1,721,062 research outputs found
Brain energy depletion caused by a diffuse head injury in rats is not ameliorated by the infusion of sodium lactate
No full textEarly onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy.
No full textMethylmalonic aciduria and homocystinuria, cblC type, is the most common inborn error of vitamin B(12) (cobalamin) metabolism. The recent cloning of the disease gene, MMACHC, has permitted genotype-phenotype correlation. In a 1-year-old girl, compound heterozygous c.271dupA and c.616C>T mutations in MMACHC were identified as causing an early onset methylmalonic aciduria and homocystinuria, cblC type, which was complicated by sensorimotor peripheral demyelinating neuropathy
Chromosomal 17p13.3 microdeletion unmasking recessive Canavan disease mutation
No full textUnmasking a recessive allele on one chromosome by a deletion on the other is a disease causing mechanism often invoked but rarely proven. We report on an Italian female patient with Canavan disease (OMIM# 271900) due to a missense mutation of the aspartoacylase (ASPA) gene and a 17p13.3 chromosomal microdeletion.
In the case described herein, Canavan disease was suspected for relative macrocephaly and developmental delay. HPLC analysis of body fluids [1] revealed an increased N-acetylaspartic acid (NAA) in both plasma (16.3 μmol/l; not detected in normal controls) and urine (680 μmol/mmol creatinine; 1.65 ± 1.50 μmol/mmol creatinine in normal controls), thereby confirming the diagnosis of Canavan disease. ASPA sequencing identified an apparently homozygous mutation (c.G859A) resulting in the substitution of alanine with threonine at the amino acid position 287 (p.A287T) which was previously reported in Canavan disease patients [2]. However, parental studies showed that only the mother was a carrier of the p.A287T. Therefore, a microdeletion affecting ASPA gene was suspected and a loss of copy number on 17p13.3 in both the proband and her father was detected by an Affymetrix Genome Wide Human SNP array 6.0 (Fig. 1A). The deletion was confirmed by real time quantitative PCR (qPCR) using primers within and flanking the deleted region (primer sequences are available upon request; Fig. 1B). The 74 Kb copy number loss encompasses nucleotide 3,324,311-to-3,398,497 and includes ASPA and TRPV3 genes (Fig. 1A). TRPV3 has not been so far associated to human diseases. A previous patient with large homozygous deletion involving ASPA and TRPV3 genes did not show additional clinical features to those commonly observed in Canavan patients [3].In summary, the patient described in this report illustrates that large deletions encompassing the ASPA gene should be considered in Canavan disease patients when mutations cannot be identified by direct gene sequencing. This information is important for accurate carrier testing and prenatal diagnosis. Therefore, high resolution SNP array and qPCR are valuable diagnostic tools for detection of chromosomal deletion unmasking recessive Canavan disease alleles
Response to Letter Regarding Article High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury
No full textIn his letter, Greyson questions whether enhanced myocardial blood flow rather than altered high-energy phosphate (HEP) metabolism reduced infarct size and better preserved ATP and ADP levels in hearts pretreated with folic acid (FA). He argues that by measuring relative rather than absolute flow reduction between remote and ischemic territories, we missed higher total flows to the heart in FA-pretreated animals despite similar relative flow reduction. However, this question presents a chicken-egg problem: Does FA primarily enhance flow to improve function and ischemic outcome, or is it the other way around? Although our flow analysis has limitations, and further studies with more comprehensive flow analysis would be useful, we believe our findings1 favor the latter hypothesis.
First, in isolated hearts in which coronary perfusion was constant, postischemic myocardial preservation was similar to that for the in vivo studies. Although HEP analysis was not performed in these hearts, the data indicate that relevant alternative mechanisms beyond coronary flow must exist. Second, systolic pressure during ischemia was 80 versus 100 mm Hg for FA-treated versus control rats, respectively. Both values fall in an autoregulating range for rats,2 so this difference would not necessarily result in a meaningful disparity of absolute flow and improved function. Although left ventricular end-diastolic pressure rose somewhat more in controls, potentially further reducing the transcoronary pressure gradient, this occurred in the first 10 minutes after occlusion, when function (dP/dtmax, stroke work, relaxation, etc) was similarly maintained in both groups
Concussion occurence and knowledge in Italian Football (soccer)
No full textThe purpose of the study was to investigate concussion history, knowledge, injury identification, and management strategies among athletes, coaches, and medical staff in Italian club level football (soccer) clubs. Surveys (N= 727) were distributed among Italian football clubs. Athletes' surveys were designed to evaluate athlete knowledge of concussive signs and symptoms and injury reporting. Coaches' surveys explored the understanding of concussive signs and symptoms and management practices. Medical staff surveys explored the standard of care regarding concussions. A total of 342 surveys were returned, for a 47% response rate. Descriptive analyses indicated 10% of athletes sustaining a concussion in the past year and 62% of these injuries were not reported, primarily due to the athletes not thinking the injury was serious enough. Coaches consistently identified non-concussion related symptoms (98.7%), but were unable to identify symptoms associated with concussion (38.9%). Most understood that loss of consciousness is not the sole indicator of injury (82.6%). Medical staff reported a heavy reliance on the clinical exam (92%) and athlete symptom reports (92%) to make the concussion diagnosis and return to play decision, with little use of neurocognitive (16.7%) or balance (0.0%) testing. Italian football athletes appear to report concussions at a rate similar to American football players, with a slightly higher rate of unreported injuries. Most of these athletes were aware they were concussed, but did not feel the injury was serious enough to report. Although coaches served as the primary person to whom concussions were reported, the majority of coaches were unable to accurately identify concussion related symptoms. With little use for neurocognitive and postural control assessments, the medical personnel may be missing injuries or returning athletes to play too soon. Collectively, these findings suggest that athletes, coaches, and medical personnel would benefit from concussion based educational materials on the signs, symptoms, and evaluative techniques of concussion
Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients.
No full textConcussive head injury opens a temporary window of brain vulnerability due to the impairment of cellular energetic metabolism. As experimentally demonstrated, a second mild injury occurring during this period can lead to severe brain damage, a condition clinically described as the second impact syndrome. To corroborate the validity of proton magnetic resonance spectroscopy in monitoring cerebral metabolic changes following mild traumatic brain injury, apart from the magnetic field strength (1.5 or 3.0 T) and mode of acquisition, we undertook a multicentre prospective study in which a cohort of 40 athletes suffering from concussion and a group of 30 control healthy subjects were admitted. Athletes (aged 16-35 years) were recruited and examined at three different institutions between September 2007 and June 2009. They underwent assessment of brain metabolism at 3, 15, 22 and 30 days post-injury through proton magnetic resonance spectroscopy for the determination of N-acetylaspartate, creatine and choline-containing compounds. Values of these representative brain metabolites were compared with those observed in the group of non-injured controls. Comparison of spectroscopic data, obtained in controls using different field strength and/or mode of acquisition, did not show any difference in the brain metabolite ratios. Athletes with concussion exhibited the most significant alteration of metabolite ratios at Day 3 post-injury (N-acetylaspartate/creatine: -17.6%, N-acetylaspartate/choline: -21.4%; P < 0.001 with respect to controls). On average, metabolic disturbance gradually recovered, initially in a slow fashion and, following Day 15, more rapidly. At 30 days post-injury, all athletes showed complete recovery, having metabolite ratios returned to values detected in controls. Athletes self-declared symptom clearance between 3 and 15 days after concussion. Results indicate that N-acetylaspartate determination by proton magnetic resonance spectroscopy represents a non-invasive tool to accurately measure changes in cerebral energy metabolism occurring in mild traumatic brain injury. In particular, this metabolic evaluation may significantly improve, along with other clinical assessments, the management of athletes suffering from concussion. Further studies to verify the effects of a second concussive event occurring at different time points of the recovery curve of brain metabolism are needed
Cobalt-Protoporphyrin Improves Heart Function by Blunting Oxidative Stress and Restoring NO Synthase Equilibrium in an Animal Model of Experimental Diabetes
Full text linkMyocardial dysfunction and coronary macro/microvascular alterations are the hallmarks of diabetic cardiomyopathy and are ascribed to increased oxidative stress and altered nitric oxide synthase (NOS) activity. We hypothesize that pre-treatment by cobalt-protoporphyrin IX (CoPP) ameliorates both myocardial function and coronary circulation in streptozotocin (STZ)-induced diabetic rats. Isolated hearts from diabetic rats in Langendorff configuration displayed lower left ventricular function and higher coronary resistance (CR) compared to hearts from control animals. CoPP treatment of diabetic animals (0.3 mg/100 g body weight i.p., once a week for 3 weeks) significantly increased all the contractile/relaxation indexes (p < 0.01), while decreasing CR (p < 0.01). CoPP enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the significant (p < 0.05) decrease in heart % GSSG, [Formula: see text] and malondialdehyde (MDA) levels. CoPP increased adiponectin levels and phosphorylation of AKT and AMPK and reversed the eNOS/iNOS expression imbalance observed in the untreated diabetic heart. Furthermore, after CoPP treatment, a rise in malonyl-CoA as well as a decrease in acetyl-CoA was observed in diabetic hearts. In this experimental model of diabetic cardiomyopathy, CoPP treatment improved both cardiac function and coronary flow by blunting oxidative stress, restoring eNOS/iNOS expression balance and increasing HO-1 levels, thereby favoring improvement in both endothelial function and insulin sensitivity
Reply to: Comments on "Glucose ameliorates the metabolic profile and mitochondrial function of platelet concentrates during storage in autologous plasma"
No full textDear Sirs,
We thank you for the opportunity to reply to the letter entitled "Comments on Glucose ameliorates the metabolic profile and mitochondrial function of platelet concentrates during storage in autologous plasma"1 in which Dr. Badlou (the Author of the letter) critically commented the results reported in our study on the beneficial effect of glucose addition to improve storage of platelet concentrates2
High dose folic acid pre-treatment blunts cardiac dysfunction during ischemia coupled to maintenance of high energy phosphates and reduces post-reperfusion injury
No full textBACKGROUND: The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury.
METHODS AND RESULTS: Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5x10(-6) mol/L i.c.) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (Delta dP/dtmax, -878+/-586 versus -1956+/-351 mm Hg/s placebo; P=0.03), and regional thickening was better preserved (37.3+/-5.3% versus 5.1+/-0.6% placebo; P=0.004). Anterior wall perfusion fell similarly (-78.4+/-9.3% versus -71.2+/-13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740+/-58 nmol/g; ischemia, 947+/-55 nmol/g; ischemia plus FA, 1332+/-101 nmol/g; P=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124+/-280 cpm/mg FA versus 5898+/-474 cpm/mg placebo; P=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8+/-1.2% versus 60.3+/-4.1% placebo area at risk; P<0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA.
CONCLUSIONS: FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death
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