance of dorzolamide for the treatment of foveal lesions in this disease. The authors, using optical coherence tomography, describe findings in a patient with X-linked juvenile retinoschisis, before and after a topical use of dorzolamide. Besides the improvement in his visual acuity, further studies are required to elucidate the real prevalence of nonresponse to dorzolamide and the frequency with which there may be a recurrence of foveal cystic changes during continued treatment.

Effects of creatine supplementation on cardiac autonomic functions in bodybuilders.

PubMed

Mert, Kadir Uğur; Ilgüy, Serdar; Dural, Muhammet; Mert, Gurbet Özge; Özakin, Engin

2017-06-01

Bodybuilder-type workouts may affect heart rate variability (HRV), which has considerable potential to assess the role of autonomic nervous system (ANS). A scientifically designed approach is necessary for bodybuilders to achieve better results while protecting their health. In this study, we aimed to investigate HRV parameters in bodybuilders compared to healthy control subjects and effects of creatine supplementation. A total of 48 male participants (16 controls, 16 supplement (-), 16 supplement (+)) were evaluated in our study. Bodybuilders who were taking creatine supplementation were enrolled in supplement (+) group. HRV parameters were measured from 24-hour Holter recordings of all participants. When mean heart rates were compared with control group (71.5 ± 12.6 beats/min), statistically significant difference was revealed in supplement (-) group (61.8 ± 6.8 beats/min; P = 0.022) unlike supplement (+) group (69.63 ± 14.1 beats/min; P = 0.650). HRV analyses revealed significant parasympathetic shift in supplement (-) group. No significant difference was demonstrated on HRV parameters, except high frequency (P = 0.029) in supplement (+) group. Conclusively, elevated parasympathetic modulation, which is favorable cardiovascular outcome of exercise, was demonstrated in bodybuilders. However, our study also revealed that creatine supplementation attenuates this favorable effect in ANS by limiting elevation of parasympathetic modulation. Although the sympathetic slight shift is attributed to creatine supplementation, it cannot be discriminated from the effects of over training. © 2017 Wiley Periodicals, Inc.

Creatine kinase MB isoenzyme in dermatomyositis: a noncardiac source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Larca, L.J.; Coppola, J.T.; Honig, S.

1981-03-01

Three patients with polymyositis had elevated serum levels of creatine kinase MB isoenzyme. The presence of this isoenzyme is used extensively to diagnose myocardial infarction, but the isoenzyme is also found in sera of patients with primary muscular and neuromuscular disorders. Researchers studied cardiac function in two of our patients with electrocardiograms, technetium stannous pyrophosphate scanning, and technetium 99m-labeled erythrocyte gated blood pool imaging and in the third patient by postmortem examination. There was no evidence of myocardial involvement to account for the high serum levels of isoenzyme. Creatine kinase MB in the sera of patients with polymyositis does notmore » necessarily indicate myocardial necrosis.« less

X-2 on Transportation Dolly

NASA Technical Reports Server (NTRS)

1952-01-01

This 1952 photograph shows the X-2 #2 aircraft mounted on a special transportation dolly at Edwards Air Force Base, California. The dolly was steerable and was used for transporting the X-2 around and for towing it off the lakebed at Edwards Air Force Base after a landing. This was the number 2 airplane (46-675), which was lost on May 12, 1953, on a captive flight over Lake Ontario when the airplane exploded during a liquid-oxygen topoff test, killing the pilot, Jean Ziegler, and EB-50A crewman Frank Wolko. Almost no debris was recovered from Lake Ontario, so no cause for the explosion could be determined. Later, however, investigations of similar explosions in the X-1 #3, X-1A, and X-1D traced the problem to Ulmer leather gaskets, which exuded tricresyl phosphate. This substance caused detonations in the supercold atmosphere of the airplanes' liquid oxygen tanks. As the X-2 #2 also had these gaskets, they were probably the cause of the explosion in that aircraft as well. The X-2 was a swept-wing, rocket-powered aircraft designed to fly faster than Mach 3 (three times the speed of sound). It was built for the U.S. Air Force by the Bell Aircraft Company, Buffalo, New York. The X-2 was flown to investigate the problems of aerodynamic heating as well as stability and control effectiveness at high altitudes and high speeds (in excess of Mach 3). Bell aircraft built two X-2 aircraft. These were constructed of K-monel (a copper and nickel alloy) for the fuselage and stainless steel for the swept wings and control surfaces. The aircraft had ejectable nose capsules instead of ejection seats because the development of ejection seats had not reached maturity at the time the X-2 was conceived. The X-2 ejection canopy was successfully tested using a German V-2 rocket. The X-2 used a skid-type landing gear to make room for more fuel. The airplane was air launched from a modified Boeing B-50 Superfortress Bomber. X-2 Number 1 made its first unpowered glide flight on Aug. 5, 1954

Lamellar macular hole in X linked retinoschisis

PubMed Central

Kumar, Vinod; Goel, Neha

2016-01-01

X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. PMID:27170611

Optical coherence tomography in the diagnosis of juvenile X-linked retinoschisis.

PubMed

Eriksson, Urban; Larsson, Eva; Holmström, Gerd

2004-04-01

To describe the value of optical coherence tomography (OCT) as a diagnostic tool in the diagnosis of X-linked retinoschisis. We report three boys aged between 8 and 17 years, diagnosed with X-linked retinoschisis. During investigations they were examined with OCT (Zeiss Humphrey OCT 1, upgraded version). Single scans of the central posterior pole and the region around the vascular arcades were obtained. Two of the boys underwent full-field ERG according to ISCEV standards. Genetic analysis was performed in all three boys, with sequencing of the XLRS gene. The OCT results revealed a pattern with a cleavage of the retina in two distinct planes, one deep (outer retina) and one superficial. This was very obvious in one patient and a similar but not as pronounced pattern was seen in the other two cases. The two layers were superficially connected with thin-walled, vertical palisades, separated by low reflective, cystoid spaces, confluent and most prominent in the foveal region. Full-field ERG and/or DNA analysis are well known methods used for diagnosis of X-linked juvenile retinoschisis. In this paper, we suggest that OCT can also be a helpful diagnostic tool.

X-linked cataract and Nance-Horan syndrome are allelic disorders.

PubMed

Coccia, Margherita; Brooks, Simon P; Webb, Tom R; Christodoulou, Katja; Wozniak, Izabella O; Murday, Victoria; Balicki, Martha; Yee, Harris A; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J; Maher, Eamonn R; Moore, Anthony T; Russell-Eggitt, Isabelle M; Hardcastle, Alison J

2009-07-15

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.

X-linked cataract and Nance-Horan syndrome are allelic disorders

PubMed Central

Coccia, Margherita; Brooks, Simon P.; Webb, Tom R.; Christodoulou, Katja; Wozniak, Izabella O.; Murday, Victoria; Balicki, Martha; Yee, Harris A.; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K.; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J.; Maher, Eamonn R.; Moore, Anthony T.; Russell-Eggitt, Isabelle M.; Hardcastle, Alison J.

2009-01-01

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved. PMID:19414485

Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

PubMed

Favor, J; Pretsch, W

1990-01-01

Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

Protective Effect of Creatine Elevation against Ischaemia Reperfusion Injury Is Retained in the Presence of Co-Morbidities and during Cardioplegia.

PubMed

Whittington, Hannah J; McAndrew, Debra J; Cross, Rebecca L; Neubauer, Stefan; Lygate, Craig A

2016-01-01

Ischaemic heart disease is most prevalent in the ageing population and often exists with other comorbidities; however the majority of laboratory research uses young, healthy animal models. Several recent workshops and focus meetings have highlighted the importance of using clinically relevant models to help aid translation to realistic patient populations. We have previously shown that mice over-expressing the creatine transporter (CrT-OE) have elevated intracellular creatine levels and are protected against ischaemia-reperfusion injury. Here we test whether elevating intracellular creatine levels retains a cardioprotective effect in the presence of common comorbidities and whether it is additive to protection afforded by hypothermic cardioplegia. CrT-OE mice and wild-type controls were subjected to transverse aortic constriction for two weeks to induce compensated left ventricular hypertrophy (LVH). Hearts were retrogradely perfused in Langendorff mode for 15 minutes, followed by 20 minutes ischaemia and 30 minutes reperfusion. CrT-OE hearts exhibited significantly improved functional recovery (Rate pressure product) during reperfusion compared to WT littermates (76% of baseline vs. 59%, respectively, P = 0.02). Aged CrT-OE mouse hearts (78±5 weeks) also had enhanced recovery following 15 minutes ischaemia (104% of baseline vs. 67%, P = 0.0007). The cardioprotective effect of hypothermic high K+ cardioplegic arrest, as used during cardiac surgery and donor heart transplant, was further enhanced in prolonged ischaemia (90 minutes) in CrT-OE Langendorff perfused mouse hearts (76% of baseline vs. 55% of baseline as seen in WT hearts, P = 0.02). These observations in clinically relevant models further support the development of modulators of intracellular creatine content as a translatable strategy for cardiac protection against ischaemia-reperfusion injury.

Human X-Linked genes regionally mapped utilizing X-autosome translocations and somatic cell hybrids.

PubMed Central

Shows, T B; Brown, J A

1975-01-01

Human genes coding for hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8; IMP:pyrophosphate phosphoribosyltransferase), glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49; D-glucose-6-phosphate:NADP+ 1-oxidoreductase), and phosphoglycerate kinase (PGK, EC 2.7.2.3; ATP:3-phospho-D-glycerate 1-phosphotransferase) have been assigned to specific regions on the long arm of the X chromosome by somatic cell gentic techniques. Gene assignment and linear order were determined by employing human somatic cells possessing an X/9 translocation or an X/22 translocation in man-mouse cell hybridization studies. The X/9 translocation involved the majority of the X long arm translocated to chromosome 9 and the X/22 translocation involved the distal half of the X long arm translocated to 22. In each case these rearrangements appeared to be reciprocal. Concordant segregation of X-linked enzymes and segments of the X chromosome generated by the translocations indicated assignment of the PGK gene to a proximal long arm region (q12-q22) and the HPRT and G6PD genes to the distal half (q22-qter) of the X long arm. Further evidence suggests a gene order on the X long arm of centromere-PGK-HPRT-G6PD. Images PMID:1056018

Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults.

PubMed

Burke, Darren G; Candow, Darren G; Chilibeck, Philip D; MacNeil, Lauren G; Roy, Brian D; Tarnopolsky, Mark A; Ziegenfuss, Tim

2008-08-01

The purpose of this study was to compare changes in muscle insulin-like growth factor-I (IGF-I) content resulting from resistance-exercise training (RET) and creatine supplementation (CR). Male (n=24) and female (n=18) participants with minimal resistance-exercise-training experience (=1 year) who were participating in at least 30 min of structured physical activity (i.e., walking, jogging, cycling) 3-5 x/wk volunteered for the study. Participants were randomly assigned in blocks (gender) to supplement with creatine (CR: 0.25 g/kg lean-tissue mass for 7 days; 0.06 g/kg lean-tissue mass for 49 days; n=22, 12 males, 10 female) or isocaloric placebo (PL: n=20, 12 male, 8 female) and engage in a whole-body RET program for 8 wk. Eighteen participants were classified as vegetarian (lacto-ovo or vegan; CR: 5 male, 5 female; PL: 3 male, 5 female). Muscle biopsies (vastus lateralis) were taken before and after the intervention and analyzed for IGF-I using standard immunohistochemical procedures. Stained muscle cross-sections were examined microscopically and IGF-I content quantified using image-analysis software. Results showed that RET increased intramuscular IGF-I content by 67%, with greater accumulation from CR (+78%) than PL (+54%; p=.06). There were no differences in IGF-I between vegetarians and nonvegetarians. These findings indicate that creatine supplementation during resistance-exercise training increases intramuscular IGF-I concentration in healthy men and women, independent of habitual dietary routine.

Role of creatine supplementation on exercise-induced cardiovascular function and oxidative stress

PubMed Central

Cunningham, Daniel; Mason, Laura; Kilduff, Liam P; McEneny, Jane

2009-01-01

Many degenerative diseases are associated with increased oxidative stress. Creatine has the potential to act as an indirect and direct antioxidant; however, limited data exist to evaluate the antioxidant capabilities of creatine supplementation within in vivo human systems. This study aimed to investigate the effects of oral creatine supplementation on markers of oxidative stress and antioxidant defenses following exhaustive cycling exercise. Following preliminary testing and two additional familiarization sessions, 18 active males repeated two exhaustive incremental cycling trials (T1 and T2) separated by exactly 7 days. The subjects were assigned, in a double-blind manner, to receive either 20 g of creatine (Cr) or a placebo (P) for the 5 days preceding T2. Breath-by-breath respiratory data and heart rate were continually recorded throughout the exercise protocol and blood samples were obtained at rest (preexercise), at the end of exercise (postexercise), and the day following exercise (post24 h). Serum hypdroperoxide concentrations were elevated at postexercise by 17 ± 5% above preexercise values (p = 0.030). However, supplementation did not influence lipid peroxidation (serum hypdroperoxide concentrations), resistance of low density lipoprotein to oxidative stress (t1/2max LDL oxidation) and plasma concentrations of non-enzymatic antioxidants (retinol, α-carotene, β-carotene, α-tocopherol, γ-tocopherol, lycopene and vitamin C). Heart rate and oxygen uptake responses to exercise were not affected by supplementation. These findings suggest that short-term creatine supplementation does not enhance non-enzymatic antioxidant defence or protect against lipid peroxidation induced by exhaustive cycling in healthy males. PMID:20716911

Supplemented creatine induces changes in human metabolism of thiocompounds and one- and two-carbon units.

PubMed

Navrátil, T; Kohlíková, E; Petr, M; Pelclová, D; Heyrovský, M; Pristoupilová, K

2010-01-01

The administration of creatine (5 g/day for one month) to 11 young active sportsmen affected their urinary excretion of creatine, creatinine, and thiodiglycolic acid (TDGA) as well as blood levels of homocysteine, vitamin B12 and folates. The probands were divided into four groups, according to the amount of creatine found in urine, and of folates and vitamin B12 determined in blood. The changes of folates and vitamin B12 were mutually reciprocal. Each group utilized CR as donor of one- and two-carbon (1C and 2C) units by means of homocysteine (HoCySH), folates, and vitamin B12, in different metabolic pathways. In 10 men the creatine administration was accompanied by an increase of HoCySH level in blood, while in the last man, with accidentally discovered hyperhomocysteinemia, the HoCySH level dropped by 50%. Differences between initial and terminal TDGA levels indicate that creatine affects equilibria of redox processes. Creatinine excretion into urine changed in the dependence on the extent of metabolic disturbances.

Lamellar macular hole in X linked retinoschisis.

PubMed

Kumar, Vinod; Goel, Neha

2016-05-11

X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. 2016 BMJ Publishing Group Ltd.

A comparison of mutagen production in fried ground chicken and beef: effect of supplemental creatine.

PubMed

Knize, M G; Shen, N H; Felton, J S

1988-11-01

Ground chicken breast and ground beef with either endogenous or a 10-fold increase in the concentration of creatine were fried at 220 degrees C for 10 min per side. One patty (100 g) of chicken meat yielded 120,000 Salmonella (TA1538) revertants following metabolic activation. The pan residues had 39% of the total activity. Added creatine (10-fold the endogenous level) increased mutagen yields an average of 2-fold. Beef cooked under identical conditions yielded 150,000 revertants/100 g for the meat patties and pan residues combined. Added creatine to beef prior to cooking increased mutagen yields 3-fold. The mutagenic profiles following initial HPLC separation showed that chicken samples with endogenous or added creatine were remarkably similar. Chicken and beef HPLC mutagenicity profiles were also similar to each other, but not identical. This suggests that the general mutagen-forming reactions with the two different types of muscle are qualitatively similar with only minor quantitative differences. The pan residues from both meat types with and without added creatine showed some significant differences in the mutagen peak profile. This work suggests that the types of mutagens formed in chicken are similar to those formed in beef and that creatine appears to be involved in the formation of all the mutagenic compounds produced from fried muscle tissue.

A major X-linked locus affects kidney function in mice

PubMed Central

Leduc, Magalie S.; Savage, Holly S.; Stearns, Timothy M.; Cario, Clinton L.; Walsh, Kenneth A.; Paigen, Beverly; Berndt, Annerose

2012-01-01

Chronic kidney disease is a common disease with increasing prevalence in the western population. One common reason for chronic kidney failure is diabetic nephropathy. Diabetic nephropathy and hyperglycemia are characteristics of the mouse inbred strain KK/HlJ, which is predominantly used as a model for metabolic syndrome due to its inherited glucose intolerance and insulin resistance. We used KK/HlJ, an albuminuria-sensitive strain, and C57BL/6J, an albuminuria-resistant strain, to perform a quantitative trait locus (QTL) cross to identify the genetic basis for chronic kidney failure. Albumin-creatinine-ratio (ACR) was measured in 130 F2 male offspring. One significant QTL was identified on chromosome (Chr) X and four suggestive QTLs were found on Chrs 6, 7, 12, and 13. Narrowing of the QTL region was focused on the X-linked QTL and performed by incorporating genotype and expression analyses for genes located in the region. From the 485 genes identified in the X-linked QTL region, a few candidate genes were identified using a combination of bioinformatic evidence based on genomic comparison of the parental strains and known function in urine homeostasis. Finally, this study demonstrates the significance of the X chromosome in the genetic determination of albuminuria. PMID:23011808

The Effects of Creatine Monohydrate on Permeability of Coronary Artery Endothelium and Level of Blood Lipoprotein in Diabetic Rats.

PubMed

Rahmani, Asghar; Asadollahi, Khairollah; Soleimannejad, Kourosh; Khalighi, Zahra; Mohsenzadeh, Yosouf; Hemati, Ruhollah; Moradkhani, Atefeh; Abangah, Ghobad

2016-09-01

Creatine monohydrate has beneficial effects on serum glucose. This study aimed to investigate the effects of creatine on serum biochemical markers and permeability of coronary arteries among diabetic rats. 32 Wistar rats, which weighed 150-200 grams were randomly divided into 4 groups including: group I, control; group II, creatine monohydrate; group III, diabetic rats; and group IV, diabetic rats + creatine. Creatine monohydrate was applied by 400 mg/kg/daily for 5 months. Animals' weights and blood samples were taken before and after the study. Endothelial permeability rate was measured by Evans Blue method. Data were analysed by SPSS 16. At the end of fifth month, rats' weights in diabetic group under treatment with creatine, compared to those without, increased significantly (p<0.0001). Also, the serum levels of triglyceride (TG), cholesterol, glucose and low density lipoprotein (LDL)- cholesterol decreased significantly among those under treatment with creatine (p<0.05), but high density lipoprotein (HDL)- cholesterol increased significantly (p<0.002). Permeability rate of coronary arteries was reduced significantly in the diabetic group treated by creatine compared to untreated groups, closed to the intact group (p<0.001). Results of this study showed that creatine monohydrate caused an improvement of serum biochemical markers associated with diabetes and reduced the permeability rate of coronary arteries among diabetic rats. © 2016 by the Association of Clinical Scientists, Inc.

The effects of polyethylene glycosylated creatine supplementation on anaerobic performance measures and body composition.

PubMed

Camic, Clayton L; Housh, Terry J; Zuniga, Jorge M; Traylor, Daniel A; Bergstrom, Haley C; Schmidt, Richard J; Johnson, Glen O; Housh, Dona J

2014-03-01

The purpose of this study was to examine the effects of 28 days of polyethylene glycosylated creatine (PEG-creatine) supplementation (1.25 and 2.50 g·d) on anaerobic performance measures (vertical and broad jumps, 40-yard dash, 20-yard shuttle run, and 3-cone drill), upper- and lower-body muscular strength and endurance (bench press and leg extension), and body composition. This study used a randomized, double-blind, placebo-controlled parallel design. Seventy-seven adult men (mean age ± SD, 22.1 ± 2.5 years; body mass, 81.7 ± 10.8 kg) volunteered to participate and were randomly assigned to a placebo (n = 23), 1.25 g·d of PEG-creatine (n = 27), or 2.50 g·d of PEG-creatine (n = 27) group. The subjects performed anaerobic performance measures, muscular strength (one-repetition maximum [1RM]), and endurance (80% 1RM) tests for bench press and leg extension, and underwater weighing for the determination of body composition at day 0 (baseline), day 14, and day 28. The results indicated that there were improvements (p < 0.0167) in vertical jump, 20-yard shuttle run, 3-cone drill, muscular endurance for bench press, and body mass for at least one of the PEG-creatine groups without changes for the placebo group. Thus, the present results demonstrated that PEG-creatine supplementation at 1.25 or 2.50 g·d had an ergogenic effect on lower-body vertical power, agility, change-of-direction ability, upper-body muscular endurance, and body mass.

Abnormalities in Human Brain Creatine Metabolism in Gulf War Illness Probed with MRS

DTIC Science & Technology

2014-12-01

TYPE Final 3. DATES COVERED 30 Sep 2012 - 29 Sep 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Abnormalities in Human Brain Creatine Metabolism in...levels of total creatine (tCr) in veterans with Gulf War Illness have been observed in prior studies. The goal of this research is to estimate amounts and

Studies of the haemodynamic effects of creatine phosphate in man.

PubMed Central

Hurlow, R A; Aukland, A; Hardman, J; Whittington, J R

1982-01-01

1 The haemodynamic effects of intravenous creatine phosphate 1000 mg have been studied. 2 During the first 60 min following drug administration heart rate and blood pressure did not change but cardiac output fell significantly by approximately 18%. Calculated total peripheral resistance showed a corresponding significant rise, the maximum increase being approximately 24%. All these changes were beginning to diminish within 90 min after the injection. 3 Total limb blood flow measured in both arm and leg (using venous occlusion strain-gauge plethysmography) showed no appreciable changes following injection of creatine phosphate. 4 There was a progressive reduction in leg muscle blood flow (Xe133 clearance method) following injection which was statistically significant with respect to the initial level and reached a minimum (46% reduction) 50 min after the injection. 5 Skin blood flow, estimated by infra-red photoplethysmography, showed changes complementary to those seen with muscle flow. There was a progressive and significant rise to a peak (73% increase) 30 min after the injection. 6 No adverse reactions to the injections were noted. 7 Reduced cardiac output in the absence of altered total limb blood flow presumably reflects a reduction in visceral blood flow, which was not measured in this study. Within the limbs, creatine phosphate appears to result in a redistribution of blood flow from muscle to skin. Thus, these preliminary results suggest that intravenous creatine phosphate could be clinically useful in situations where short term improvement in skin blood flow would be advantageous and that further controlled studies would be justified. PMID:7093109

Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder.

PubMed

Yoon, Sujung; Kim, Jieun E; Hwang, Jaeuk; Kim, Tae-Suk; Kang, Hee Jin; Namgung, Eun; Ban, Soonhyun; Oh, Subin; Yang, Jeongwon; Renshaw, Perry F; Lyoo, In Kyoon

2016-09-15

Creatine monohydrate (creatine) augmentation has the potential to accelerate the clinical responses to and enhance the overall efficacy of selective serotonin reuptake inhibitor treatment in women with major depressive disorder (MDD). Although it has been suggested that creatine augmentation may involve the restoration of brain energy metabolism, the mechanisms underlying its antidepressant efficacy are unknown. In a randomized, double-blind, placebo-controlled trial, 52 women with MDD were assigned to receive either creatine augmentation or placebo augmentation of escitalopram; 34 subjects participated in multimodal neuroimaging assessments at baseline and week 8. Age-matched healthy women (n = 39) were also assessed twice at the same intervals. Metabolic and network outcomes were measured for changes in prefrontal N-acetylaspartate and changes in rich club hub connections of the structural brain network using proton magnetic resonance spectroscopy and diffusion tensor imaging, respectively. We found MDD-related metabolic and network dysfunction at baseline. Improvement in depressive symptoms was greater in patients receiving creatine augmentation relative to placebo augmentation. After 8 weeks of treatment, prefrontal N-acetylaspartate levels increased significantly in the creatine augmentation group compared with the placebo augmentation group. Increment in rich club hub connections was also greater in the creatine augmentation group than in the placebo augmentation group. N-acetylaspartate levels and rich club connections increased after creatine augmentation of selective serotonin reuptake inhibitor treatment. Effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women with MDD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine.

PubMed

Kreider, Richard B; Kalman, Douglas S; Antonio, Jose; Ziegenfuss, Tim N; Wildman, Robert; Collins, Rick; Candow, Darren G; Kleiner, Susan M; Almada, Anthony L; Lopez, Hector L

2017-01-01

Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson's, Huntington's disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly. Moreover, significant health benefits may be provided by ensuring habitual low dietary creatine ingestion (e.g., 3 g/day) throughout the lifespan. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN).

VDAC electronics: 3. VDAC-Creatine kinase-dependent generation of the outer membrane potential in respiring mitochondria.

PubMed

Lemeshko, Victor V

2016-07-01

Mitochondrial energy in cardiac cells has been reported to be channeled into the cytosol through the intermembrane contact sites formed by the adenine nucleotide translocator, creatine kinase and VDAC. Computational analysis performed in this study showed a high probability of the outer membrane potential (OMP) generation coupled to such a mechanism of energy channeling in respiring mitochondria. OMPs, positive inside, calculated at elevated concentrations of creatine are high enough to restrict ATP release from mitochondria, to significantly decrease the apparent K(m,ADP) for state 3 respiration and to maintain low concentrations of Ca(2+) in the mitochondrial intermembrane space. An inhibition by creatine of Ca(2+)-induced swelling of isolated mitochondria and other protective effects of creatine reported in the literature might be explained by generated positive OMP. We suggest that VDAC-creatine kinase-dependent generation of OMP represents a novel physiological factor controlling metabolic state of mitochondria, cell energy channeling and resistance to death. Copyright © 2016 Elsevier B.V. All rights reserved.

Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fain, P.R.; Barker, D.F.; Chance, P.F.

1994-02-01

Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

High temperature transport properties of co-substituted Ca{sub 1−x}Ln{sub x}Mn{sub 1−x}Nb{sub x}O{sub 3} (Ln = Yb, Lu; 0.02 ≤ x ≤ 0.08)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nag, Abanti, E-mail: abanti@nal.res.in; Bose, Rapaka S.C.

Highlights: • The thermoelectric Ca{sub 1−x}Ln{sub x}Mn{sub 1−x}Nb{sub x}O{sub 3} (Ln = Yb, Lu) perovskite are prepared by solid state reaction. • The high temperature transport properties are explored. • The co-substituted Ca{sub 1−x}Ln{sub x}Mn{sub 1−x}Nb{sub x}O{sub 3} shows non-metal-like temperature dependence of resistivity. • The Seebeck coefficient of Ca{sub 1−x}Ln{sub x}Mn{sub 1−x}Nb{sub x}O{sub 3} exhibits metallic nature. • The puzzling transport phenomenon is originated from oxygen vacancy related defect centres. - Abstract: The co-substituted Ca{sub 1−x}Ln{sub x}Mn{sub 1−x}Nb{sub x}O{sub 3} (Ln = Yb, Lu; 0.02 ≤ x ≤ 0.08) are synthesized by solid-state reaction and the electronic transport propertiesmore » are investigated. Rietveld refinement confirms the formation of single phase orthorhombic structure with gradual increase of cell parameters with doping level. The electronic transport properties such as Seebeck coefficient and electrical resistivity decrease with increasing the dopant concentration for both the co-substituted compositions. All the compositions of Ca{sub 1−x}Ln{sub x}Mn{sub 1−x}Nb{sub x}O{sub 3} show nonmetal-like temperature dependence of resistivity; whereas metal-like temperature dependence of thermopower. This inconsistency is explained by the formation of oxygen vacancy associated defect centres that originates from partial reduction of Mn{sup 4+} to Mn{sup 3+} due to co-substitution. The defect centres act as extrinsic carriers and cause additional contribution to the entropy of the system, leading to increase of Seebeck coefficient as a function of temperature. The transport mechanism of charge carriers is explained in the framework of Mott’s small polaron hopping mechanism.« less

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

21 CFR 862.1210 - Creatine test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Creatine test system. 862.1210 Section 862.1210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

X-linked Alport syndrome caused by splicing mutations in COL4A5.

PubMed

Nozu, Kandai; Vorechovsky, Igor; Kaito, Hiroshi; Fu, Xue Jun; Nakanishi, Koichi; Hashimura, Yuya; Hashimoto, Fusako; Kamei, Koichi; Ito, Shuichi; Kaku, Yoshitsugu; Imasawa, Toshiyuki; Ushijima, Katsumi; Shimizu, Junya; Makita, Yoshio; Konomoto, Takao; Yoshikawa, Norishige; Iijima, Kazumoto

2014-11-07

X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism. In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities. Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics. This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked

Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Braun, A.; Ambach, H.; Kammerer, S.

Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-bindingmore » domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.« less

X-linked hypophosphatemia. A phenotype in search of a cause.

PubMed

Tenenhouse, H S; Scriver, C R

1992-05-01

XLH is an important disease, it is the subject of several classic articles in the medical sciences (Scriver et al., 1991), and it has been an important stimulus to study renal hypophosphatemias and how they are involved in rickets and osteomalacia (Scriver, 1974; Scriver and Tenenhouse, 1991). Renal transport is the major determinant of phosphate homeostasis in mammals and it is unlikely that this important biochemical parameter would have been left by evolution to a single renal transport system. Together physiologists and geneticists found that the mammalian kidney has several gene products dedicated to phosphate transport. That has implications for biochemists in search of a membrane protein to clone and explain XLH, for example. Let us suppose the transporter affected in XLH is cloned. Will it be the product of the XLH (or Hyp or Gy) locus? One will not know until the transporter gene is mapped. There is no question of the X-chromosome locus product being protein kinase C for example, since it maps to autosomes. But where does one start in the search for the X-chromosome locus? With the elusive putative diffusible factor or with the transporter, or perhaps with an enzyme in vitamin D hormone metabolism? Which goes to say that it is necessary to know the phenotype to arrive at the right locus. Or is it? Sufficient physical mapping of region Xp22.31-p21.3 will eventually lead to positional cloning of the Hyp gene. What will it be?(ABSTRACT TRUNCATED AT 250 WORDS)

X linked exudative vitreoretinopathy: clinical features and genetic linkage analysis.

PubMed

Fullwood, P; Jones, J; Bundey, S; Dudgeon, J; Fielder, A R; Kilpatrick, M W

1993-03-01

A four generation family in which familial exudative vitreoretinopathy is inherited as an X linked condition is described. Essentially the condition is one of abnormal vascularisation and signs at birth are those of a retinopathy superficially resembling retinopathy of prematurity, retinal folds, or, in advanced cases, enophthalmos or even phthisis. Prognosis depends on the progression of the retinal changes. The family members, including seven affected males and five obligate carrier females, have been types for 20 DNA markers, and linkage analysis suggests a gene locus either at Xq21.3 or at Xp11. As the latter region includes the locus for the gene for Norrie disease, it is possible that this and X linked vitreoretinopathy are allelic. We can further speculate that the differences in severity of the clinical manifestations are dependent only upon the timing of the insult.

A family with X-linked anophthalmia: exclusion of SOX3 as a candidate gene.

PubMed

Slavotinek, Anne; Lee, Stephen S; Hamilton, Steven P

2005-10-01

We report on a four-generation family with X-linked anophthalmia in four affected males and show that this family has LOD scores consistent with linkage to Xq27, the third family reported to be linked to the ANOP1 locus. We sequenced the SOX3 gene at Xq27 as a candidate gene for the X-linked anophthalmia based on the high homology of this gene to SOX2, a gene previously mutated in bilateral anophthlamia. However, no amino acid sequence alterations were identified in SOX3. We have improved the definition of the phenotype in males with anophthalmia linked to the ANOP1 locus, as microcephaly, ocular colobomas, and severe renal malformations have not been described in families linked to ANOP1. (c) 2005 Wiley-Liss, Inc.

Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo.

PubMed

Edison, Erica E; Brosnan, Margaret E; Meyer, Christian; Brosnan, John T

2007-12-01

A fraction of the body's creatine and creatine phosphate spontaneously degrades to creatinine, which is excreted by the kidneys. In humans, this amounts to approximately 1-2 g/day and demands a comparable rate of de novo creatine synthesis. This is a two-step process in which l-arginine:glycine amidinotransferase (AGAT) catalyzes the conversion of glycine and arginine to ornithine and guanidinoacetate (GAA); guanidinoacetate methyltransferase (GAMT) then catalyzes the S-adenosylmethionine-dependent methylation of GAA to creatine. AGAT is found in the kidney and GAMT in the liver, which implies an interorgan movement of GAA from the kidney to the liver. We studied the renal production of this metabolite in both rats and humans. In control rats, [GAA] was 5.9 microM in arterial plasma and 10.9 microM in renal venous plasma for a renal arteriovenous (A-V) difference of -5.0 microM. In the rat, infusion of arginine or citrulline markedly increased renal GAA production but infusion of glycine did not. Rats fed 0.4% creatine in their diet had decreased renal AGAT activity and mRNA, an arterial plasma [GAA] of 1.5 microM, and a decreased renal A-V difference for GAA of -0.9 microM. In humans, [GAA] was 2.4 microM in arterial plasma, with a renal A-V difference of -1.1 microM. These studies show, for the first time, that GAA is produced by both rat and human kidneys in vivo.

Surfactant-enhanced remediation of a trichloroethene-contaminated aquifer. 1. Transport of triton X-100

USGS Publications Warehouse

Smith, J.A.; Sahoo, D.; Mclellan, H.M.; Imbrigiotta, T.E.

1997-01-01

Transport of a nonionic surfactant (Triton X-100) at aqueous concentrations less than 400 mg/L through a trichloroethene-contaminated sand-and-gravel aquifer at Picatinny Arsenal, NJ, has been studied through a series of laboratory and field experiments. In the laboratory, batch and column experiments were conducted to quantify the rate and amount of Triton X-100 sorption to the aquifer sediments. In the field, a 400 mg/L aqueous Triton X-100 solution was injected into the aquifer at a rate of 26.5 L/min for a 35-d period. The transport of Triton X-100 was monitored by sampling and analysis of groundwater at six locations surrounding the injection well. Equilibrium batch sorption experiments showed that Triton X-100 sorbs strongly and nonlinearly to the field soil with the sharpest inflection point of the isotherm occurring at an equilibrium aqueous Triton X-100 concentration close to critical micelle concentration. Batch, soil column, and field experimental data were analyzed with zero-, one-, and two- dimensional (respectively) transient solute transport models with either equilibrium or rate-limited sorption. These analyses reveal that Triton X- 100 sorption to the aquifer solids is slow relative to advective and dispersive transport and that an equilibrium sorption model cannot simulate accurately the observed soil column and field data. Comparison of kinetic sorption parameters from batch, column, and field transport data indicate that both physical heterogeneities and Triton X-100 mass transfer between water and soil contribute to the kinetic transport effects.Transport of a nonionic surfactant (Triton X-100) at aqueous concentrations less than 400 mg/L through a trichloroethene-contaminated sand-and-gravel aquifer was studied. Equilibrium batch sorption experiments showed that Triton X-100 sorbs strongly and nonlinearly to the field soil with the sharpest inflection point of the isotherm occurring at an equilibrium aqueous Triton X-100 concentration close to

CAPILLARY NETWORK ALTERATIONS IN X-LINKED RETINOSCHISIS IMAGED ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PubMed

Romano, Francesco; Arrigo, Alessandro; Chʼng, Soon Wai; Battaglia Parodi, Maurizio; Manitto, Maria Pia; Martina, Elisabetta; Bandello, Francesco; Stanga, Paulo E

2018-06-05

To assess foveal and parafoveal vasculature at the superficial capillary plexus, deep capillary plexus, and choriocapillaris of patients with X-linked retinoschisis by means of optical coherence tomography angiography. Six patients with X-linked retinoschisis (12 eyes) and seven healthy controls (14 eyes) were recruited and underwent complete ophthalmologic examination, including best-corrected visual acuity, dilated fundoscopy, and 3 × 3-mm optical coherence tomography angiography macular scans (DRI OCT Triton; Topcon Corp). After segmentation and quality review, optical coherence tomography angiography slabs were imported into ImageJ 1.50 (NIH; Bethesda) and digitally binarized. Quantification of vessel density was performed after foveal avascular zone area measurement and exclusion. Patients were additionally divided into "responders" and "nonresponders" to dorzolamide therapy. Foveal avascular zone area resulted markedly enlarged at the deep capillary plexus (P < 0.001), particularly in nonresponders. Moreover, patients disclosed a significant deep capillary plexus rarefaction, when compared with controls (P: 0.04); however, a subanalysis revealed that this damage was limited to the fovea (P: 0.006). Finally, the enlargement of foveal avascular zone area positively correlated with a decline in best-corrected visual acuity (P: 0.01). Prominent foveal vascular impairment is detectable in the deep capillary plexus of patients with X-linked retinoschisis. Our results correlate with functional outcomes, suggesting a possible vascular role in X-linked retinoschisis clinical manifestations.

AB067. X-linked adrenoleukodystrophy: Phenotype and genotype in Vietnamese patients

PubMed Central

Nguyen, Khanh Ngoc; Nguyen, Ha Thu; Can, Ngoc Thi Bich; Bui, Thao Phuong; Nobuyuki, Shimozawa; Vu, Huynh Anh; Do, Mai Thi Thanh; Vu, Dung Chi

2017-01-01

Background X-linked adrenoleukodystrophy (X-ALD) is caused by a defect in the gene ABCD1, which maps to Xq28 and codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily. This disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. Objective is to identify phenotype and genotype in Vietnamese patients with X-ALD. Methods Genomic DNA from 20 Vietnamese patients from 18 unrelated families was extracted using standard procedures from the peripheral blood leukocytes. Mutation analysis of ABCD1 was performed using polymerase chain reaction (PCR) and DNA direct sequencing. Results We identified 17 different mutations of ABCD1 in 20 patients including missense mutations (2/17), deletion (4/17), frameshift mutation (1/17) and splice site mutation (1/17). Of which, six novel mutations including c.1202G>T (p.Arg401Trp); c.1208T>A (p.Met403Lys); IVS8+28-551bp del; c.1668G>C (p.Q556H); c.292_296delTCGGC (p.S98RfsX95); and the extent of deletion included between IVS1+505 and IVS2+1501, containing whole the exon 2 (4243bp), plus insertion of 79bp from BAP31 and 8bp from unknown origin in this deleted region were identified in six unrelated patients. Eleven reported mutations including c.796G>A (p.Gly266Arg); c.1628C>T (p.Pro543Leu); c.1553G>A (p.Arg518Gln); c.1552 C>T (p.Arg518Trp); c.854G>C (p.R285P); c.1825G>A (p.E609K); c.1415_1416delAG (p.Q472RfsX83) and c.46-53del insG, c.1553G>A (p.Arg518Gln), c.1946-1947insA (p.Asp649fsX733), c.1978C>T (p.Arg660Trp) were identified in 14 patients from 12 families. Most of patients (17/20) presented cerebral ALD type with/without adrenal insufficiency and only 3 patients presented Addison type. Conclusions Mutation analysis of ABCD1 gene helped confirmation of diagnosis of X-ALD, genetic counselling and prenatal diagnosis but could not be used to predict the specific phenotype of X-ALD.

Creatine enhances the duration of sperm capacitation: a novel factor for improving in vitro fertilization with small numbers of sperm.

PubMed

Umehara, Takashi; Kawai, Tomoko; Goto, Masaaki; Richards, JoAnne S; Shimada, Masayuki

2018-06-01

Why are many sperm required for successful fertilization of oocytes in vitro, even though fertilization occurs in vivo when only a few sperm reach the oocyte? Creatine produced in the ovary promotes efficient fertilization in vivo; however, in vitro, creatine is not contained in the in vitro fertilization (IVF) medium. The IVF medium enables capacitation of sperm. However, the IVF medium does not fully mimic the in vivo environment during fertilization. Consequently, fertilization in vitro is more inefficient than in the oviduct. Follicular and oviductal fluids were collected and then analyzed for creatine and glucose levels. To determine the physiological functions of creatine, the creatine antagonist 3-guanidinopropionic acid (GPA) was injected into hormonally primed mice. Using conventional IVF protocols, sperm were pre-incubated in IVF medium with creatine and then co-cultured with 10 ovulated cumulus-oocyte complexes (1-1000 per oocyte) in 50 μl medium droplets. Glucose and creatine levels were measured using commercial enzymatic assay kits. The effect of creatine in vivo was assessed by mating experiments using mice treated with or without GPA just before ovulation. To assess the functions of sperm incubated in IVF medium containing creatine, we analyzed (1) the motility of sperm using computer-assisted sperm assay, (2) the capacitation level of sperm by western blot analyses, and (3) the condition of sperm acrosomes by peanut agglutinin lectin-FITC staining. Oviductal creatine levels were significantly increased following ovulation. Injecting mice with GPA just before ovulation significantly reduced the number of fertilized oocytes. The addition of creatine to IVF medium enhanced sperm capacitation by increasing ATP levels. Successful fertilization was achieved with as few as five sperm/oocyte in the creatine group, and the number of fertilized oocytes was significantly higher than in the control without creatine (P < 0.01). In the present study, a

Effects of creatine supplementation on biomarkers of hepatic and renal function in young trained rats.

PubMed

Souza, William Marciel; Heck, Thiago Gomes; Wronski, Evanio Castor; Ulbrich, Anderson Zampier; Boff, Everton

2013-11-01

Creatine supplementation has been widely used by athletes and young physical exercise practioneers in order of increasing muscle mass and enhancing athletic performance, but their use/overuse may represent a health risk on hepatic and renal impaired function. In this study, we evaluated the effects of 40 days of oral creatine supplementation on hepatic and renal function biomarkers in a young animal model. Wistar rats (5 weeks old) were divided in five groups (n = 7): control (CONTR), oral creatine supplementation (CREAT), moderate exercise training (EXERC), moderate exercise training plus oral creatine supplementation (EXERC + CREAT) and pathological group (positive control for liver and kidney injury) by the administration of rifampicin (RIFAMPICIN). Exercise groups were submitted to 60 min/day of swimming exercise session with a 4% of body weight workload for six weeks. The EXERC + CREAT showed the higher body weight at the end of the training protocol. The CREAT and EXERC + CREAT group showed an increase in hepatic (Aspartate transaminase and gamma-glutamyl transpeptidase) and renal (urea and creatinine) biomarkers levels (p < 0.05). Our study showed that the oral creatine supplementation promoted hepatic and renal function challenge in young rats submitted to moderate exercise training.

X-linked Acrogigantism (X-LAG) Syndrome: Clinical Profile and Therapeutic Responses

PubMed Central

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J.; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H.; Bours, Vincent; Liu, Pengfei; De Herder, Wouter; Pellegata, Natalia; Lupski, James R.; Daly, Adrian F.; Stratakis, Constantine A.

2015-01-01

X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

Transport properties of Y1-xNdxCo2 compounds

NASA Astrophysics Data System (ADS)

Uchima, K.; Takeda, M.; Zukeran, C.; Nakamura, A.; Arakaki, N.; Komesu, S.; Takaesu, Y.; Hedo, M.; Nakama, T.; Yagasaki, K.; Uwatoko, Y.; Burkov, A. T.

2012-12-01

Electrical resistivity ρ and thermopower S of light rare earth-based pseudo-binary Y1-xNdxCo2 alloys have been measured at temperatures from 2 K to 300 K and under pressures up to 3.5 GPa. The Curie temperature of the alloys, TC, determined from characteristic features in the temperature dependences of the transport properties, decreases with decreasing Nd concentration x and vanishes around xc = 0.3. The residual resistivity has a pronounced maximum at x = xc. The temperature coefficient of thermopower dS/dT at low temperature limit shows a complex dependence on alloy composition: it changes its sign from negative to positive at x ≍ 0.2, having a maximum at x = xc, and is nearly composition independent at x > 0.5. The pressure dependences of TC and ρ0 of Yo.6Ndo.4Co2 reveal the behavior similar to that observed in the Y1-xRxHCo2 (RH = heavy rare earth) alloy systems, which implies that the magnetic state of the Co-3d electron subsystem is responsible for the transport properties in the Y1-xNdxCo2 alloys.

Umbrella sampling of proton transfer in a creatine-water system

NASA Astrophysics Data System (ADS)

Ivchenko, Olga; Bachert, Peter; Imhof, Petra

2014-04-01

Proton transfer reactions are among the most common processes in chemistry and biology. Proton transfer between creatine and surrounding solvent water is underlying the chemical exchange saturation transfer used as a contrast in magnetic resonance imaging. The free energy barrier, determined by first-principles umbrella sampling simulations (EaDFT 3 kcal/mol) is in the same order of magnitude as the experimentally obtained activation energy. The underlying mechanism is a first proton transfer from the guanidinium group to the water pool, followed by a second transition where a proton is "transferred back" from the nearest water molecule to the deprotonated nitrogen atom of creatine.

Erythrocyte creatine as a marker of intravascular hemolysis due to left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

PubMed

Kubo, Toru; Okumiya, Toshika; Baba, Yuichi; Hirota, Takayoshi; Tanioka, Katsutoshi; Yamasaki, Naohito; Sugiura, Tetsuro; Doi, Yoshinori L; Kitaoka, Hiroaki

2016-03-01

Erythrocyte creatine, a marker of erythrocyte age that increases with shortening of erythrocyte survival, has been reported to be a quantitative and reliable marker for intravascular hemolysis. We hypothesized that hemolysis could also occur due to intraventricular obstruction in patients with hypertrophic cardiomyopathy (HCM). The purpose of this study was to examine the presence of subclinical hemolysis and the relation between intravascular hemolysis and intraventricular pressure gradient (IVPG). We measured erythrocyte creatine in 92 HCM patients. Twelve patients had left ventricular outflow tract obstruction (LVOTO), 4 had midventricular obstruction (MVO), and the remaining 76 were non-obstructive. Erythrocyte creatine levels ranged from 0.92 to 4.36μmol/g hemoglobin. Higher levels of erythrocyte creatine were associated with higher IVPG (r=0.437, p<0.001). If erythrocyte creatine levels are high (≥1.8μmol/g hemoglobin), subclinical hemolysis is considered to be present. Half of LVOTO patients and no MVO patients showed high erythrocyte creatine levels. Although non-obstructive patients did not show significant intraventricular obstruction at rest, some showed high erythrocyte creatine levels. When LVOT-PG was measured during the strain phase of the Valsalva maneuver in 20 non-obstructive patients, 7 of those 20 patients showed LVOTO. In the 20 patients, there was no relation between erythrocyte creatine levels and LVOT-PG before the Valsalva maneuver (r=0.125, p=0.600), whereas there was a significant correlation between erythrocyte creatine and LVOT-PG provoked by the Valsalva maneuver (r=0.695, p=0.001). There is biochemical evidence of subclinical hemolysis in patients with HCM, and this hemolysis seems to be associated with LVOTO provoked by daily physical activities. Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Measuring the lactate-to-creatine ratio via 1H NMR spectroscopy can be used to noninvasively evaluate apoptosis in glioma cells after X-ray irradiation.

PubMed

Li, Hongxia; Cui, Yi; Li, Fuyan; Shi, Wenqi; Gao, Wenjing; Wang, Xiao; Zeng, Qingshi

2018-01-01

Radiotherapy is among the commonly applied treatment options for glioma, which is one of the most common types of primary brain tumor. To evaluate the effect of radiotherapy noninvasively, it is vital for oncologists to monitor the effects of X-ray irradiation on glioma cells. Preliminary research had showed that PKC-ι expression correlates with tumor cell apoptosis induced by X-ray irradiation. It is also believed that the lactate-to-creatine (Lac/Cr) ratio can be used as a biomarker to evaluate apoptosis in glioma cells after X-ray irradiation. In this study, we evaluated the relationships between the Lac/Cr ratio, apoptotic rate, and protein kinase C iota (PKC-ι) expression in glioma cells. Cells of the glioma cell lines C6 and U251 were randomly divided into 4 groups, with every group exposed to X-ray irradiation at 0, 1, 5, 10 and 15 Gy. Single cell gel electrophoresis (SCGE) was conducted to evaluate the DNA damage. Flow cytometry was performed to measure the cell cycle blockage and apoptotic rates. Western blot analysis was used to detect the phosphorylated PKC-ι (p-PKC-ι) level. 1 H NMR spectroscopy was employed to determine the Lac/Cr ratio. The DNA damage increased in a radiation dose-dependent manner ( p  < 0.05). With the increase in X-ray irradiation, the apoptotic rate also increased (C6, p  < 0.01; U251, p  < 0.05), and the p-PKC-ι level decreased (C6, p  < 0.01; U251, p  < 0.05). The p-PKC-ι level negatively correlated with apoptosis, whereas the Lac/Cr ratio positively correlated with the p-PKC-ι level. The Lac/Cr ratio decreases with an increase in X-ray irradiation and thus can be used as a biomarker to reflect the effects of X-ray irradiation in glioma cells.

Genetic Analysis of a Kindred With X-linked Mental Handicap and Retinitis Pigmentosa

PubMed Central

Aldred, M. A.; Dry, K. L.; Knight-Jones, E. B.; Hardwick, L. J.; Teague, P. W.; Lester, D. H.; Brown, J.; Spowart, G.; Carothers, A. D.; Raeburn, J. A.; Bird, A. C.; Fielder, A. R.; Wright, A. F.

1994-01-01

A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5'-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. PMID:7977353

Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials.

PubMed

Avgerinos, Konstantinos I; Spyrou, Nikolaos; Bougioukas, Konstantinos I; Kapogiannis, Dimitrios

2018-07-15

Creatine is a supplement used by sportsmen to increase athletic performance by improving energy supply to muscle tissues. It is also an essential brain compound and some hypothesize that it aids cognition by improving energy supply and neuroprotection. The aim of this systematic review is to investigate the effects of oral creatine administration on cognitive function in healthy individuals. A search of multiple electronic databases was performed for the identification of randomized clinical trials (RCTs) examining the cognitive effects of oral creatine supplementation in healthy individuals. Six studies (281 individuals) met our inclusion criteria. Generally, there was evidence that short term memory and intelligence/reasoning may be improved by creatine administration. Regarding other cognitive domains, such as long-term memory, spatial memory, memory scanning, attention, executive function, response inhibition, word fluency, reaction time and mental fatigue, the results were conflicting. Performance on cognitive tasks stayed unchanged in young individuals. Vegetarians responded better than meat-eaters in memory tasks but for other cognitive domains no differences were observed. Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear. Findings suggest potential benefit for aging and stressed individuals. Since creatine is safe, future studies should include larger sample sizes. It is imperative that creatine should be tested on patients with dementias or cognitive impairment. Copyright © 2018 Elsevier Inc. All rights reserved.

A Pilot Study of Creatine as a Novel Treatment for Depression in Methamphetamine Using Females

PubMed Central

Hellem, Tracy L.; Sung, Young-Hoon; Shi, Xian-Feng; Pett, Marjorie A.; Latendresse, Gwen; Morgan, Jubel; Huber, Rebekah S.; Kuykendall, Danielle; Lundberg, Kelly J.; Renshaw, Perry F.

2015-01-01

Objective Depression among methamphetamine users is more prevalent in females than males, but gender specific treatment options for this comorbidity have not been described. Reduced brain phosphocreatine levels have been shown to be lower in female methamphetamine users compared to males, and, of relevance, studies have demonstrated an association between treatment resistant depression and reduced brain phosphocreatine concentrations. The nutritional supplement creatine monohydrate has been reported to reduce symptoms of depression in female adolescents and adults taking antidepressants, as well as to increase brain phosphocreatine in healthy volunteers. Therefore, the purpose of this pilot study was to investigate creatine monohydrate as a treatment for depression in female methamphetamine users. Methods Fourteen females with depression and comorbid methamphetamine dependence were enrolled in an 8 week open label trial of 5 grams of daily creatine monohydrate and of these 14, eleven females completed the study. Depression was measured using the Hamilton Depression Rating Scale (HAMD) and brain phosphocreatine levels were measured using phosphorus magnetic resonance spectroscopy pre- and post-creatine treatment. Secondary outcome measures included anxiety symptoms, measured with the Beck Anxiety Inventory (BAI), as well as methamphetamine use, monitored by twice weekly urine drug screens and self-reported use. Results The results of a linear mixed effects repeated measures model showed significantly reduced HAMD and BAI scores as early as week 2 when compared to baseline scores. This improvement was maintained through study completion. Brain phosphocreatine concentrations were higher at the second phosphorus magnetic resonance spectroscopy scan compared to the baseline scan; Mbaseline = 0.223 (SD = 0.013) vs. Mpost-treatment = 0.233 (SD = 0.009), t(9) = 2.905, p < .01, suggesting that creatine increased phosphocreatine levels. Also, a reduction in methamphetamine

A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX).

PubMed

Zhou, Qi; Yao, Fengxia; Wang, Feng; Li, Hui; Chen, Rui; Sui, Ruifang

2018-01-01

Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR. © 2017 Wiley Periodicals, Inc.

Foveomacular schisis in juvenile X-linked retinoschisis: an optical coherence tomography study.

PubMed

Yu, Jia; Ni, Yingqin; Keane, Pearse A; Jiang, Chunhui; Wang, Wenji; Xu, Gezhi

2010-06-01

To explore the structural features of juvenile X-linked retinoschisis using spectral-domain optical coherence tomography (OCT). Retrospective, observational cross-sectional study. Eighteen male patients (34 eyes) who were diagnosed with juvenile X-linked retinoschisis at the Eye & ENT Hospital of Fudan University over an 18-month period were included. Their OCT images, which were obtained using spectral-domain OCT (Cirrus HD-OCT; Carl Zeiss Meditec), were analyzed. The anatomic location of the schisis cavity in juvenile X-linked retinoschisis was characterized by direct inspection of OCT images. On OCT, the schisis cavity was visible at the fovea in all 34 eyes, and it was associated with increased retinal thickness. Schisis was present at the retinal nerve fiber layer in 4 eyes, at the inner nuclear layer in 29 eyes, and at the outer nuclear layer/outer plexiform layer in 22 eyes. In most cases, widespread foveomacular schisis was detected using OCT; however, in 9 eyes (6 patients), the schisis was confined to the fovea. Schisis of the inner nuclear layer and outer nuclear layer/outer plexiform layer almost always involved the foveal center, but retinal nerve fiber layer schisis was seen only in the parafoveal area. Despite conventional wisdom, in patients with X-linked retinoschisis, the schisis cavity can occur in a number of different layers of the neurosensory retina (retinal nerve fiber layer, inner nuclear layer, and outer nuclear layer/outer plexiform layer). In addition, different forms of schisis may affect different locations in the macula (foveal vs parafoveal), and, in most eyes, the schisis involves the entire foveomacular region. Copyright 2010 Elsevier Inc. All rights reserved.

A Novel Mutation in the XLRS1 Gene in a Korean Family with X-linked Retinoschisis

PubMed Central

Jwa, Nam Soo; Kim, Sung Soo; Lee, Sung Chul; Kwon, Oh Woong

2006-01-01

Purpose To report a novel missense mutation in the XLRS1 gene in a Korean family with X-linked retinoschisis. Methods Observation case report of a family with a proband with X-linked retinoschisis underwent complete ophthalmologic examination. Genomic DNA was excluded from the family's blood and all exons of the XLRS1 gene were amplified by polymerase chain reaction and analyzed using a direct sequencing method. Results A novel Leu103Phe missense mutation was identified. Conclusions A novel Leu103Phe mutation is an additional missense mutation which is responsible for the pathogenesis of X-linked retinoschisis. PMID:16768192

Structural asymmetry and intersubunit communication in muscle creatine kinase.

PubMed

Ohren, Jeffrey F; Kundracik, Melisa L; Borders, Charles L; Edmiston, Paul; Viola, Ronald E

2007-03-01

The structure of a transition-state analog complex of a highly soluble mutant (R134K) of rabbit muscle creatine kinase (rmCK) has been determined to 1.65 A resolution in order to elucidate the structural changes that are required to support and regulate catalysis. Significant structural asymmetry is seen within the functional homodimer of rmCK, with one monomer found in a closed conformation with the active site occupied by the transition-state analog components creatine, MgADP and nitrate. The other monomer has the two loops that control access to the active site in an open conformation and only MgADP is bound. The N-terminal region of each monomer makes a substantial contribution to the dimer interface; however, the conformation of this region is dramatically different in each subunit. Based on this structural evidence, two mutational modifications of rmCK were conducted in order to better understand the role of the amino-terminus in controlling creatine kinase activity. The deletion of the first 15 residues of rmCK and a single point mutant (P20G) both disrupt subunit cohesion, causing the dissociation of the functional homodimer into monomers with reduced catalytic activity. This study provides support for a structural role for the amino-terminus in subunit association and a mechanistic role in active-site communication and catalytic regulation.

Creatine and creatinine contents in different diet types for dogs - effects of source and processing.

PubMed

Dobenecker, B; Braun, U

2015-12-01

The concentrations of creatine and its degradation product creatinine were determined in a variety of unprocessed as well as processed feedstuffs suitable for dogs. Unprocessed feedstuffs were categorised as single feedstuffs, bone and raw food diets (BARF), and small vertebrates, for example prey animals. Processed feedstuffs were categorised as meat/meat and bone meals, complete wet diets and complete dry diets. The feedstuffs were chosen to cover a broad range of each of the three defined processed and unprocessed feed categories available on the market without further subclustering. The creatine content of the samples was compared on a dry matter, protein and energy basis. The relation of creatine to crude protein permitted a rating of the meat quality in terms of muscle tissue. We found no difference in creatine concentrations between the three categories of unprocessed feedstuffs (raw single feedstuffs, prey and BARF diets), neither on a dry matter basis nor when expressed relative to crude protein and metabolisable energy respectively. Significantly lower levels were determined in meat/meat and bone meal and commercial dry diets (e.g. 303 mg creatine/MJ ME in unprocessed vs. 6 mg/MJ ME in processed feedstuffs; p < 0.001). We conclude that in relation to ME, the exclusive use of conventionally processed diets for dogs, especially dry diets, leads to considerably lower intake of creatine which is a natural compound of the diet of this carnivorous and omnivorous species. © 2015 The Authors. Journal of Animal Physiology and Animal Nutrition Published by Blackwell Verlag GmbH.

X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.

PubMed Central

Bichet, D G; Arthus, M F; Lonergan, M; Hendy, G N; Paradis, A J; Fujiwara, T M; Morgan, K; Gregory, M C; Rosenthal, W; Didwania, A

1993-01-01

In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene. Images PMID:8104196

Burosumab Therapy in Children with X-Linked Hypophosphatemia.

PubMed

Carpenter, Thomas O; Whyte, Michael P; Imel, Erik A; Boot, Annemieke M; Högler, Wolfgang; Linglart, Agnès; Padidela, Raja; Van't Hoff, William; Mao, Meng; Chen, Chao-Yin; Skrinar, Alison; Kakkis, Emil; San Martin, Javier; Portale, Anthony A

2018-05-24

X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both

The forensic value of X-linked markers in mixed-male DNA analysis.

PubMed

He, HaiJun; Zha, Lagabaiyila; Cai, JinHong; Huang, Jian

2018-05-04

Autosomal genetic markers and Y chromosome markers have been widely applied in analysis of mixed stains at crime scenes by forensic scientists. However, true genotype combinations are often difficult to distinguish using autosomal markers when similar amounts of DNA are contributed by multiple donors. In addition, specific individuals cannot be determined by Y chromosomal markers because male relatives share the same Y chromosome. X-linked markers, possessing characteristics somewhere intermediate between autosomes and the Y chromosome, are less universally applied in criminal casework. In this paper, X markers are proposed to apply to male mixtures because their true genes can be more easily and accurately recognized than the decision of the genotypes of AS markers. In this study, an actual two-man mixed stain from a forensic case file and simulated male-mixed DNA were examined simultaneously with the X markers and autosomal markers. Finally, the actual mixture was separated successfully by the X markers, although it was unresolved by AS-STRs, and the separation ratio of the simulated mixture was much higher using Chr X tools than with AS methods. We believe X-linked markers provide significant advantages in individual discrimination of male mixtures that should be further applied to forensic work.

Variation in the X-Linked EFHC2 Gene Is Associated with Social Cognitive Abilities in Males

PubMed Central

Startin, Carla M.; Fiorentini, Chiara; de Haan, Michelle; Skuse, David H.

2015-01-01

Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males. PMID:26107779

Three-step preparation and purification of phosphorus-33-labeled creatine phosphate of high specific activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Savabi, F.; Geiger, P.J.; Bessman, S.P.

1984-03-01

Rabbit heart mitochondria were used as a source of enzymes for the synthesis of phosphorus-labeled creatine phosphate. This method is based on the coupled reaction between mitochondrial oxidative phosphorylation and mitochondrial-bound creatine kinase. It is possible to convert more than 90% of the inorganic phosphate (P/sub i/) to creatine phosphate. The method used only small amounts of adenine nucleotides which led to a product with only slight nucleotide contamination. This could be removed by activated charcoal extraction. For further purification, a method for the removal of residual P/sub i/ is described. 20 references.

A family with X-linked optic atrophy linked to the OPA2 locus Xp11.4-Xp11.2.

PubMed

Katz, Bradley J; Zhao, Yu; Warner, Judith E A; Tong, Zongzhong; Yang, Zhenglin; Zhang, Kang

2006-10-15

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic atrophy. Clinical features of ADOA include a slowly progressive bilateral loss of visual acuity, constriction of peripheral visual fields, central scotomas, and color vision abnormalities. Although ADOA is the most commonly inherited optic atrophy, autosomal recessive, X-linked, mitochondrial, and sporadic forms have also been reported. Four families with X-linked optic atrophy (XLOA) were previously described. One family was subsequently linked to Xp11.4-Xp11.2 (OPA2). This investigation studied one multi-generation family with an apparently X-linked form of optic atrophy and compared their clinical characteristics with those of the previously described families, and determined whether this family was linked to the same genetic locus. Fifteen individuals in a three-generation Idaho family underwent complete eye examination, color vision testing, automated perimetry, and fundus photography. Polymorphic markers were used to genotype each individual and to determine linkage. Visual acuities ranged from 20/30 to 20/100. All affected subjects had significant optic nerve pallor. Obligate female carriers were clinically unaffected. Preliminary linkage analysis (LOD score = 1.8) revealed that the disease gene localized to the OPA2 locus on Xp11.4-Xp11.2. Four forms of inherited optic neuropathy, ADOA, autosomal recessive optic atrophy (Costeff Syndrome), Leber hereditary optic neuropathy, and Charcot-Marie-Tooth disease with optic atrophy, are associated with mitochondrial dysfunction. Future identification of the XLOA gene will reveal whether this form of optic atrophy is also associated with a mitochondrial defect. Identification of the XLOA gene will advance our understanding of the inherited optic neuropathies and perhaps suggest treatments for these diseases. An improved understanding of inherited optic neuropathies may in turn advance our understanding of acquired optic nerve diseases, such

The effects of creatine pyruvate and creatine citrate on performance during high intensity exercise

PubMed Central

Jäger, Ralf; Metzger, Jan; Lautmann, Karin; Shushakov, Vladimir; Purpura, Martin; Geiss, Kurt-Reiner; Maassen, Norbert

2008-01-01

Background A double-blind, placebo-controlled, randomized study was performed to evaluate the effect of oral creatine pyruvate (Cr-Pyr) and creatine citrate (Cr-Cit) supplementation on exercise performance in healthy young athletes. Methods Performance during intermittent handgrip exercise of maximal intensity was evaluated before (pretest) and after (posttest) 28 days of Cr-Pyr (5 g/d, n = 16), Cr-Cit (5 g/d, n = 16) or placebo (pla, 5 g/d, n = 17) intake. Subjects performed ten 15-sec exercise intervals, each followed by 45 sec rest periods. Results Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) significantly increased mean power over all intervals. Cr-Cit increased force during the first and second interval (p < 0.01) compared to placebo. The effect of Cr-Cit on force decreased over time and the improvement was not significant at the sixth and ninth interval, whereas Cr-Pyr significantly increased force during all intervals (p < 0.001). Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) resulted in an increase in contraction velocity, whereas only Cr-Pyr intake significantly (p < 0.01) increased relaxation velocity. Oxygen consumption measured during rest periods significantly increased with Cr-Pyr (p < 0.05), whereas Cr-Cit and placebo intake did not result in significant improvements. Conclusion It is concluded that four weeks of Cr-Pyr and Cr-Cit intake significantly improves performance during intermittent handgrip exercise of maximal intensity and that Cr-Pyr might benefit endurance, due to enhanced activity of the aerobic metabolism. PMID:18269769

Application of carrier testing to genetic counseling for X-linked agammaglobulinemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allen, R.C.; Nachtman, R.G.; Belmont, J.W.

Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19[sup +] peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLAmore » demonstrated >95% skewing of X inactivation in peripheral blood CD19[sup +] cells but not in CD19[sup [minus

Creatine Loading, Resistance Exercise Performance, and Muscle Mechanics.

ERIC Educational Resources Information Center

Stevenson, Scott W.; Dudley, Gary A.

2001-01-01

Examined whether creatine (CR) monohydrate loading would alter resistance exercise performance, isometric strength, or in vivo contractile properties of the quadriceps femoris muscle compared with placebo loading in resistance-trained athletes. Overall, CR loading did not provide an ergogenic benefit for the unilateral dynamic knee extension…

Meiotic drive impacts expression and evolution of x-linked genes in stalk-eyed flies.

PubMed

Reinhardt, Josephine A; Brand, Cara L; Paczolt, Kimberly A; Johns, Philip M; Baker, Richard H; Wilkinson, Gerald S

2014-01-01

Although sex chromosome meiotic drive has been observed in a variety of species for over 50 years, the genes causing drive are only known in a few cases, and none of these cases cause distorted sex-ratios in nature. In stalk-eyed flies (Teleopsis dalmanni), driving X chromosomes are commonly found at frequencies approaching 30% in the wild, but the genetic basis of drive has remained elusive due to reduced recombination between driving and non-driving X chromosomes. Here, we used RNAseq to identify transcripts that are differentially expressed between males carrying either a driving X (XSR) or a standard X chromosome (XST), and found hundreds of these, the majority of which are X-linked. Drive-associated transcripts show increased levels of sequence divergence (dN/dS) compared to a control set, and are predominantly expressed either in testes or in the gonads of both sexes. Finally, we confirmed that XSR and XST are highly divergent by estimating sequence differentiation between the RNAseq pools. We found that X-linked transcripts were often strongly differentiated (whereas most autosomal transcripts were not), supporting the presence of a relatively large region of recombination suppression on XSR presumably caused by one or more inversions. We have identified a group of genes that are good candidates for further study into the causes and consequences of sex-chromosome drive, and demonstrated that meiotic drive has had a profound effect on sequence evolution and gene expression of X-linked genes in this species.

Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome?

PubMed Central

Jonsson, J J; Renieri, A; Gallagher, P G; Kashtan, C E; Cherniske, E M; Bruttini, M; Piccini, M; Vitelli, F; Ballabio, A; Pober, B R

1998-01-01

We describe a family with four members, a mother, two sons, and a daughter, who show clinical features consistent with X linked Alport syndrome. The two males presented with additional features including mental retardation, dysmorphic facies with marked midface hypoplasia, and elliptocytosis. The elliptocytosis was not associated with any detectable abnormalities in red cell membrane proteins; red cell membrane stability and rigidity was normal on ektacytometry. Molecular characterisation suggests a submicroscopic X chromosome deletion encompassing the entire COL4A5 gene. We propose that the additional abnormalities found in the affected males of this family are attributable to deletion or disruption of X linked recessive genes adjacent to the COL4A5 gene and that this constellation of findings may represent a new X linked contiguous gene deletion syndrome. Images PMID:9598718

Creatine pretreatment prevents birth asphyxia-induced injury of the newborn spiny mouse kidney.

PubMed

Ellery, Stacey J; Ireland, Zoe; Kett, Michelle M; Snow, Rod; Walker, David W; Dickinson, Hayley

2013-02-01

Acute kidney injury (AKI) is a major complication for infants following an asphyxic insult at birth. We aimed to determine if kidney structure and function were affected in an animal model of birth asphyxia and if maternal dietary creatine supplementation could provide an energy reserve to the fetal kidney, maintaining cellular respiration during asphyxia and preventing AKI. Pregnant spiny mice were maintained on normal chow or chow supplemented with creatine from day 20 gestation. On day 38 (term ~39 d), pups were delivered by cesarean section (c-section) or subjected to intrauterine asphyxia. Twenty-four hours after insult, kidneys were collected for histological or molecular analysis. Urine and plasma were also collected for biochemical analysis. AKI was evident at 24 h after birth asphyxia, with a higher incidence of shrunken glomeruli (P < 0.02), disturbance to tubular arrangement, tubular dilatation, a twofold increase (P < 0.02) in expression of Ngal (early marker of kidney injury), and decreased expression of the podocyte differentiation marker nephrin. Maternal creatine supplementation prevented the glomerular and tubular abnormalities observed in the kidney at 24 h and the increased expression of Ngal. Maternal creatine supplementation may prove useful in ameliorating kidney injury associated with birth asphyxia.

Creatine supplementation and physical training in patients with COPD: A double blind, placebo-controlled study

PubMed Central

Faager, Gun; Söderlund, Karin; Sköld, Carl Magnus; Rundgren, Siw; Tollbäck, Anna; Jakobsson, Per

2006-01-01

Study objectives Patients with chronic obstructive pulmonary disease (COPD) have low exercise capacity and low content of high energetic phosphates in their skeletal muscles. The aim of the present study was to investigate whether creatine supplementation together with exercise training may increase physical performance compared with exercise training in patients with COPD. Design In a randomized, double-blind, placebo-controlled study, 23 patients with COPD (forced expiratory volume in one second [FEV1] < 70% of predicted) were randomized to oral creatine (n = 13) or placebo (n = 10) supplementation during an 8-week rehabilitation programme including exercise training. Physical performance was assessed by Endurance Shuttle Walking Test (ESWT), dyspnea and leg fatigue with Borg CR-10, quality of life with St George’s Respiratory Questionnaire (SGRQ). In addition, lung function test, artery blood gases, grip strength test, muscle strength and fatigue in knee extensors were measured. Results COPD patients receiving creatine supplementation increased their average walking time by 61% (ESWT) (p < 0.05) after the training period compared with 48% (p = 0.07) in the placebo group. Rated dyspnea directly after the ESWT decreased significantly from 7 to 5 (p < 0.05) in the creatine group. However, the difference between the groups was not statistically significant neither in walking time nor in rated dyspnea. Creatine supplementation did not increase the health related quality of life, lung function, artery blood gases, grip strength and knee extensor strength/fatigue. Conclusions Oral creatine supplementation in combination with exercise training showed no significant improvement in physical performance, measured as ESWT, in patients with COPD compared with exercise training alone. PMID:18044100

Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

PubMed

Russell-Eggitt, I M

2000-12-01

When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR.

PubMed

Riveiro-Alvarez, Rosa; Trujillo-Tiebas, Maria José; Gimenez-Pardo, Ascension; Garcia-Hoyos, Maria; Cantalapiedra, Diego; Lorda-Sanchez, Isabel; Rodriguez de Alba, Marta; Ramos, Carmen; Ayuso, Carmen

2005-09-02

Norrie disease (OMIM 310600) is a rare X-linked disorder characterized by congenital blindness in males. Approximately 40 to 50% of the cases develop deafness and mental retardation. X-linked familial exudative vitreoretinopathy (XL-FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Both X-linked disorders are due to mutations in the NDP gene, which encodes a 133 amino acid protein called Norrin, but autosomal recessive (AR) and autosomal dominant (AD) forms of FEVR have also been described. In this study, we report the molecular findings and the related phenotype in five Spanish families affected with Norrie disease or XL-FEVR due to mutations of the NDP gene. The study was conducted in 45 subjects from five Spanish families. These families were clinically diagnosed with Norrie disease or similar conditions. The three exons of the NDP gene were analyzed by automatic DNA sequencing. Haplotype analyses were also performed. Two new nonsense mutations, apart from other mutations previously described in the NDP gene, were found in those patients affected with ND or X-linked FEVR. An important genotype-phenotype variation was found in relation to the different mutations of the NDP gene. In fact, the same mutation may be responsible for different phenotypes. We speculate that there might be other molecular factors that interact in the retina with Norrin, which contribute to the resultant phenotypes.

Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aldred, M.A.; Dry, K.L.; Hardwick, L.J.

1994-11-01

A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538more » and 5{prime}-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. 33 refs., 2 figs., 2 tabs.« less

[Chemical Exchange Saturation Transfer Imaging of Creatine Metabolites: a 3.0 T MRI Pilot].

PubMed

Guo, Ying-kun; Li, Zhen-lin; Rong, Yu; Xia, Chun-chao; Zhang, Li-zhi; Peng, Wan-ling; Liu, Xi; Xu, Hua-yan; Zhang, Ti-jiang; Zuo, Pan-li; Schmitt, Benjamin

2016-03-01

To determine the feasibility of using chemical exchange saturation transfer (CEST) imaging to measure creatine (Cr) metabolites with 3.0 T MR. Phantoms containing different concentrations of Cr under various pH conditions were studied with CEST sequence on 3.0 T MR imaging. CEST effect and Z spectra were analyzed. Cr exhibited significant CEST effect (± 1.8 ppm, F = 99.08, P < 0.001) on 3.0 T MR imaging, and positive correlation was found between the signal intensity and concentration of Cr (r = 0.963, P < 0.001). The CEST effect showed pH dependency of Cr (r = 0.41, P = 0.035). Creatine CEST imaging can be performed on 3.0 T MR imaging. Creatine concentrations and pH influence CEST effect.

Efficacy and safety of creatine supplementation in juvenile dermatomyositis: A randomized, double-blind, placebo-controlled crossover trial.

PubMed

Solis, Marina Yazigi; Hayashi, Ana Paula; Artioli, Guilherme Giannini; Roschel, Hamilton; Sapienza, Marcelo Tatit; Otaduy, Maria Concepción; De Sã Pinto, Ana Lucia; Silva, Clovis Artur; Sallum, Adriana Maluf Elias; Pereira, Rosa Maria R; Gualano, Bruno

2016-01-01

It has been suggested that creatine supplementation is safe and effective for treating idiopathic inflammatory myopathies, but no pediatric study has been conducted to date. The objective of this study was to examine the efficacy and safety of creatine supplementation in juvenile dermatomyositis (JDM) patients. In this study, JDM patients received placebo or creatine supplementation (0.1 g/kg/day) in a randomized, crossover, double-blind design. Subjects were assessed at baseline and after 12 weeks. The primary outcome was muscle function. Secondary outcomes included body composition, aerobic conditioning, health-related quality of life, and muscle phosphocreatine (PCr) content. Safety was assessed by laboratory parameters and kidney function measurements. Creatine supplementation did not affect muscle function, intramuscular PCr content, or any other secondary outcome. Kidney function was not affected, and no side effects were reported. Twelve weeks of creatine supplementation in JDM patients were well-tolerated and free of adverse effects, but treatment did not affect muscle function, intramuscular PCr, or any other parameter. © 2015 Wiley Periodicals, Inc.

[Prenatal diagnosis of X-linked anhidrotic ectodermal dysplasia with X-chromosome inversion].

PubMed

Shi, Hui-juan; Fang, Qun; Wang, Lian-tang

2005-07-13

To investigate the possibility of prenatal diagnosis of the fetal suspected to be affected by anhidrotic ectodermal dysplasia (EDA) in a family with X-linked EDA so as to provide a basis for prenatal diagnosis and genetic counseling of this disorder. Pedigree analysis and genetic counseling were performed in a family after a proband was diagnosed with EDA. The peripheral blood samples were collected from the proband, a 12-year-old boy, his mother, and his 2 aunts, one being pregnant, to undergo chromosome karyotype analysis. The fetus Puncture of umbilical vein was performed to collect the blood of fetus for chromosome examination. Induced abortion was conducted due to the diagnosis of the fetus with EDA. Autopsy, immunohistochemistry of the skin tissues of face, breast, epigastrium, and thigh, and X-ray photography of the lower jawbone were made. Pericentric inversion occurring at one of the X-chromosome [inv (x) (p22q13)] was found in the proband and his nephew (the fetus), both patients, and his mother and his second aunt (the pregnant woman), both carriers. Autopsy of the fetus showed epidermis dysplasia and deficiency of hair follicle and sebaceous gland. Immunohistochemistry showed that epithelial membrane antigen and cytokeratin were negatively expressed in the fetal skin tissues. Pedigree analysis and genetic counseling for the family members of EDA patients and prenatal and postpartum examination for the fetus help diagnose EDA.

A Complex Genetic Basis to X-Linked Hybrid Male Sterility Between Two Species of House Mice

PubMed Central

Good, Jeffrey M.; Dean, Matthew D.; Nachman, Michael W.

2008-01-01

The X chromosome plays a central role in the evolution of reproductive isolation, but few studies have examined the genetic basis of X-linked incompatibilities during the early stages of speciation. We report the results of a large experiment focused on the reciprocal introgression of the X chromosome between two species of house mice, Mus musculus and M. domesticus. Introgression of the M. musculus X chromosome into a wild-derived M. domesticus genetic background produced male-limited sterility, qualitatively consistent with previous experiments using classic inbred strains to represent M. domesticus. The genetic basis of sterility involved a minimum of four X-linked factors. The phenotypic effects of major sterility QTL were largely additive and resulted in complete sterility when combined. No sterility factors were uncovered on the M. domesticus X chromosome. Overall, these results revealed a complex and asymmetric genetic basis to X-linked hybrid male sterility during the early stages of speciation in mice. Combined with data from previous studies, we identify one relatively narrow interval on the M. musculus X chromosome involved in hybrid male sterility. Only a handful of spermatogenic genes are within this region, including one of the most rapidly evolving genes on the mouse X chromosome. PMID:18689897

A complex genetic basis to X-linked hybrid male sterility between two species of house mice.

PubMed

Good, Jeffrey M; Dean, Matthew D; Nachman, Michael W

2008-08-01

The X chromosome plays a central role in the evolution of reproductive isolation, but few studies have examined the genetic basis of X-linked incompatibilities during the early stages of speciation. We report the results of a large experiment focused on the reciprocal introgression of the X chromosome between two species of house mice, Mus musculus and M. domesticus. Introgression of the M. musculus X chromosome into a wild-derived M. domesticus genetic background produced male-limited sterility, qualitatively consistent with previous experiments using classic inbred strains to represent M. domesticus. The genetic basis of sterility involved a minimum of four X-linked factors. The phenotypic effects of major sterility QTL were largely additive and resulted in complete sterility when combined. No sterility factors were uncovered on the M. domesticus X chromosome. Overall, these results revealed a complex and asymmetric genetic basis to X-linked hybrid male sterility during the early stages of speciation in mice. Combined with data from previous studies, we identify one relatively narrow interval on the M. musculus X chromosome involved in hybrid male sterility. Only a handful of spermatogenic genes are within this region, including one of the most rapidly evolving genes on the mouse X chromosome.

Localisation of the gene for X-linked reticulate pigmentary disorder with systemic manifestations (PDR), previously known as X-linked cutaneous amyloidosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gedeon, A.K.; Mulley, J.C.; Kozman, H.

1994-08-01

X-linked reticulate pigmentary disorder (PDR), previously reported as X-linked cutaneous amyloidosis (MIM No. 301220), is characterized by brown pigmentation of the skin which follows the lines of Blaschko in females but appears as reticulate sheets in males. Males may suffer severe gastrointestinal disorders in infancy with failure to thrive and early death. Nowadays symptomatic treatment allows survival and other manifestations may appear such as corneal dystrophy with severe photophobia or chronic respiratory disease. Amyloid deposition in the skin may be no more than an age-dependent secondary manifestation. The PDR gene was localized by linkage analysis to Xp21-p22. The background geneticmore » map is Xpter-DXS996-22.5-DXS207-3.3-DXS999-3.3-DXS365-14.2-DXS989-4.1-3`DMD-3.5-DXS997-1.0-STR44-9.3-DYSI-2.3-DXS1068-11.0-DXS228 with distances between markers given in cM. Recombinants detected with DXS999 distally and DXS228 proximally, define the limits to the localization. Linkage was found with several markers within this interval. Peak lod scores of 3.21 at {theta} = 0.0 were obtained between PDR and DXS989 and between PDR and 5`DYSI within the dystrophin locus. 29 refs., 2 figs., 2 tabs.« less

Characterization of Primary Carrier Transport Properties of the Light-Harvesting Chalcopyrite Semiconductors CuIn(S 1–xSe x) 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frick, Jessica J.; Kushwaha, Satya K.; Cava, Robert J.

We report the carrier transport properties of CuIn(S 1-xSe x) 2 (0 ≤ x ≤ 1), a promising chalcopyrite semiconductor series for solar water splitting. A low concentration Mg dopant is used to decrease the carrier resistivity through facilitating bulk p-type transport at ambient temperature. Temperature-dependent resistivity measurements reveal a four-order magnitude decrease in bulk electrical resistivity (from 10 3 to 10 –1 Ohm cm) for 1% Mg-doped CuIn(S 1–xSe x) 2 as x increases from 0 to 1. Hall effect measurements at room temperature reveal p-type majority carrier concentrations that vary from 10 15 to 10 18 cm –3more » and mobilities of approximately 1–10 cm 2 V –1 s –1. These results provide insights into the fundamental carrier transport properties of CuIn(S 1–xSe x) 2 and will be of value in optimizing these materials further for photoelectrochemistry applications.« less

Characterization of Primary Carrier Transport Properties of the Light-Harvesting Chalcopyrite Semiconductors CuIn(S 1–xSe x) 2

DOE PAGES

Frick, Jessica J.; Kushwaha, Satya K.; Cava, Robert J.; ...

2017-07-27

We report the carrier transport properties of CuIn(S 1-xSe x) 2 (0 ≤ x ≤ 1), a promising chalcopyrite semiconductor series for solar water splitting. A low concentration Mg dopant is used to decrease the carrier resistivity through facilitating bulk p-type transport at ambient temperature. Temperature-dependent resistivity measurements reveal a four-order magnitude decrease in bulk electrical resistivity (from 10 3 to 10 –1 Ohm cm) for 1% Mg-doped CuIn(S 1–xSe x) 2 as x increases from 0 to 1. Hall effect measurements at room temperature reveal p-type majority carrier concentrations that vary from 10 15 to 10 18 cm –3more » and mobilities of approximately 1–10 cm 2 V –1 s –1. These results provide insights into the fundamental carrier transport properties of CuIn(S 1–xSe x) 2 and will be of value in optimizing these materials further for photoelectrochemistry applications.« less

MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome

PubMed Central

Siew, Wei-Hong; Tan, Kai-Leng; Babaei, Maryam Abbaspour; Cheah, Pike-See; Ling, King-Hwa

2013-01-01

Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)]. PMID:23596395

Effects of creatine supplementation associated with resistance training on oxidative stress in different tissues of rats

PubMed Central

2014-01-01

Background Creatine supplementation is known to exert an effect by increasing strength in high intensity and short duration exercises. There is a hypothesis which suggests that creatine supplementation may provide antioxidant activity by scavenging Reactive Oxygen Species. However, the antioxidant effect of creatine supplementation associated with resistance training has not yet been described in the literature. Therefore, we investigated the effect of creatine monohydrate supplementation associated with resistance training over maximum strength gain and oxidative stress in rats. Methods Forty male Wistar rats (250-300 g, 90 days old) were randomly allocated into 4 groups: Sedentary (SED, n = 10), Sedentary + Creatine (SED-Cr, n = 10), Resistance Training (RT, n = 10) and Resistance Training + Creatine (RT-Cr, n = 10). Trained animals were submitted to the RT protocol (4 series of 10–12 repetitions, 90 second interval, 4 times per week, 65% to 75% of 1MR, for 8 weeks). Results In this study, greater strength gain was observed in the SED-Cr, RT and RT-Cr groups compared to the SED group (P < 0.001). The RT-Cr group showed a higher maximum strength gain when compared to other groups (P < 0.001). Creatine supplementation associated with resistance training was able to reduce lipoperoxidation in the plasma (P < 0.05), the heart (P < 0.05), the liver (P < 0.05) and the gastrocnemius (P < 0.05) when compared to control groups. However, the supplementation had no influence on catalase activity (CAT) in the analyzed organs. Only in the heart was the CAT activity higher in the RT-Cr group (P < 0.05). The activity of superoxide dismutase (SOD) was lower in all of the analyzed organs in the SED-Cr group (P < 0.05), while SOD activity was lower in the trained group and sedentary supplemented group (P < 0.05). Conclusions Creatine was shown to be an effective non-enzymatic antioxidant with supplementation alone

[Characteristics of specifications of transportable inverter-type X-ray equipment].

PubMed

Yamamoto, Keiichi; Miyazaki, Shigeru; Asano, Hiroshi; Shinohara, Fuminori; Ishikawa, Mitsuo; Ide, Toshinori; Abe, Shinji; Negishi, Toru; Miyake, Hiroyuki; Imai, Yoshio; Okuaki, Tomoyuki

2003-07-01

Our X-ray systems study group measured and examined the characteristics of four transportable inverter-type X-ray equipments. X-ray tube voltage and X-ray tube current were measured with the X-ray tube voltage and the X-ray tube current measurement terminals provided with the equipment. X-ray tube voltage, irradiation time, and dose were measured with a non-invasive X-ray tube voltage-measuring device, and X-ray output was measured by fluorescence meter. The items investigated were the reproducibility and linearity of X-ray output, error of pre-set X-ray tube voltage and X-ray tube current, and X-ray tube voltage ripple percentage. The waveforms of X-ray tube voltage, the X-ray tube current, and fluorescence intensity draw were analyzed using the oscilloscope gram and a personal computer. All of the equipment had a preset error of X-ray tube voltage and X-ray tube current that met JIS standards. The X-ray tube voltage ripple percentage of each equipment conformed to the tendency to decrease when X-ray tube voltage increased. Although the X-ray output reproducibility of system A exceeded the JIS standard, the other systems were within the JIS standard. Equipment A required 40 ms for X-ray tube current to reach the target value, and there was some X-ray output loss because of a trough in X-ray tube current. Owing to the influence of the ripple in X-ray tube current, the strength of the fluorescence waveform rippled in equipments B and C. Waveform analysis could not be done by aliasing of the recording device in equipment D. The maximum X-ray tube current of transportable inverter-type X-ray equipment is as low as 10-20 mA, and the irradiation time of chest X-ray photography exceeds 0.1 sec. However, improvement of the radiophotographic technique is required for patients who cannot move their bodies or halt respiration. It is necessary to make the irradiation time of the equipments shorter for remote medical treatment.

Investigation of cross-linking characteristics of novel hole-transporting materials for solution-processed phosphorescent OLEDs

NASA Astrophysics Data System (ADS)

Lee, Jaemin; Ameen, Shahid; Lee, Changjin

2016-04-01

After the success of commercialization of the vacuum-evaporated organic light-emitting diodes (OLEDs), solutionprocessing or printing of OLEDs are currently attracting much research interests. However, contrary to various kinds of readily available vacuum-evaporable OLED materials, the solution-processable OLED materials are still relatively rare. Hole-transporting layer (HTL) materials for solution-processed OLEDs are especially limited, because they need additional characteristics such as cross-linking to realize multilayer structures in solution-processed OLEDs, as well as their own electrically hole-transporting characteristics. The presence of such cross-linking characteristics of solutionprocessable HTL materials therefore makes them more challenging in the development stage, and also makes them essence of solution-processable OLED materials. In this work, the structure-property relationships of thermally crosslinkable HTL materials were systematically investigated by changing styrene-based cross-linking functionalities and modifying the carbazole-based hole-transporting core structures. The temperature dependency of the cross-linking characteristics of the HTL materials was systematically investigated by the UV-vis. absorption spectroscopy. The new HTL materials were also applied to green phosphorescent OLEDs, and their device characteristics were also investigated based on the chemical structures of the HTL materials. The device configuration was [ITO / PEDOT:PSS / HTL / EML / ETL / CsF / Al]. We found out that the chemical structures of the cross-linking functionalities greatly affect not only the cross-linking characteristics of the resultant HTL materials, but also the resultant OLED device characteristics. The increase of the maximum luminance and efficiency of OLEDs was evident as the cross-linking temperature decreases from higher than 200°C to at around 150°C.

Creatine and creatinine evolution during the processing of dry-cured ham.

PubMed

Mora, Leticia; Hernández-Cázares, Aleida S; Sentandreu, Miguel Angel; Toldrá, Fidel

2010-03-01

Dry-curing of ham involves many biochemical reactions that depend on the processing conditions. The aim of this study was to evaluate the effect of the dry-cured processing on the concentration of creatine, creatinine and the creatinine/creatine ratio. Dry-cured hams under study were salted using three different salt mixtures (100% NaCl; NaCl and KCl at 50% each; and 55% NaCl, 25% KCl, 15% CaCl(2) and 5% MgCl(2)) in order to observe its influence on creatinine formation but no significant differences were found between them at any time of processing. However, significant differences between different post-salting times (20, 50 and 80 days) and the ripened hams (7, 9 and 11 months of ripening) were observed. Results showed that creatine and creatinine remain stable once the ripening period is reached. These results were confirmed when analysing dry-cured ham samples submitted to extreme conditions of temperature and time (20, 30, 40 and 70 degrees C during 0, 20, 40 and 60 min) as well as commercial dry-cured hams with more than 12 months of processing. Copyright 2009 Elsevier Ltd. All rights reserved.

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

PubMed Central

Fenouille, Nina; Bassil, Christopher F.; Ben-Sahra, Issam; Benajiba, Lina; Alexe, Gabriela; Ramos, Azucena; Pikman, Yana; Conway, Amy S.; Burgess, Michael R.; Li, Qing; Luciano, Frédéric; Auberger, Patrick; Galinsky, Ilene; DeAngelo, Daniel J.; Stone, Richard M.; Zhang, Yi; Perkins, Archibald S.; Shannon, Kevin; Hemann, Michael T.; Puissant, Alexandre; Stegmaier, Kimberly

2017-01-01

Expression of the EVI1 proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A pooled shRNA screen identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as a metabolic dependency in EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted cell cycle arrest and apoptosis of human EVI1-positive AML cells, and prolonged survival in human orthotopic and mouse primary AML models. CKMT1 inhibition alters mitochondrial respiration and ATP production, an effect that is abrogated by phospho-creatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens. PMID:28191887

Transport and magnetic properties of disordered Li xV yO 2 ( x=0.8 and y=0.8)

NASA Astrophysics Data System (ADS)

Du, Fei; Li, Ang; Liu, Daliang; Zhan, Shiying; Hu, Fang; Wang, Chunzhong; Chen, Yan; Feng, Shouhua; Chen, Gang

2009-07-01

The magnetic and electron transport properties of rhombohedral Li xV yO 2 ( x=0.8 and y=0.8) are studied. The dc susceptibility of Li xV yO 2 can be well fitted to the modified Curie-Weiss law, which verified the paramagnetic ground state. The magnetic hysteresis and ac susceptibility also confirm this paramagnetism. The Li xV yO 2 exhibits semiconducting behavior, which is explained by thermal activated process at high temperature and variable-range hopping mechanism at low temperature. Anderson localization plays an important role in both the electron transport behavior and the magnetic behavior due to the site disorder between the Li + ion and V 4+ ion.

[Clinical and molecular study in a child with X-linked hypohidrotic ectodermal dysplasia].

PubMed

Callea, Michele; Yavuz, Izzet; Clarich, Gabriella; Cammarata-Scalisi, Francisco

2015-12-01

Ectodermal dysplasia encompasses more than 200 clinically distinct entities, which affect at least two structures derived from the ectoderm, including the skin, hair, nails, teeth, sweat glands, and sebaceous glands. X-linked hypohidrotic ectodermal dysplasia is the most common type and is caused by mutation of the EDA gene that encodes Ectodysplasin-A. It occurs in less than 1 in 100 000 individuals and is clinically characterized by hypodontia, hypohidrosis, hypotrichosis, and eye dis orders. We present a child evaluated in a multidisciplinary manner with clinical and molecular diagnosis of X-linked hypohidrotic ectodermal dysplasia with type missense mutation c.1133C> T; p.T378M in EDA gene.

Incubating Isolated Mouse EDL Muscles with Creatine Improves Force Production and Twitch Kinetics in Fatigue Due to Reduction in Ionic Strength

PubMed Central

Head, Stewart I.; Greenaway, Bronwen; Chan, Stephen

2011-01-01

Background Creatine supplementation can improve performance during high intensity exercise in humans and improve muscle strength in certain myopathies. In this present study, we investigated the direct effects of acute creatine incubation on isolated mouse fast-twitch EDL muscles, and examined how these effects change with fatigue. Methods and Results The extensor digitorum longus muscle from mice aged 12–14 weeks was isolated and stimulated with field electrodes to measure force characteristics in 3 different states: (i) before fatigue; (ii) immediately after a fatigue protocol; and (iii) after recovery. These served as the control measurements for the muscle. The muscle was then incubated in a creatine solution and washed. The measurement of force characteristics in the 3 different states was then repeated. In un-fatigued muscle, creatine incubation increased the maximal tetanic force. In fatigued muscle, creatine treatment increased the force produced at all frequencies of stimulation. Incubation also increased the rate of twitch relaxation and twitch contraction in fatigued muscle. During repetitive fatiguing stimulation, creatine-treated muscles took 55.1±9.5% longer than control muscles to lose half of their original force. Measurement of weight changes showed that creatine incubation increased EDL muscle mass by 7%. Conclusion Acute creatine application improves force production in isolated fast-twitch EDL muscle, and these improvements are particularly apparent when the muscle is fatigued. One likely mechanism for this improvement is an increase in Ca2+ sensitivity of contractile proteins as a result of ionic strength decreases following creatine incubation. PMID:21850234

Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance Horan syndrome, on the mouse X chromosome.

PubMed

Stambolian, D; Favor, J; Silvers, W; Avner, P; Chapman, V; Zhou, E