The immature platelet fraction is a useful marker for predicting the timing of platelet recovery in patients with cancer after chemotherapy and hematopoietic stem cell transplantation.

Prediction of the timing of platelet recovery after chemotherapy and hematopoietic stem cell transplantation (HSCT) allows for optimal platelet transfusion. We assessed the clinical utility of the percentage value of the immature platelet fraction (IPF%) monitored using an XE-2100 automated hematology analyzer to predict the timing of platelet recovery after chemotherapy and HSCT. The IPF% was serially monitored in 31 patients with cancer who received 66 courses of chemotherapy and HSCT. In patients with cancer undergoing chemotherapy and HSCT, a transient increase in IPF% was observed 1-11 days prior to platelet recovery (>30 × 109 /l). In patients undergoing chemotherapy with a peak IPF% >10%, platelet recovery occurred significantly earlier than in those with IPF% peak values ≤10% (median periods were 2 and 5 days; P < 0.05). Platelet recovery appears to occur earlier in patients undergoing HSCT with a peak IPF% >10% than in those with IPF% peak values ≤10% (median periods were 2 and 6 days). Thus, the IPF% peak value is a useful parameter for predicting the timing of platelet recovery after chemotherapy and HSCT and has the potential to facilitate optimal platelet transfusion.

MEFV mutation analysis of familial Mediterranean fever in Japan.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever with serosal inflammation. FMF gene (MEFV) mutations have been identified primarily in patients from Mediterranean populations. Although several clinical cases have been reported in Japan, there have been few reports to date on mutation analysis. We studied FMF patients and their relatives to examine the clinical and genetic features of this disease in the Japanese population. METHODS: Twelve Japanese FMF patients who met the Tel Hashomer criteria and a total of 17 relatives from 5 of 10 families underwent molecular genetic studies to detect MEFV mutations. The characteristics of these Japanese FMF patients and geno-phenotypical correlations were examined. RESULTS: Almost all of our patients had been suffering for a long time from fever of unknown origin and one patient also had systemic amyloidosis. In our 12 FMF patients, we detected the substitutions E84K, L110P, E148Q, R761H and M694I. We also newly diagnosed 2 relatives as having FMF based on clinical symptoms and the existence of FMF mutations. One patient was homozygous for E148Q, the patient with systemic amyloidosis was a homozygote for M694I and 4 patients from 3 families were compound heterozygotes for E148Q and M694I. Three patients in one family were compound heterozygotes for E148Q, L110P and M694I. There were 3 patients who were heterozygous for E84K, L110P-E148Q or M694I and had no other nucleotide changes in the exons of MEFV. On the other hand, 2 relatives who had never experienced symptoms of FMF were homozygous for L110P-E148Q as well as compound heterozygous for E148Q/E148Q-R761H. E148Q and M694I were the most frequently detected substitutions in our study. CONCLUSIONS: MEFV mutations occur in Japanese FMF patients though FMF is rare in Japan. The identification of MEFV mutations could be a reliable diagnostic test for FMF. The results of genetic analyses on 14 Japanese FMF patients in this study revealed that E148Q and M694I are frequent alleles.

Anemia as a risk factor for chronic kidney disease.

Chronic kidney disease (CKD) is an important and leading cause of end-stage renal disease (ESRD) and moreover, plays a role in the morbidity and mortality due to cardiovascular disease, infection, and cancer. Anemia develops during the early stages of CKD and is common in patients with ESRD. Anemia is an important cause of left ventricular hypertrophy and congestive heart failure. Correction of anemia by erthyropoiesis-stimulating agent (ESA) has been shown to improve survival in patients with congestive heart failure. Anemia is counted as one of the non-conventional risk factors associated with CKD. Hypoxia is one of the common mechanisms of CKD progression. Treatment by ESA is expected to improve quality of life, survival, and prevent the CKD progression. Several clinical studies have shown the beneficial effects of anemia correction on renal outcomes. However, recent prospective trials both in ESRD and in CKD stages 3 and 4 failed to confirm the beneficial effects of correcting anemia on survival. Similarly, treatment of other risk factors such as hyperlipidemia by statin showed no improvement in the survival of dialysis patients. Given the high prevalence of anemia in ESRD and untoward effects of anemia in CKD stages 3 and 4, appropriate and timely intervention on renal anemia using ESA is required for practicing nephrologists and others involved in the care of high-risk population. Lessons from the recent studies are to correct renal anemia (hemoglobin <10 g/dl not hemoglobin > or =13 g/dl). Early intervention for renal anemia is a part of the treatment option in the prevention clinic. In this study, clinical significance of anemia management in patients with CKD is discussed.

Concurrence of non-myasthenic symptoms with myasthenia gravis.

Myasthenia gravis (MG) is a disease that is known to be accompanied by various complications. But the relationship between these complications and MG and the treatment for these complications still partly remain unknown. We report two cases of MG with unusual complications. The first one is a case of a 72-year-old woman with lingual dyskinesia, and the second is a 28-year-old man with dysgeusia. Both symptoms improved in parallel after the treatment of MG. Here we report these cases and review similar cases in the literature.

Successful management of critical limb ischemia with intravenous sodium thiosulfate in a chronic hemodialysis patient.

Vascular calcification is common among hemodialysis (HD) patients and contributes to the development of peripheral arterial disease. A 57-year-old Japanese man who had been on HD for 30 years was referred to us for severe pain with multiple ulcers on his toes and fingers. He was an ex-smoker and had no diabetes mellitus. On admission, he had ulcers on his big toes bilaterally and right 2nd - 4th fingers. Peripheral pulses were strong and his ankle-brachial pressure index was above 1.3. Laboratory data were as follows: calcium 9.9 mg/dl, albumin 3.3 g/dl, phosphate 3.0 mg/dl, Ca x P product 30, and parathyroid hormone 98 pg/ml. He had a parathyroidectomy in 1998 and 1999. X-rays of his hands and legs showed diffuse subcutaneous arteriolar calcification. Angiography revealed no local stenotic lesions. Despite intensive therapies including hyperbaric oxygen therapy, painful gangrene developed on his right big toe and the pain was so intense that he could not go to sleep in a supine position. We infused intravenous sodium thiosulfate (20 g) 3 times weekly, based on previous reports. Within 4 - 5 days, he experienced rapid and dramatic symptom relief. The score of the visual analogue pain scale improved from 10/10 - 2/10. The signs of ischemia, measured by transcutaneous partial oxygen pressure and thermography, improved significantly. During the infusion of sodium thiosulfate, the patient complained of nausea, vomiting and hyperosmia. These adverse symptoms were resolved after discontinuation of the infusion. Pain relief was sustained and he could walk after 2 weeks of infusion. Our case supports the use of sodium thiosulfate as a novel therapeutic choice for critical limb ischemia with severe vascular calcification in chronic HD patients.

Two unusual cases of Anderson-Fabry disease in a Japanese family.

A 16-year-old Japanese girl was admitted to our hospital on February 27, 2001, for acute renal failure. She had not shown proteinuria or hematuria in any school examination through 2000. The first renal biopsy specimen showed focal segmental glomerulosclerosis and tubulointerstitial change. Electron microscopy showed numerous myeloid bodies in the glomerular epithelium suggesting the diagnosis of Anderson-Fabry disease. After electron microscopy, we measured WBC alpha-galactosidase A, which was slightly decreased to 36.1 nmol/mg P/h (normal: 49.8 - 116.4). WBC alpha-galactosidase A levels for other family members were 74.3 for the mother, 4.8 for the father, 45.6 for the elder sister, and 16.3 for the younger sister. During the follow-up, she had two episodes of nephrotic syndrome, which responded well to steroid therapy. Both second and third renal biopsy showed numerous myeloid bodies by electron microscopy. A 52-year-old man, the father of the case one patient, was admitted for renal biopsy because of proteinuria and low levels of WBC alpha-galactosidase. Biopsy specimen showed typical changes under light microscopy and typical myeloid bodies by electron microscopy. Our cases underscore the importance of electron microscopy when examining the biopsy specimen and suggest that undiagnosed Anderson-Fabry disease may be present, in particular on chronic dialysis.

Effect of the establishment of dominance relationships on cortisol and other metabolic parameters in Nile tilapia (Oreochromis niloticus)

The objective of the present study was to investigate the influence of the establishment of dominance relationships and social stress on plasma cortisol and metabolite levels in Nile tilapia (Oreochromis niloticus). During the 30-day experiment, the fish weighing 236 ± 29 g were kept in individual aquaria, except for two pairings lasting 6 h each. Blood samples were taken from the animals before and after pairing. Display, approach, attack, rebuff, chase flight, and coloration were carried out on days 16 and 30. Activities and behaviors characteristic of the establishment of dominance relationships were described. It was possible to classify all experimental fish (N = 30) as dominant or subordinate. No differences were detected between dominant (N = 15) and subordinate (N = 15) fish during isolation or after pairing in cortisol (isolated: 5.76 ± 0.98 vs 5.42 ± 0.63; paired: 10.94 ± 1.62 vs 11.21 ± 2.45 æg/dl), glucose (isolated: 60.02 ± 4.9 vs 67.85 ± 16.16; paired: 110.44 ± 15.72 vs 136.26 ± 22.46 mg/dl), triglyceride (isolated: 167.87 ± 5.06 vs 185.68 ± 7.24; paired: 210.85 ± 13.40 vs 221.82 ± 12.70 mg/dl) or total protein levels (isolated: 7.01 ± 0.42 vs 6.69 ± 0.59; paired: 9.21 ± 0.62 vs 9.51 ± 0.66 g/dl). However, when isolated (N = 30) and paired (N = 30) tilapia were compared, there were significant differences in cortisol and metabolite levels. The similar response presented by dominant and subordinate tilapia indicates that establishment of dominance relationships was a stressor for both groups.

Expression of the novel transcription factor OASIS, which belongs to the CREB/ATF family, in mouse embryo with special reference to bone development.

The OASIS gene, which encodes a novel CREB/ATF family member, was isolated from long-term cultured astrocytes that were employed as an in vitro gliosis model. In the present study, we examined the expression pattern of the OASIS gene in the developing mouse embryo by in situ hybridization histochemistry and compared it with the expression of osteogenesis markers. OASIS mRNA expression was most strongly detected in preosteoblasts of the outer bony cortex of the ribs. Alveolar bone also showed strong signals for OASIS gene expression. OASIS mRNA was also localized to the preodontoblast of tooth buds. Expression began at embryonic day 12 (D12.5), peaked around D14.5-16.5, and continued to D18.5. The pattern of expression was very similar to that of hXBP-1 mRNA, which encodes another CREB/ATF family member. Spatiotemporal patterns of OASIS partly overlapped that of osteopontin, osteonectin, and alpha1 type I procollagen genes. Among these, the time course of OASIS mRNA expression was most similar to that of osteopontin mRNA expression, suggesting that the OASIS protein is involved in the late phase of osteoblast differentiation, as compared to the Cbfa1 that regulates early phases of osteoblast differentiation.

Outcomes of hemodiafiltration based on Japanese dialysis patient registry.

Effectiveness of various therapeutic modalities was analyzed among 1,196 patients entered in the registry of the Japanese Society for Dialysis Therapy who were on hemopurification therapy as of the end of 1998 and developed dialysis-related amyloidosis during 1999. In the investigation, the effectiveness of various hemopurification modalities on the dialysis-related amyloidosis was ranked as exacerbation, unchanged, or alleviation, so as to analyze the possible relationship between the hemopurification modality and its effectiveness. The analysis was performed using a logistic regression approach, and the results were shown as "the risk of a worse therapeutic ranking" among the hemopurification modalities. The smaller "the risk of a worse therapeutic effect" was, the more effective the treatment modality. When the risk of a worse therapeutic effect for the hemodialysis patients treated by a regular membrane was put at 1.0, the risk for hemodialysis patients using high-flux membrane was 0.489, the off-line hemodiafiltration risk was 0.117, the on-line hemodiafiltration risk was 0.013, and the risk of push/pull hemodiafiltration was 0.017. For hemodialysis with a beta(2)-microglobulin adsorption column, a low risk of 0.054 was found. The results indicated that hemodiafiltration therapy and simultaneous hemodialysis with beta(2)-microglobulin adsorption therapy were more effective treatment for dialysis-related amyloidosis.

Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis.

Quantification of coronary artery calcification (CAC) determined by electron-beam computed tomography (EBCT), known as the CAC score (CACS), correlates with total plaque amount and coronary risk factors and strongly associates with maximal stenosis in the epicardial arteries. However, data are limited concerning the CACS in chronic dialysis patients, although atherosclerotic vascular disease is the most frequent complication. We examined the relation between coronary risk factors, metabolic factors of calcium and other minerals, and CACS progression in 24 dialysis patients. The mean patient age was 53 +/- 14 (SD) years, and mean duration of dialysis was 64 +/- 69 months. In each patient, the CACS was measured twice, with a mean interscan period of 17 +/- 3 months. The mean CACS progressed from 449 +/- 605 to 669 +/- 894 overall, and the mean change in CACS (DeltaCACS) was 220 +/- 78. Patients were divided into two groups: slow progressors, with DeltaCACS of 7.5 +/- 31 (n = 12), and rapid progressors, with DeltaCACS of 432 +/- 458 (n = 12). Triglyceride concentrations (198 +/- 65 versus 103 +/- 50 mg/dL; P < 0.001) were high, and high-density lipoprotein cholesterol (HDL-C) concentrations (46 +/- 11 versus 60 +/- 18 mg/dL; P < 0.05) were low in rapid progressors. Rapid progression of CAC was associated with high triglyceride and low HDL-C concentrations. The clinical significance of these observations remains to be determined.

Family history of hypertension and blood pressure in a screened cohort.

We sought to determine whether a family history of hypertension is quantitatively associated with the prevalence of hypertension and blood pressure in a screened cohort. Clinical data and family (parents and siblings) histories regarding hypertension were collected from 9,914 individuals (probands) who were interviewed and examined during a one-day clinic by the Okinawa General Health Maintenance Association in 1997. We used logistic analysis to calculate odds ratios with adjustments for age, sex, body mass index, total cholesterol, presence of diabetes mellitus, alcohol use, cigarette smoking, and status of physical exercise. The age- and sex-adjusted hypertension prevalences in probands were 29.0% for those with 1 family member with a history of hypertension (n=2,112), 37.6% for those with 2 hypertensive family members (n=374), and 47.3% for those with 3 or more hypertensive family members (n=68). In contrast, only 16.4% of probands who reported no family history of hypertension (n=7,360) were hypertensive themselves. The trend of the prevalence according to the number of family members with a history of hypertension was significantly positive (p=0.003). The adjusted odds ratios (95% confidence interval) of hypertension were 2.74 (2.43-3.10) for 1 member, 4.62 (3.62-5.90) for 2 members, and 6.04 (3.51-10.4) for 3 or more members with a history of hypertension. In patients without antihypertensive medication (n=9,009), systolic/diastolic blood pressure (mean +/- SD) was 121 +/- 17/75 +/- 11 for 1 member, 124 +/- 18/77 +/- 12 for 2 members, and 127 +/- 17/78 +/- 11 for 3 or more members with a history of hypertension. In contrast, the mean systolic/diastolic blood pressure of probands who reported no family history of hypertension (n=7,360) was 119 +/- 15/74 +/- 10 mmHg, which was significantly (p<0.05) lower than that of any of the groups with hypertensive family members. In conclusion, an increase in the number of family members with hypertension was associated with an increasing prevalence of hypertension and blood pressure in the probands, independent of conventional risk factors for hypertension. Family members of hypertensive subjects may need to be treated in primary prevention efforts related to hypertension.

Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects.

A high level of serum creatinine (S-Cr) is a predictor of end-stage renal disease (ESRD), but only a few studies have investigated the prevalence of high S-Cr and its correlates in a large population. We analyzed the data collected from 6,403 subjects (4,222 men and 2,181 women) who participated in the Okinawa General Health Maintenance Association (OGHMA) screening both at 1997 and 1999. The computer-saved data included sex, age, blood chemistries, blood pressure, medical histories, and lifestyles. Multivariate Cox proportional hazard analyses were performed to identify the correlates of developing high S-Cr levels: > or = 1.4 mg/dl in men and > or = 1.2 mg/dl in women. The prevalence of high S-Cr was 3.0% (N=193), which was 4.1% in men (N=175) and 0.8% in women (N=18), and increased with age in both sexes at the 1997 screening. Among those who showed normal levels of S-Cr in 1997 (N=6,210), 241 subjects (223 men and 18 women) developed high S-Cr. The 2-year cumulative incidence of high S-Cr was 5.5% in men and 0.8% in women. Other than sex, serum uric acid was the most significant correlate for developing high S-Cr. The adjusted relative risk (95% confidence interval) of those with serum uric acid 8.0 mg/dl and over was 2.91 (1.79-4.75) in men and 10.39 (1.91-56.62) in women when compared to those with serum uric acid less than 5.0 mg/dl. Prevalence of high levels of S-Cr was relatively high in men. Other than gender, serum uric acid was a significant positive correlate of developing high S-Cr in this sample of the Japanese population.

Effectiveness of the near-infrared electronic endoscope for diagnosis of the depth of involvement of gastric cancers.

BACKGROUND: Near-infrared light penetrates deeply into tissue but is not visible with a conventional endoscope. We developed a new infrared electronic endoscope system and evaluated its usefulness for assessing the depth of involvement of gastric cancers. METHODS: A total of 61 patients with depressed or ulcerated gastric cancers underwent infrared endoscopy after intravenous injection of indocyanine green. RESULTS: Intramucosal cancers were observed as tumors with or without a homogeneous tumor stain, whereas submucosal or deeper cancers were observed as tumors with an inhomogeneous stain or with pooling of the dye. Histologic examination showed staining properties of gastric cancers were significantly correlated with the characteristics of the vascular bed. The accuracy for depth of cancer invasion was 89% for mucosal cancers and 89% for submucosal or deeper cancers. CONCLUSION: Our new infrared electronic endoscope system was useful for distinguishing mucosal cancers from submucosal or deeper cancers either with or without ulcerative changes.

Multiple risk factor clustering of hypertension in a screened cohort.

OBJECTIVE: A family history of hypertension, obesity, diabetes mellitus, hypercholesterolaemia and hypertriglyceridaemia have all been associated with the risk for hypertension. We evaluated whether the clustering of these risk factors increases the risk for hypertension or whether the accumulation of risk factors is associated with the blood pressure level in non-hypertensive subjects. METHODS AND SUBJECTS: We assessed the clinical data and family history of hypertension (in parents and siblings) for 9914 individuals (6163 men and 3751 women, 18-89 years old) who were screened in Okinawa, Japan, in 1997. RESULTS: In 9914 subjects (2465 hypertensive and 7449 non-hypertensive subjects), all the five factors were positively associated with hypertension. The odds ratios (95% confidence interval) for the number of risk factors were 1.88 (1.62-2.18) for one risk factor, 3.06 (2.62-3.57) for two, 5.25 (4.37-6.30) for three, 8.71 (6.48-11.72) for four and 24.48 (8.49-70.56) for five, after adjusting for age, sex, alcohol consumption, cigarette smoking and physical exercise habits. In non-hypertensive subjects, multivariate regression analyses showed that the number of risks was positively correlated with blood pressure; the regression coefficient was 1.96 (P < 0.0001) for systolic blood pressure, and 1.47 (P < 0.0001) for diastolic blood pressure after adjusting for age and sex. CONCLUSIONS: Clustering of risk factors was significantly associated with hypertension. The number of risk factors positively correlated with the blood pressure levels in nonhypertensive subjects. The accumulation of risk factors may play an important role in the pathogenesis of hypertension, and thus the aggregation of risk factors may need to be addressed in primary prevention efforts related to hypertension.

Measurement of carcinoembryonic antigen in colonic effluent as a high-risk marker for colorectal carcinoma.

We evaluated the usefulness of carcinoembryonic antigen (CEA) concentrations in colonic effluent as a high-risk marker for colorectal carcinoma (CRC). After 213 patients ingested 1,800 ml of a 5% isotonic solution of magnesium citrate, colonic effluent was collected from them before routine colonoscopy from February through June 1992. Of these patients, 27 who had undergone colonoscopy after a mean of 2.6 years were selected as subjects. The relationship between the CEA concentration in the colonic effluent and the occurrence of new colorectal tumors was examined. The CEA concentration in colonic effluent was adjusted on the basis of alkaline phosphatase activity. New colorectal tumors were noted significantly more frequently (P = .006) in patients with a high CEA level in colonic effluent (5 of 5; 100%) than in those with low a CEA level (6 of 22; 27%). The CEA concentration in colonic effluent is a simple and practical biomarker for identification of patients at high risk for CRC.

Endoscopic piecemeal resection with submucosal saline injection of large sessile colorectal polyps.

BACKGROUND: Because endoscopic en bloc resection of large, sessile colorectal polyps is technically difficult, they are usually resected piecemeal. However, piecemeal resection makes it difficult to evaluate the completeness of the resection histopathologically. In this study the efficacy of endoscopic piecemeal resection of large, sessile colorectal polyps was investigated after follow-up greater than 1 year. METHODS: We removed 56 sessile colorectal polyps 2 cm or greater in diameter in 56 patients by using an endoscopic submucosal saline injection technique. Endoscopic examinations were repeated at 3, 6, and 12 months and longer after initial endoscopic resection. If no residual tumor was found endoscopically and histologically, the patient was considered to be "cured." RESULTS: Of the 56 polyps, 14 (25%) were resected en bloc, and 42 (75%) were resected piecemeal. Of the 42 patients treated with piecemeal resection, 23 (55%) required additional endoscopic or surgical interventions. In patients followed 1 year or longer after initial treatment, the cure rate by en bloc resection was 100% (14 of 14) and that by piecemeal resection was 83% (35 of 42). Arterial bleeding occurred in 4 patients (7%) during or after endoscopic resection. In 3 of them, bleeding was stopped by endoscopic clipping, but 1 patient required emergent laparotomy. CONCLUSIONS: Endoscopic piecemeal resection after submucosal saline injection with an intensive follow-up program is a safe and effective treatment for large, sessile colorectal polyps.

Propofol dosage achieving spontaneous breathing during balanced regional anesthesia with the laryngeal mask airway.

STUDY OBJECTIVE: To assess an anesthetic technique achieving spontaneous breathing through the laryngeal mask airway (LMA) during combined epidural block and propofol anesthesia. DESIGN: Prospective, consecutive case series study. SETTING: Operating room at a general hospital. PATIENTS: 112 ASA physical status I and II adult surgery patients; 32 patients for lower extremity surgery are enrolled into study 1, and 30 patients for lower extremity surgery and 50 patients for lower abdominal gynecology surgery are enrolled into study 2. INTERVENTIONS: In study 1, patients were given 1.5 to 2.0 mg/kg followed by a 3 mg/kg/h of infusion of propofol, after epidural block, and they were fitted with the LMA. Thirty minutes after induction, the dose of propofol was increased to 4, 5, 6, and 7 mg/kg/h every 15 minutes. In study 2, the patients were given 1.5 to 2.0 mg/kg and 5 mg/kg/h of propofol and the LMA insertion, after epidural block. MEASUREMENTS AND MAIN RESULTS: PaO(2)/FIO(2), PaCO(2), tidal volume or respiratory rate, blood pressure, heart rate, and eye opening and motor response scales in conformity with Glasgow coma scale were recorded. Study 1 suggested an induction dose of 1.5 to 2.0 mg/kg and an infusion of 5 mg/kg/h as an appropriate dose to preserve spontaneous breathing with the LMA and to maintain reasonable depth of anesthesia. Study 2 showed that respiratory and circulatory conditions, depth of anesthesia, and other data related to anesthesia were clinically acceptable. CONCLUSIONS: The best infusion dose of propofol to achieve spontaneous breathing with the LMA seems to be 5 mg/kg/h, and the present balanced regional anesthesia with the LMA, using propofol infusion at 1.5 to 2.0 mg/kg and 5 mg/kg/h combined with epidural block, may be useful in clinical practice for lower extremity and lower abdominal gynecologic operations.

Diverse regulations of albumin gene expression by hepatocyte growth factor in HepG2 human hepatoma cells and primary culture of rat hepatocytes.

The effects of HGF on albumin gene expression in HepG2 human hepatoma cells and rat hepatocytes were investigated. HGF reduced the levels of albumin mRNA in HepG2 cells but the level was augmented in rat hepatocytes. By the transfection assay, HGF stimulated albumin promoter activity but repressed alpha-fetoprotein (AFP) enhancer activity regulating both AFP and albumin promoters in HepG2 cells. In contrast, HGF stimulated albumin promoter and AFP enhancer activities in rat hepatocytes. These results suggest that HGF elicits diverse responses of albumin gene expression in HepG2 cells and rat hepatocytes through the different biological actions on AFP enhancer in these cells.

beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter.

Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is associated with carnitine deficiency. A potential mechanism for the development of carnitine deficiency is competition between cephaloridine and carnitine for the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter that is responsible for Na(+)-coupled transport of carnitine in the kidney and other tissues. We investigated the interaction of several beta-lactam antibiotics with OCTN2 using human cell lines that express the transporter constitutively as well as using cloned human and rat OCTN2s expressed heterologously in human cell lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-mediated carnitine transport. These antibiotics possess a quaternary nitrogen as does carnitine. Several other beta-lactam antibiotics that do not possess this structural feature did not interact with OCTN2. The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine. Interestingly, many of the beta-lactam antibiotics that were not recognized by OCTN2 were good substrates for the H(+)-coupled peptide transporters PEPT1 and PEPT2. In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and PEPT2. The interaction of cephaloridine with OCTN2 was Na(+)-dependent, whereas the interaction of cefoselis and cefepime with OCTN2 was largely Na(+)-independent. Furthermore, the Na(+)-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements. These studies show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain beta-lactam antibiotics such as cephaloridine and that cephaloridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.