Arginine challenge unravels persistent disturbances of urea cycle and gluconeogenesis in abstinent alcoholics

AIMS: Data on recovery from hormonal and metabolic sequelae of alcoholism in strictly controlled alcohol abstinence are mainly restricted to short-term abstention. Our previous findings of persistently decreased plasma and urinary urea concentrations in long-term abstinent alcoholics prompted us to further elucidate this unexplained phenomenon. METHODS: The response of circulating urea cycle metabolites and glucose-regulating hormones to an intravenous load (30 g) of arginine hydrochloride was investigated in abstinent male alcoholics (n = 14) after complete recovery of all routine liver parameters and compared with that in healthy male controls (n = 15). RESULTS: The arginine challenge provoked (i) higher peak concentrations of arginine and increased arginine/ornithine and ornithine/citrulline ratios in the plasma of abstinent alcoholics; (ii) augmented plasma glutamine concentrations in alcoholics in the presence of comparable levels in both experimental groups of plasma glutamate, ammonia, and nitrate/nitrite; (iii) parallel increases in plasma urea concentrations over the respective baseline levels but distinctly higher urinary urea excretion in controls; (iv) a blunted blood glucose response to arginine in alcoholics together with a reduced insulin and glucagon surge; and (v) an elevated growth hormone peak as compared with controls. CONCLUSIONS: Application of an intravenous arginine challenge reveals profound and lasting metabolic and hormonal disturbances in abstinent alcoholics, affecting urea cycle and gluconeogenesis. The common denominator of many of these changes may be an acquired irreversible deficiency in cellular energy regulation.     

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

In 1996, the US Food and Drug Administration mandated the fortification of grain products with folic acid, a nutrient that has been associated with lower risk of colorectal neoplasia. We assessed the relation of plasma folate and homocysteine and colorectal adenoma recurrence separately in 2 studies: the first involved an intervention of a cereal supplement that contained folic acid, wheat bran fiber (WBF), and the second was conducted primarily during postfortification of the food supply using ursodeoxycholic acid (UDCA). Analyses were stratified for multivitamin use. Results show that plasma folate and homocysteine concentrations were associated with adenoma recurrence among nonusers of multivitamins only. Among nonmultivitamin users, the odds ratio [OR] (95% confidence interval [CI]) for those in the highest versus the lowest folate quartile was 0.65 (0.40-1.06) for the WBF study and 0.56 (0.31-1.02) for the UDCA; likewise, individuals in the highest versus the lowest quartile of homocysteine had higher odds of adenoma recurrence, in both the WBF (OR = 2.25; 95% CI = 1.38-3.66) and UDCA (OR = 1.93; 95% CI = 1.07-3.49) populations. Analyses comparing multivitamin users to different plasma folate concentrations among nonusers show that odds of recurrence for supplement users was lower only when compared to nonusers who had lower concentrations. Our results show that higher plasma folate or lower homocysteine levels are associated with lower odds of recurrence among nonusers of multivitamins in both studies. Our finding, suggesting that multivitamins or supplemental folate only benefit individuals with lower plasma folate concentrations, should be taken into consideration when designing and interpreting results of intervention studies.     

The ACE inhibitory dipeptide Met-Tyr diminishes free radical formation in human endothelial cells via induction of heme oxygenase-1 and ferritin

Food sources such as soybeans and fish contain angiotensin I converting enzyme (ACE) inhibitory peptides with antihypertensive properties. Methionine-tyrosine (Met-Tyr) is an ACE inhibitory dipeptide derived from sardine muscle. The present study investigates the effect of Met-Tyr on the expression of the antioxidant stress proteins, heme oxygenase-1 (HO-1) and ferritin, in endothelial cells derived from the human umbilical vein and their contribution to the decrease in radical formation that occurs under the influence of this dipeptide. Preincubation of endothelial cells with Met-Tyr (10-300 micromol/L) followed by washout markedly diminished subsequently induced NADPH-mediated radical formation. This indirect protection was associated with a significant increase in protein expression of HO-1 and ferritin and abolished by the HO inhibitor zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG). The HO product bilirubin produced antioxidant effects comparable to those of Met-Tyr. Met-Tyr raised HO-1 mRNA levels by enhancing mRNA stability. Antioxidant effects were specific for Met-Tyr and not observed with other methionine-containing dipeptides or ACE inhibitory agents. Our results demonstrate that Met-Tyr protects endothelial cells from oxidative stress via induction of HO-1 and ferritin but independently of its ACE inhibitory properties. This pathway represents a novel, potentially antiatherogenic mechanism of Met-Tyr and dietary proteins releasing Met-Tyr during gastrointestinal digestion.     

Endothelial dysfunction in chronic kidney disease: determinant of susceptibility to end-organ damage and therapeutic response

Endothelial dysfunction (ED) seems to be a crucial mediator of increased cardiovascular risk observed among patients with chronic kidney disease (CKD). Importantly, systemic ED does not only occur in patients with severe renal failure, but also in individuals with earlier stages of CKD. Close association between microalbuminuria and systemic ED renders renal vascular function an important marker for the severity of cardiovascular damage. Furthermore, changes in renal endothelium might be actively involved in the progression of renal end-organ damage. Recently, experimental evidence showed that interindividual variability in endothelial function of healthy rats predicts susceptibility to renal damage and the efficacy of renoprotective treatment. Therefore, a specific manipulation of renal and systemic ED might provide benefits in various stages of CKD. ED thus may represent an ideal therapeutic target not only for treatment, but also for primary prevention of renal disease.     

Skin temperature during regional anesthesia of the lower extremity

Increase in skin temperature (Ts) occurs early during neuraxial blocks. However, the reliability of Ts to predict successful peripheral block is unknown. Therefore, we investigated whether an increase in Ts more than 1 degrees C precedes or follows an impairment of sensation after combined femoral and sciatic nerve block as well as after epidural anesthesia. In this prospective, nonrandomized study we determined Ts changes in 33 patients undergoing knee or foot surgery under femoral and sciatic nerve block and 10 patients undergoing epidural anesthesia. Perception and motor function were assessed every 5 min. An increase in Ts (> or =1 degrees C) at the foot occurred later after sciatic nerve block than after epidural anesthesia (10.3 +/- 2.8 versus 5.0 min; P < 0.01). Alterations of Ts at skin innervated by the femoral nerve were <1 degrees C. Ts increase preceded sensory block after sciatic nerve block in 6.6% of patients but indicated a successful block (sensitivity, specificity, and accuracy = 100%). We conclude that an increase of Ts is a reliable, but late, sign of successful sciatic nerve block. Therefore it is of limited clinical value. Ts changes after femoral nerve block are negligible and late.     

Comparison of Spinal Cord Protection Utilizing Left Atrial-Femoral with Femoral-Femoral Bypass in Patients with Traumatic Rupture of the Aortic Isthmus

Introduction Postoperative paraplegia remains a dreaded complication of repair of traumatic rupture of the aortic isthmus. Claims have been made that left atrial-femoral bypass provides better spinal cord protection. To test the hypothesis that left atrial-femoral bypass is better than femoral vein-to-femoral artery bypass in regard to postoperative paraplegia, we concurrently compared the two techniques. Methods We compared the occurrence of paraplegia in 18 patients whose ruptures were repaired utilizing left atrial-femoral bypass with 10,000 units of systemic heparin (group A) and 72 patients with femoral-femoral bypass with heparin 300 units/kg and an oxygenator (group B) operated on between January 1995 and July 2004. Results The mortality rate was 5.6% (5/90), with no statistical difference between the two groups. Postoperative paraplegia was present in three (16.7%) group A patients and five group B (6.9%) patients. However, the specific etiology of the neurologic defect was not clear, as one patient’s paraplegia was transient following a period of cardiac arrest, and four others had had neurologic injuries prior to the aortic repair. Median aortic cross-clamp times were shorter in group A (34 minutes vs. 49 minutes). No patient required reexploration for bleeding, and no patient developed a graft infection. Conclusions Paraplegia rates were higher in the left atrial-femoral group, but the difference was not statistically significant. This occurred despite the decreased cross-clamp times in this group. In patients undergoing repair of traumatic rupture of the aortic isthmus, left atrial-femoral bypass does not provide better spinal cord protection than femoral-femoral bypass.     

Impulse-forces during walking are not increased in patients with knee osteoarthritis

Background Impulsive forces in the knee joint have been suspected to be a co-factor in the development and progression of knee osteoarthritis. We thus evaluated the impulsive sagittal ground reaction forces (iGRF), shock waves and lower extremity joint kinematics at heel strike during walking in knee osteoarthritis (OA) patients and compared them to those in healthy subjects.

Subjects and methods We studied 9 OA patients and 10 healthy subjects using three-dimensional gait analyses concentrated on the heel strike. Impulse GRF (iGRF) was measured together with peak accelerations (PA) at the tibial tuberosity and sacrum. Sagittal lower extremity joint angles at heel strike were extracted from the gait analyses. As OA is painful and pain might alter movement strategies, the patient group was also evaluated following pain relief by intraarticular lidocaine injections.

Results The two groups showed similar iGRF, similar tibial and sacral PA, and similar joint angles at heel strike. Following pain relief, the OA patients struck the ground with more extended hip and knee joints and lower tibial PA compared to the painful condition. Although such changes occurred after pain relief, all parameters were within their normal ranges.

Interpretation OA patients and healthy subjects show similar impulse-forces and joint kinematics at heel strike. Following pain relief in the patient group, changes in tibial PA and in hip and knee joint angles were observed but these were still within the normal range. Our findings make us question the hypothesis that impulse-forces generated at heel strike during walking contribute to progression of OA.