D-2-hydroxyglutaric acid inhibits creatine kinase activity from cardiac and skeletal muscle of young rats

BACKGROUND: Tissue accumulation of high amounts of D-2-hydroxyglutaric acid (DGA) is the biochemical hallmark of the inherited neurometabolic disorder D-2-hydroxyglutaric aciduria (DHGA). Patients affected by this disease usually present hypotonia, muscular weakness, hypertrophy and cardiomyopathy, besides severe neurological findings. However, the underlying mechanisms of muscle injury in this disorder are virtually unknown. MATERIALS AND METHODS: In the present study we have evaluated the in vitro role of DGA, at concentrations ranging from 0.25 to 5.0 mM, on total, cytosolic and mitochondrial creatine kinase activities from skeletal and cardiac muscle of 30-day-old Wistar rats. We also tested the effects of various antioxidants on the effects elicited by DGA. RESULTS: We first verified that total creatine kinase (CK) activity from homogenates was significantly inhibited by DGA (22-24% inhibition) in skeletal and cardiac muscle, and that this activity was approximately threefold higher in skeletal muscle than in cardiac muscle. We also observed that CK activities from mitochondrial (Mi-CK) and cytosolic (Cy-CK) preparations from skeletal muscle and cardiac muscle were also inhibited (12-35% inhibition) by DGA at concentrations as low as 0.25 mm, with the effect being more pronounced in cardiac muscle preparations. Finally, we verified that the DGA-inhibitory effect was fully prevented by preincubation of the homogenates with reduced glutathione and cysteine, suggesting that this effect is possibly mediated by modification of essential thiol groups of the enzyme. Furthermore, alpha-tocopherol, melatonin and the inhibitor of nitric oxide synthase L-NAME were unable to prevent this effect, indicating that the most common reactive oxygen and nitrogen species were not involved in the inhibition of CK provoked by DGA. CONCLUSION: Considering the importance of creatine kinase activity for cellular energy homeostasis, our results suggest that inhibition of this enzyme by increased levels of DGA might be an important mechanism involved in the myopathy and cardiomyopathy of patients affected by DHGA.     

Perioperative monitoring of total body water by bio-electrical impedance in children undergoing open heart surgery

Knowledge of the changes in total body water (TBW) following cardiac surgery (OHS) in children would be of value in fluid therapy and in researching the causes and management of capillary leak. We have validated a bioelectrical impedance technique (BEI) for non-invasive estimation of TBW in children after OHS. We report the use of this method in a longitudinal study. Twenty patients (mean age 4.7 years +/- 3.5 (SD), mean weight (WT) 16.2 kg +/- 1 kg) undergoing a variety of complex OHS procedures were studied from 1 day preoperatively to 4 days postoperatively. Anaesthetic and basic bypass (CPB) techniques were uniform. Six patients underwent CPB at less than 20 degrees C, 10 at 20 degrees - 25 degrees C and 4 at 26 degrees - 33 degrees C. TBW (BEI), core (ctemp) and peripheral (ptemp) temperatures and fluid balance (TFB) were recorded at frequent intervals. TBW (by BEI) rose (P less than 0.001) following CPB in all patients from 62% +/- 9% (SD) body weight preoperatively to 73% +/- 13% in the ICU (an increase of 11% +/- 5%). TBW remained significantly elevated until the 3rd postoperative day. Multivariate analysis (MVA) confirmed that TBW was significantly related to TFB, but not to ctemp or ptemp. MVA also revealed smaller patient size (height and weight), younger age and longer CPB time as incremental risk factors for the rise in TBW. Conclusions: (1) BEI permits the non-invasive study of TBW in children after OHS, when TBW variation may be considerable. (2) The smaller the child and the longer the CPB, the greater the rise in TBW. (3) The technique should be a valuable tool in researching the major water fluxes associated with CPB in children.     

Motion artifact reduction in MR imaging of the abdomen: gradient moment nulling versus respiratory-sorted phase encoding

Two currently available methods of reducing motion-induced artifact on magnetic resonance (MR) images, respiratory-sorted phase encoding (RSPE) and gradient moment nulling (GMN), were compared in images of the upper abdomen obtained with long repetition and long echo times. For ten subjects, two series of axial MR images were obtained with identical parameters except that RSPE was used in one and GMN in the other. Images were evaluated by three independent radiologists, and region-of-interest measurements were obtained to calculate signal-difference-to-noise ratios (SD/Ns) for liver versus gallbladder and liver versus the right kidney. Maximum ghost intensity and the standard deviation of motion-induced noise were also calculated. GMN was superior to RSPE for motion artifact reduction in all ten cases. The SD/N for liver versus both gallbladder and right kidney was significantly higher with GMN. Presaturation pulses applied outside the volume of interest reduced aortic and inferior vena cava signal and virtually eliminated artifact from these vessels but did not noticeably affect signal from intrahepatic vessels. GMN combined with presaturation pulses is a highly effective method of motion artifact reduction in the upper abdomen.     

Left ventricular wall stress and contractile function in transposition of the great arteries after the Rastelli operation

Left ventricular wall stress and contractile function were determined by echocardiographic methods in 11 patients studied 0.7 to 13.8 years (mean +/- standard error of the mean = 5.6 +/- 1.2 years) after undergoing the Rastelli operation for transposition of the great arteries associated with ventricular septal defect and left ventricular outflow tract obstruction. Age at operation ranged from 4.6 to 11.3 years (mean +/- standard error of the mean = 7.4 +/- 0.7 years). Data were compared with data of 24 normal subjects of similar age and heart rate. Left ventricular end-diastolic dimension and end-diastolic volume were significantly higher than normal, averaging 134% +/- 8% of normal dimension (p less than 0.004) and 106 +/- 13 ml/m2 versus a normal volume of 60 +/- 3 ml/m2) (p less than 0.007). In addition left ventricular wall mass was 215 +/- 40 gm/m2 versus a normal value of 72 + 6 gm/m2 (p less than 0.004). Both meridional and circumferential end-systolic and peak systolic stress values were not significantly different between normal subjects and Rastelli patients. Estimates of ventricular pump function including shortening fraction, rate-corrected velocity of circumferential fiber shortening, and ejection fraction were all depressed when compared with normal values. Velocity of fiber shortening, evaluated as a function of end-systolic stress, demonstrated abnormal contractile function in eight of 11 (73%) patients. These data indicate that left ventricular function is usually abnormal and residual left ventricular dilation and wall hypertrophy remain despite successful use of the Rastelli operation for repair in patients with transposition of the great arteries, ventricular septal defect, and left ventricular outflow tract obstruction.     

Imaging of the Kock continent ileal urinary reservoir

The Kock continent ileal urinary reservoir (Kock pouch) is a new urinary bypass system that can overcome some of the principal complications associated with other forms of urinary diversion. It is important to understand the anatomy and radiology of this new technique since radiologists play an important role in evaluating the function of the Kock pouch as well as assessing its complications. The authors review the clinical and radiographic findings in 193 patients who had undergone Kock pouch urinary diversion. Patients are evaluated radiographically in the immediate postoperative period and at regular postoperative intervals for as long as 3 years. Routine evaluation consists of Kock pouch cystography followed by intravenous urography. When indicated, computed tomography, ultrasound, and interventional radiologic procedures are used. The normal anatomy as well as the radiographic appearance of the Kock pouch is presented. In addition, the radiographic appearance of pouch complications and their frequency are reviewed.     

Procainamide in vivo modulates suppressor T lymphocyte activity

Autoantibodies to histone and denatured DNA have been found in 80% of patients treated with procainamide. Of these 10 to 20% will eventually develop a Systemic Lupus Erythematosus-like syndrome. Although the mechanism by which procainamide exerts its effect is unknown, in vitro studies suggest that procainamide may inhibit suppressor T cell activity. We have studied the immune function of 18 patients receiving a two hour infusion of procainamide during transvenous catheter electrophysiologic studies. There was no difference between pre and post infusion samples with respect to T and B cell mitogenesis or pokeweed mitogen-induced immunoglobulin secretion. However, in seventeen of eighteen patients, there was a marked decrease in Concanavalin A-inducible suppressor cell activity. This decrease appeared to be related to the amount of procainamide infused as high dose samples showed less suppressor activity than low dose samples. Thus the data show that procainamide, when given in vivo, leads to a rapid and dose dependent decrease in suppressor cell activity.