Jer-Chia Tsai

Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine.

Although hyperhomocysteinemia has been recognized recently as a prevalent risk factor for myocardial infarction and stroke, the mechanisms by which it accelerates arteriosclerosis have not been elucidated, mostly because the biological effects of homocysteine can only be demonstrated at very high concentrations and can be mimicked by cysteine, which indicates a lack of specificity. We found that 10–50 μm of homocysteine (a range that overlaps levels observed clinically) but not cysteine inhibited DNA synthesis in vascular endothelial cells (VEC) and arrested their growth at the G1 phase of the cell cycle. Homocysteine in this same range had no effect on the growth of vascular smooth muscle cells (VSMC) or fibroblasts. Homocysteine decreased carboxyl methylation of p21 ras (a G1 regulator whose activity is regulated by prenylation and methylation in addition to GTP-GDP exchange) by 50% in VEC but not VSMC, a difference that may be explained by the ability of homocysteine to dramatically increase levels ofS-adenosylhomocysteine, a potent inhibitor of methyltransferase, in VEC but not VSMC. Moreover, homocysteine-induced hypomethylation in VEC was associated with a 66% reduction in membrane-associated p21 ras and a 67% reduction in extracellular signal-regulated kinase 1/2, which is a member of the mitogen-activated protein (MAP) kinase family. Because the MAP kinases have been implicated in cell growth, the p21 ras -MAP kinase pathway may represent one of the mechanisms that mediates homocysteine’s effect on VEC growth. VEC damage is a hallmark of arteriosclerosis. Homocysteine-induced inhibition of VEC growth may play an important role in this disease process.

Intravenous Repletion of Phosphorus Deficiency in the Chronic Renal Failure Patients With Severe Hypophosphatemia

Severe hypophosphatemia is a potentially life-threatening medical condition and might lead to a fatal outcome in critically ill patients. The situation is further complicated by the co-morbid renal failure. We evaluated the efficacy and safety of the intravenous phosphate repletion in 15 renal failure patients with severe hypophosphatemia. Six patients with advanced renal failure and nine patients under maintenance hemodialysis, 7 males and 8 females, aged between 42 and 83 years old, were found to have serum phosphate level < 1.2 mg/dL from various medical conditions and were treated with intravenous phosphate infusion. The phosphate solution prepared from sodium dihydrogen phosphate (NaH2PO4), containing 13 mg/ml phosphate and 0.5 meq/ml sodium, in the dosage 2.5-3.0 mg phosphate/Kg body weight, was administered through the central venous lins every 6-8 hours. The infusion was discontinued once serum phosphate level reached 5.0-5.5 mg/dL. Serum ionized calcium, phosphate and intact parathyroid hormone levels were serially followed at different intervals, respectively. The hemodialyzed uremic patients received their dialysis treatment as scheduled. All patients survived the hypophosphatemic period and regained normal phosphate levels after repletion. The amount of phosphate administered to reach the target level ranged between 3438 and 9150 mg and the duration of treatment varied between six and seventeen days. Hypocalcemia (< 4.2 mg/dL) was noted at eight occasions during the whole treatment period but none was symptomatic. Eleven patients recovered from the offending illness. However, four patients expired due to reasons not directly consequent to and temporally remote from hypophosphatemia. We conclude that prompt repletion of severe hypophosphatemia and phosphate deficiency with relatively slower rate of NaH2PO4 solution intravenous infusion is a safe and effective mode of treatment for renal failure and uremic patients. The longer treatment period allowed the administered minerals full equilibration. The risk of hyperkalemia is avoided and the sodium/volume load can be eliminated by dialysis.

Lack of Influence of Recombinant Human Erythropoietin on Parathyroid Function in Hemodialysis Patients with Secondary Hyperparathyroidism

The effects of recombinant human erythropoietin (rHuEPO) treatment on parathyroid function in patients on maintenance hemodialysis (HD) with secondary hyperparathyroidism (HPT) is poorly understood. We compared the levels of serum intact parathyroid hormone (PTH) and the suppressibility of PTH by intravenous calcium infusion before and after 12 weeks of rHuEPO treatment in 8 HD patients with secondary HPT. The suppressibility of PTH by calcium infusion in HD patients was also compared with that of normal subjects. After rHuEPO treatment, in HD patients hematocrit and hemoglobin levels increased significantly from 20.1 +/- 1.3% and 6.65 +/- 0.46 g/dl to 28.7 +/- 1.0% and 9.68 +/- 0.39 g/dl, respectively. The serum intact PTH levels did not change significantly (541.9 +/- 65.3 pg/ml before versus 572.9 +/- 75.3 pg/ml after rHuEPO treatment), nor did serum ionized calcium, phosphate, magnesium, aluminum, alkaline phosphatase, and 1.25(OH)2D levels. Calcium infusion significantly increased serum ionized calcium and suppressed serum PTH levels. However, the increment in serum calcium levels and the percent decrement of serum PTH showed no significant differences before and after rHuEPO treatment in HD patients. Elevations in serum calcium levels during calcium infusions were not significantly different between normal subjects and HD patients. However, the percent maximal decrement in serum PTH level was less in HD patients both before and after rHuEPO treatment than in normal subjects (-75.4 +/- 3.9 and -76.4 +/- 4.1% versus -91.4 +/- 1.4%). We conclude that rHuEPO treatment has no influence on parathyroid function in maintenance HD patients with secondary HPT. In addition, PTH secretion is less suppressed by calcium infusion in the same group of patients.

Rhabdomyolysis-Induced Acute Tubular Necrosis after the Concomitant Use of Alcohol and Pentazocine-A Case Report

A 26 year-old male patient developed rapid deterioration of renal function after the concomitant use of alcohol and pentazocine. A renal biopsy showed vacuolar necrosis and organelle degeneration in the renal tubular cells. A muscle biopsy revealed central vacuolar necrosis and atrophic change in the typeⅠmyocytes. Rhabdomyolysis-induced acute tubular necrosis was diagnosed according to the clinical and pathological findings. The patient received two courses of peritoneal dialysis. Renal function recovered gradually, but hypercalcemia developed during the diuretic phase. A TC99m bone scan showed increased radiouptakes of metastatic calcification in both lungs, stomach, left thigh and left pretibial region. The serum ionized calcium level during the follow-up period. On discharge. The patient maintained normal trunk. The possible mechanism of acute renal failure after the concomitant use of alcohol and pentazocine will be discussed.

Effects of Manidipine Hydrochloride on Blood Pressure in Hypertensive Patients - A Comparison with Nifedipine Retard

Manidipine hydrochloride (MH) is a new calcium channel antagonist which is not yet available in Taiwan. Thus, a clinical trial was performed. The clinical effects and adverse effects of MH were compared with those of nifedipine hydrochloride retard monotherapies. Sixty-three out-patients with mild to moderate hypertension and no advanced systemic diseases were randomly divided into 2 groups. Twenty patients remained in each group after some patients withdrew from the study. Blood pressure decreased significantly after treatment in both groups (p < 0.01). In the manidipine group, systolic blood pressure (SBP) decreased from 164 +/- 14 to 140 +/- 18 mmHg and diastolic BP (DBP) decreased from 99 +/- 6 to 87 +/- 7 mmHg by the 8th week. In the nifedipine group, SBP decreased from 163 +/- 11 to 134 +/- 17 mmHg and DBP decreased from 101 +/- 10 to 88 +/- 9 mmHg by the 8th week. Pulse rates did not change significantly. Antihypertensive efficacy was 18/20 (90%) and 19/22 (86.4%) in the manidipine and nifedipine groups, respectively. There were a few adverse effects in both groups, the reaction was severe as to lead to the discontinuation of medication in two patients in the nifedipine group. No significant changes in laboratory tests were identified in either group, except for minimal decreases of lactate dehydrogenase and creatine kinase in the nifedipine group. We conclude that MH was equally safe and effective as nifedipine and it may have less severe side effects compared to nifedipine.