Search

Background: Hyperhomocysteinemia is recognized as a risk factor for atherosclerotic disease. However, the mechanism of homocysteine effects on smooth muscle cell proliferation, which is a hallmark of atherosclerosis, is unknown. The object of this study was to test the effects of homocysteine on smooth muscle cell proliferation, and to examine the mitogen-activated protein (MAP) kinases, extracellular signal-regulated protein kinase 1 and 2, that are known to be involved in cell proliferation., Methods: For the proliferation study, bovine aortic smooth muscle cells (BASMC, 10, 000/well) were allowed to grow for 2 days before 2 mmol/L D,L -homocysteine was added for 2, 4, 6, and 8 days to simulate the clinical hyperhomocysteinemic condition. For the MAP kinase study, quiescent BASMC were exposed to 2 mmol/L D,L -homocysteine for 1.5, 5, 10, 20, 30, and 60 minutes, and the active forms of MAP kinase were detected with Western immunoblotting. The degree of phosphorylation of MAP kinase was determined by densitometry., Results: D,L -homocysteine stimulated BASMC proliferation by 20% by day 8. MAP kinase phosphorylation was activated as much as six fold by D,L -homocysteine, with a peak at 30 minutes. PD98059, an inhibitor of MAP kinase phosphorylation, inhibited the homocysteine-induced MAP kinase phosphorylation and attenuated the increase in BASMC proliferation., Conclusions: These data are consistent with the hypothesis that D,L -homocysteine stimulation of BASMC proliferation involves MAP kinase activation.

To evaluate the effects of oral and intravenous nutritional repletion on tumor growth and host immunocompetence in malnourished animals, 60 adult purified protein derivative (PPD) positive Buffalo rats were inoculated with Morris hepatoma 5123 and were fed a regular diet for 14 days. All animals then were switched to a high carbohydrate, protein-free diet for the next 14 days, at which time only 30% of the animals remained PPD positive. Rats then were divided into three groups: group I underwent superior vena cava catheterization and received a constant infusion of 25% dextrose--4.25% amino acid solution; group II was switched to the regular protein diet orally ad libitum; and group III remained on the oral protein-free diet. PPD reactivities were measured prior to death 7 days later. Group I animals gained an average of 14 gm of body weight, and 91% of the animals were PPD positive. Group II animals lost an average of 17 gm of body weight, but 78% of the animals were PPD positive. Group III animals lost an average of 23 gm of body weight, and only 12% of the animals remained PPD positive. Absolute tumor weight and tumor weight: body weight ratios were not significantly different among the three groups of animals. Provision of adequate nutrition intravenously to malnourished tumor-bearing animals restores body weight and host immunocompetence without adversely stimulating tumor growth out of proportion to growth of the host.

Urine ketone levels were measured in patients receiving peripheral amino acid solutions, and the results were correlated with changes in nitrogen balance. Thirty well-nourished patients who were to undergo cystectomy were placed on liquid, noncarbohydrate diets 3 days before operation, and no oral intake was allowed until 7 days after operation. Crystalline amino acid (1.3 to 1.5 gm/kg/day) solutions were infused continuously from 3 days before to 7 days after operation. Blood was obtained 3 days before and 3, 7, and 10 days after operation; 24-hour urine outputs were determined daily. Qualitative urine acetone levels were determined four times daily. During the infusion period, 14 (47%) patients developed ketonuria (group I); 16 patients did not (group II). The mean serum glucose levels ranged from 99 to 107 mg/dl in group I and from 108 to 113 mg/dl in group II (P less than 0.05). The mean serum transferrin level decreased after operation to 117 mg/dl in group I and 97 mg/dl in group II. The mean cumulative adjusted nitrogen balance was -24 +/- 8 gm in group I and -47 +/- 9 gm in group II (P less than 0.05). No patient developed sepsis. Qualitative testing of urinary ketones correlated with significant alterations in blood urea nitrogen, serum glucose, transferrin, and cumulative adjusted nitrogen balance. The bedside determination of urinary ketones may be useful in assessing a patient's adaptation to peripheral amino acid infusions.

Solutions containing balanced quantities of essential L-amino acids, hypertonic glucose, and other essential nutrients were administered by vein to ten patients who had acute or chronic renal failure associated with or resulting from catastrophic complications precluding use of the gastrointestinal tract for alimentation. Weight gain, wound healing, and positive nitrogen balance occurred uniformly during periods of total intravenous nutrition, while blood urea nitrogen remained stable or decreased and the signs and symptoms of azotemia resolved. Restoration of nutritional balance and achievement of protein synthesis is possible in patients who have renal failure and gastrointestinal dysfunction by the judicious administration of high biologic value diets exclusively by vein.