Structural basis for the coiled-coil architecture of human CtIP.

The DNA repair factor CtIP has a critical function in double-strand break (DSB) repair by homologous recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here, we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, small-angle X-ray scattering (SAXS) and diffracted X-ray tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during the recombinational repair. The zinc-binding motif in the CtIP N-terminus alters dynamically the coiled-coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.

Effect of Gadolinium on the Estimation of Myelin and Brain Tissue Volumes Based on Quantitative Synthetic MRI.

BACKGROUND AND PURPOSE: The effect of gadolinium on the estimation of myelin has not been reported. The aim of the current study was to investigate the effects of gadolinium on automatic myelin and brain tissue volumetry via quantitative synthetic MR imaging. MATERIALS AND METHODS: The study included 36 patients who were referred for brain metastases screening, and quantitative synthetic MR imaging data before and after gadolinium-based contrast agent administration were analyzed retrospectively. Brain metastases were detected in 17 patients. WM volume, GM volume, CSF volume, non-WM/GM/CSF volume, myelin volume, brain parenchymal volume, myelin fraction (myelin volume/brain parenchymal volume), and intracranial volume were estimated. T1 and T2 relaxation times, proton density, and myelin partial volume per voxel averaged across the brain parenchyma were also analyzed. RESULTS: In patients with and without metastases after gadolinium-based contrast agent administration, measurements of WM and myelin volumes, and myelin fraction were significantly increased (+26.65 and +29.42 mL, +10.14 and +12.46 mL, +0.88% and +1.09%, respectively), whereas measurements of GM, CSF, brain parenchymal, and intracranial volumes were significantly decreased (-36.23 and -34.49 mL, -20.77 and -18.94 mL, -6.76 and -2.84 mL, -27.41 and -21.84 mL, respectively). Non-WM/GM/CSF volume did not show a significant change. T1, T2, and proton density were significantly decreased (-51.34 and -46.84 ms, -2.67 and -4.70 ms, -1.05%, and -1.28%, respectively) after gadolinium-based contrast agent administration, whereas measurements of myelin partial volume were significantly increased (+0.78% and +0.75%, respectively). CONCLUSIONS: Gadolinium had a significant effect on the automatic calculation of myelin and brain tissue volumes using quantitative synthetic MR imaging, which can be explained by decreases in T1, T2, and proton density.

Superior: a novel repetitive DNA element dispersed in the rye genome.

A new class of rye-specific repetitive DNA elements designated Superior has been identified. The rye genome library was constructed by cleavage with EcoO109I, the recognition sites of which consisted of 5'-PuGGNCCPy-3' multi-sequences and were present with high frequency in the rye repetitive families. A novel 495-bp segment enriched in the rye genome was successfully identified. Southern blot hybridization and fluorescence in situ hybridization using the repetitive element showed a dispersed array through all 7 chromosomes of rye. The repetitive DNA element did not share identity with known class I or class II transposable elements or known repetitive elements. Only several DNA segments in BACs and ESTs of barley showed partial similarity to the repetitive DNA element in all DNA databases of living species. The new class of dispersed repetitive elements was designated Superior. The entire structure of Superior was determined by using a rye genomic library of lambda FIXII screened by the 495-bp probe. The Superior family consisted of 1,292-bp, 1,324-bp, and 1,432-bp elements in which the 5' regions had been destroyed, indicating the presence of considerable structural diversity. Superior might be a useful tool for studying genomic organization and differentiation.

Minimum stable structure of the receptor for advanced glycation end product possesses multi ligand binding ability.

The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in the development of diabetic complications. Although the soluble form of the extracellular domain maintains the ability to bind multi-ligands, it is unstable and degrades into several peptide species during storage. Proteolysis with thrombin or factor Xa revealed several protease sensitive sites. Most sensitive site is located between Arg228 and Val229, and peptide bond next to Arg216, Arg116, Arg114 and Trp271 are also cleaved. Seven truncated extracellular domains of RAGE were engineered in order to obtain a stable soluble fragment. RAGE 143 (Ala23-Thr143) is not only protease resistant but also shows the same ligand-binding ability as that of the full-length extracellular domain. The resultant minimum RAGE 143 works as a stable recognition devise to detect advanced glycation end products (AGEs).

Effects of postnatal isolation rearing and antidepressant treatment on the density of serotonergic and noradrenergic axons and depressive behavior in rats.

The development of monoaminergic axons is affected by pharmacological and environmental manipulations during early periods of brain development. In addition, it has been proposed that changes in the density of monoaminergic axons are involved in the pathophysiology of depression. The present experiments examined the effects of neonatal treatment with antidepressants on the density of monoaminergic axons containing 5-HT or noradrenaline (NA) and depressive behavior in rats. In this study, clomipramine (CL) was used as an antidepressant, because a large amount of data has been accumulated on the effects of neonatal CL treatment on monoaminergic neurons and depressive behavior. It was also examined whether the effects of neonatal CL treatment could be further modified by environmental conditions. In the present experiments, postweaning isolation rearing (Iso) was examined as an environmental condition, because postweaning Iso is reported to change the density of 5-HT axons in the rat brain. Unexpectedly, neonatal CL treatment alone had no effect on the density of 5-HT or NA axons or depressive behavior. Postweaning social Iso rearing reduced the density of 5-HT axons in the central nucleus and basolateral nucleus of the amygdala and CA3 of the hippocampus. In the prelimbic area and infralimbic area of medial prefrontal cortex and the dentate gyrus of the hippocampus, the density of 5-HT axons was not affected by social Iso alone, but was reduced when animals were socially isolated after neonatal CL treatment. Postweaning Iso, but not neonatal CL treatment, increased immobility in the forced swim test in adolescence/early adulthood. These findings suggest that postweaning social Iso alters the density of monoaminergic axons, particularly 5-HT axons, and induces a possible model of depression, while neonatal CL treatment alone has no effect on the density of NA or 5-HT axons or depressive behavior in adolescence/early adulthood.

Young adult-specific hyperphagia in diabetic Goto-kakizaki rats is associated with leptin resistance and elevation of neuropeptide Y mRNA in the arcuate nucleus.

The present study aimed to examine whether hyperphagia, which is frequently observed in type 1 diabetic patients and model animals, also occurs in type 2 diabetic Goto-Kakizaki (GK) rats and, if so, to explore underlying abnormalities in the hypothalamus. GK rats at postnatal weeks 6-12, compared to control Wistar rats, exhibited hyperphagia, hyperglycaemia, hyperleptinemia and increased visceral fat accumulation, whereas body weight was unaltered. The ability of leptin to suppress feeding was reduced in GK rats compared to Wistar rats of these ages. In GK rats, leptin-induced phosphorylation of signal transducer and activator of transcription 3 was significantly reduced in the cells of the hypothalamic arcuate nucleus (ARC), but not of the ventromedial hypothalamus, whereas the mRNA level of functional leptin receptor was unaltered. By real-time polymerase chain reaction and in situ hybridisation, mRNA levels of neuropeptide Y, but not pro-opiomelanocortin and galanin-like peptide, were significantly increased in the ARC of GK rats at 11 weeks, but not 26 weeks. Following i.c.v. injection of a NPY Y1 antagonist, 1229U91, the amount of food intake in GK rats was indistinguishable from that in Wistar rats, thus eliminating the hyperphagia of GK rats. These results demonstrate that young adult GK rats display hyperphagia in association with leptin resistance and increased NPY mRNA level in the ARC.

Effects of losartan on blood pressure and humoral factors in a patient who suffered from anaphylactoid reactions when treated with ACE inhibitors during LDL apheresis.

In a patient who was taking an angiotensin-converting-enzyme inhibitor, low-density lipoprotein (LDL) apheresis with dextran-sulfate cellulose provoked hypotension accompanied by lacrimation and blurred vision. Hypotension was eliminated by changing the anticoagulant from heparin to a protease inhibitor, nafamostat mesilate. A study was undertaken to clarify whether an antagonist of angiotensin type 1-receptor, losartan, could be safely used in the same patient during LDL apheresis treatment. Blood pressure and humoral factors were compared between the apheresis sessions with losartan and those without. Although angiotensin II and bradykinin plasma levels during LDL apheresis were significantly greater with losartan than without, blood pressure reduction by losartan was mild and unpleasant symptoms were not induced. Losartan was thus safely used for this patient during treatment by LDL apheresis. The greater rise in bradykinin levels during apheresis with losartan might be ascribable to angiotensin type 2-receptor stimulation.

Identification of tumor suppressor candidate genes by physical and sequence mapping of the TSLC1 region of human chromosome 11q23.

Loss of heterozygosity for a locus on human chromosome 11q22-23 is observed at high frequency in non-small cell lung carcinoma (NSCLC). Introduction of a 1.1 Mb fragmented yeast artificial chromosome (YAC) mapping to this region completely suppresses the tumorigenic properties of a human NSCLC cell line, A549. Smaller fragmented YACs give partial but not complete suppression. To further localize the gene(s) responsible for this partial suppression, a bacterial artificial chromosome (BAC) and P1-based artificial chromosome (PAC) contig was constructed, completely spanning the candidate region. End sequence generated in the construction of the BAC/PAC contig identified a previously unmapped EST and served to order genomic sequence contigs from the publicly available Celera Genomics (CG) and Human Genome Project (HGP) efforts. Comparison showed that CG provided larger contigs, while HGP provided more coverage. Neither CG nor HGP provided complete sequence coverage, alone or in combination. The sequence was used to map 110 ESTs and to predict new genes, including two GenScan gene predictions that overlapped ESTs and were shown to be differentially expressed in tumorigenic and suppressed A549 cell lines.

Isolation of the TSLL1 and TSLL2 genes, members of the tumor suppressor TSLC1 gene family encoding transmembrane proteins.

We have recently identified the TSLC1 gene as a novel tumor suppressor in human non-small cell lung cancers. TSLC1 encodes a membrane glycoprotein with an extracellular domain homologous to those of immunoglobulin superfamily proteins. Truncation of TSLC1 in the cytoplasmic domain in a primary human tumor suggests that this domain is important for tumor suppressor activity. Here, we report the isolation of two TSLC1-like genes, TSLL1 and TSLL2, based on their structural homology with the sequences corresponding to the cytoplasmic domain of TSLC1. Significant similarity was also observed in the extracellular domain as well as in the overall gene structure, indicating that these three genes form a unique subfamily (the TSLC1-gene family) in the immunoglobulin superfamily genes. In contrast to the ubiquitous expression of TSLC1, TSLL1 is expressed exclusively in adult and fetal human brain, while TSLL2 is expressed in several specific tissues including prostate, brain, kidney and some other organs. Expression of TSLL1 and TSLL2 was lost or markedly reduced in many human glioma cell lines or some prostate cancer cell lines, suggesting that loss of expression of these genes might be involved in some human cancers.

Does stent design affect probability of restenosis? A randomized trial comparing Multilink stents with GFX stents.

BACKGROUND: Experimental studies have revealed that stent configuration influences intimal hyperplasia. The purpose of this study was to evaluate clinical outcomes for 2 stent designs in a randomized trial with quantitative coronary angiography (QCA) and intravascular ultrasonography (IVUS). METHODS: We randomly assigned 100 patients with 107 lesions and symptomatic coronary artery disease to deployment of a Multilink stent (Advanced Cardiovascular Systems, Guidant, Santa Clara, Calif) or a GFX stent (Applied Vascular Engineering, Santa Rosa, Calif) with IVUS guidance. QCA and IVUS studies were performed before and after intervention and at follow-up (4.2 +/- 1.0 months). RESULTS: There were no significant differences in baseline characteristics and QCA and IVUS parameters before and after intervention between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger in the Multilink group (2.46 +/- 0.59 vs 2.08 +/- 0.79 mm, P <.05). Maximal in-stent intimal hyperplasia was significantly larger in the GFX group (2.9 +/- 1.7 vs 1.8 +/- 1.2 mm(2), P <.01). The restenosis rate differed between the 2 groups (Multilink 4% vs GFX 26%, P =.003). In multiple stepwise logistic regression analysis, the only predictor that significantly correlated with restenosis was stent type (P <.01). The odds ratio for the GFX stent-treated vessels was 18.65 (95% confidence interval 2.10-165.45). CONCLUSIONS: With deployment of the GFX stent, a thicker neointima develops within the stent. Stent configuration may affect clinical outcomes.

Dilated cardiomyopathy of Becker-type muscular dystrophy with exon 4 deletion--a case report.

The authors report a 47-year-old man with Becker-type muscular dystrophy presenting with dilated cardiomyopathy. Left ventriculography showed diffuse severe hypokinesia: left ventricular end-diastolic volume index 193 mL/m2, left ventricular end-systolic volume index 143 mL/m2, and left ventricular ejection fraction 26%. Skeletal muscle biopsy demonstrated a dystrophic process. Genetic analysis revealed a deletion of exon 4. There was a difference in immunostaining pattern between skeletal muscles and cardiac muscles. Severe cardiac dysfunction in this case may be associated with the damage in dystrophin-deficient fibers.

Renal macrostructure and cortical circulation in hypertension assessed by dynamic computed tomography.

The aim of this study was to assess the macrostructure of the kidney and the grade of heterogeneity in renal cortical circulation in the early stages of essential hypertension. The subjects consisted of 84 patients (<50 years old) who underwent dynamic computed tomography (CT) because of various abdominal diseases and who had no serious hemodynamic abnormalities. The volumes of the whole kidney, cortex, and medulla were measured with the program installed in the CT instrument. In dynamic CT under appropriate conditions, the CT number of each pixel (image element) reflects the blood volume in the pixel. The means and standard deviations were calculated from the CT numbers within the renal cortex. The coefficient of variation (CV) of CT numbers was used as the index of the heterogeneity of renal cortical circulation. The volume ratio of cortex/medulla was significantly (P < .01) smaller in the hypertensive patients (0.80 +/- 0.03 (mean +/- SE)) than in the normotensive subjects (0.92 +/- 0.03). The CV was significantly (P < .01) greater in the hypertensives (n = 23, 0.124 +/- 0.008) than in the normotensives (n = 61, 0.106 +/- 0.003). There was a significant correlation (r = -0.391, P < .001) between the CV of CT numbers and the volume ratio of cortex/medulla, and the relationship between the two variables was independent of other variables. These results suggest that the heterogeneity of renal cortical circulation is increased in the early stages of essential hypertension and is related to changes in renal macrostructure.

Acute changes in plasma levels of hepatocyte growth factor during low-density lipoprotein apheresis.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor, and angiogenesis is included in a variety of its functional effects. HGF levels were measured in 5 sessions of low-density lipoprotein (LDL) apheresis in 3 patients with severe hypercholesterolemia. Blood was collected at the start (T0) and at 1,000 ml (T1), 2,000 ml (T2), and 3,000 ml (T3) plasma treatments. During LDL apheresis, HGF levels increased from 1.59 +/- 0.78 (mean +/- SE, n = 5) ng/ml at T0 to 6.64 +/- 0.97 at T1, 6.28 +/- 0.97 at T2, and 5.20 +/- 0.94 at T3. In one apheresis session, HGF increased immediately at the 100 ml plasma treatment stage. HGF was adsorbed completely by a dextran-sulfate (DS) column. Despite the adsorption by the DS column, HGF in the patient blood increased to the levels with functional effects. The improvement of ischemic symptoms due to LDL apheresis may be related to the angiogenic activities of HGF.

TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer.

The existence of tumor-suppressor genes was originally demonstrated by functional complementation through whole-cell and microcell fusion. Transfer of chromosome 11 into a human non-small-cell lung cancer (NSCLC) cell line, A549, suppresses tumorigenicity. Loss of heterozygosity (LOH) on the long arm of chromosome 11 has been reported in NSCLC and other cancers. Several independent studies indicate that multiple tumor-suppressor genes are found in this region, including the gene PPP2R1B at 11q23-24 (ref. 7). Linkage studies of NSCLC are precluded because no hereditary forms are known. We previously identified a region of 700 kb on 11q23.2 that completely suppresses tumorigenicity of A549 human NSCLC cells. Most of this tumor-suppressor activity localizes to a 100-kb segment by functional complementation. Here we report that this region contains a single confirmed gene, TSLC1, whose expression is reduced or absent in A549 and several other NSCLC, hepatocellular carcinoma (HCC) and pancreatic cancer (PaC) cell lines. TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines. Restoration of TSLC1 expression to normal or higher levels suppresses tumor formation by A549 cells in nude mice. Only 2 inactivating mutations of TSLC1 were discovered in 161 tumors and tumor cell lines, both among the 20 primary tumors with LOH for 11q23.2. Promoter methylation was observed in 15 of the other 18 primary NSCLC, HCC and PaC tumors with LOH for 11q23.2. Thus, attenuation of TSLC1 expression occurred in 85% of primary tumors with LOH. Hypermethylation of the TSLC1 promoter would seem to represent the 'second hit' in NSCLC with LOH.

Long-term effects of bisoprolol compared with imidapril on left ventricular remodeling after reperfusion in acute myocardial infarction: an angiographic study in patients with maintained vessel patency.

BACKGROUND: Although angiotensin-converting enzyme inhibitor attenuates ventricular enlargement, whether beta-blocker therapy induces regression of left ventricular remodeling is not known. The purpose of this study was to compare the effects of bisoprolol therapy with those of imidapril therapy on left ventricular remodeling after acute myocardial infarction (AMI). METHODS: Sixty patients with AMI who underwent reperfusion therapy were randomly assigned to an imidapril group (20 patients), a bisoprolol group (20 patients), or a control group (20 patients). Administration was started within 24 hours. Left ventricular function on admission and 3 months and 1 year after AMI was investigated. RESULTS: Baseline characteristics on admission were similar in the 3 groups except for sex distribution. Mean pulmonary capillary wedge pressure and left ventricular end-diastolic pressure in the bisoprolol group were higher than those in the imidapril group 1 year after admission (pulmonary capillary wedge pressure: 12 +/- 7 vs 8 +/- 2 mm Hg, left ventricular end-diastolic pressure: 17 +/- 8 vs 11 +/- 4 mm Hg, P <. 01). Left ventricular end-diastolic volume index (EDVI) increased in the bisoprolol group throughout the 1-year period (P <.01), whereas EDVI in the imidapril group decreased (P <.01). The increases in EDVI during 1 year in the bisoprolol group were greater than those of the other 2 groups (bisoprolol: 12 +/- 10, imidapril: -9 +/- 7, control: 4 +/- 11 mL/m2, P <.01). CONCLUSIONS: Early treatment with bisoprolol in AMI cannot prevent left ventricular remodeling, whereas imidapril attenuates left ventricular dilation by decreasing preload.

Relation between stent expansion and arterial remodeling: a serial intravascular ultrasound study.

Previous studies suggested that stent area (SA) did not change after the Palmaz-Schatz stent implantation. Whether these findings apply to other types of stent, however, is unknown. This study assessed vascular response to stent implantation using intravascular ultrasound (IVUS) studies. Serial (pre-intervention to follow-up) IVUS imagings were used to study 57 native coronary lesions after the GFX stent or the Multilink stent implantation. The vessel area (VA) at lesion site increased at follow-up (16.92 +/- 3.67 mm(2) after intervention to 18.17 +/- 4.66 mm(2) at follow-up, P < 0.01). The SA also increased from 8.39 +/- 1.90 mm(2) after intervention to 8.80 +/- 2.08 mm(2) at follow-up (P = 0.02). Thirty-two percent of lesions showed late stent expansion. The stent expansion [Delta (after intervention to follow-up) SA] correlated significantly with the VA growth [Delta (after intervention to follow-up) VA] (r = 0.59, P < 0.0001). In conclusion, some lesions reveal late stent expansion after both the GFX stent and the Multilink stent implantation. Adaptive vessel remodeling may be followed by stent expansion.

Heterogeneity of renal cortical circulation in hypertension assessed by dynamic computed tomography.

The aim of this study was to assess the grade of heterogeneous disturbance in the renal cortical circulation using dynamic computed tomography and to investigate the relationship between the heterogeneity of renal cortical circulation and hypertension. We studied 125 patients who underwent dynamic computed tomography (CT) for various abdominal diseases and had no serious hemodynamic abnormalities. In dynamic computed tomography under appropriate conditions, each pixel (image element), less than 1 mm2, has a CT number that is in proportion to the concentration of contrast media, which reflects the blood volume in the pixel. The image was constructed at the hilus level about 50 s after the start of a continuous infusion of contrast medium. The mean and standard deviation were calculated from the CT numbers in the renal cortex. The coefficient of variation, ie, the standard deviation divided by the mean value, was used as the index of the heterogeneity of renal cortical circulation. The coefficient of variation was significantly (P < .001) greater in the hypertensive patients (n = 48, 0.174 +/- 0.006 [mean +/- SE]) than in normotensive subjects (n = 77, 0.140 +/- 0.004). The coefficient increased in parallel with the patient's age and with the grade of renal surface irregularity. In the patients whose serum creatinine levels were normal, this parameter also had a significant relationship (r = 0.367, P < .0001) with serum creatinine. These results suggest that the heterogeneity of renal cortical circulation is increased in hypertension and is also associated with aging. This parameter may become a sensitive indicator to detect slight deterioration in the renal cortical circulation.

Long-term follow-up of primary stenting with coil stent in acute myocardial infarction.

The authors evaluated clinical and angiographic outcomes for 1 year after primary stenting using coil stent for acute myocardial infarction. Twenty-eight patients underwent primary stenting with coil stent. Follow-up coronary arteriography at 3 months and 1 year was planned in all patients. Procedural success was achieved in 96%. There was no acute or subacute thrombosis. Minimal lumen diameter (MLD) was increased from 0.08 +/- 0.19 to 2.73 +/- 0.49 mm after stenting. MLD had decreased significantly for 3 months (MLD at 3 months: 2.03 +/- 0.86 mm, p = 0.001). On the other hand, MLD did not differ between 3-month; and 1-year follow-up (MLD at 1 year: 2.26 +/- 0.73 mm, p = NS). Only one patient manifested reocclusion at 3-month follow-up. The cumulative restenosis rate and target lesion revascularization rate at 1-year follow-up were 25.9% (7/27) and 11.1% (3/27). Primary stenting using coil stent is safe and feasible in patients with acute myocardial infarction and may improve clinical outcome and decrease restenosis and target lesion revascularization rate.

A retrospective study of late outcome in patients with peripheral arterial occlusive disease: an association between prosthetic vascular graft and cancer death?

The authors assessed the relationship between cause of death and treatment modality in patients with peripheral arterial occlusive disease. A total of 273 patients were treated with percutaneous transluminal angioplasty, surgical reconstruction, amputation, or medical therapy. We evaluated the outcome in various patient subgroups divided by treatments with a mean follow-up of 4.9 years. Most patients died because of cardiovascular or cerebrovascular events, and cancer was the second most frequent cause of death. Furthermore, there was a significant difference in cancer deaths between patients who received prosthetic vascular grafts and those with other types of treatment (9.3% vs. 2.8%, p<0.01, odds ratio = 3.34). It is noteworthy that patients with peripheral arterial occlusive disease succumbed to cancer, especially the patients with prosthetic vascular grafts.

Effects of losartan on low-density lipoprotein apheresis.

The negative charges of dextran sulfate cellulose (DSC) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by bradykinin production. This study was undertaken to see whether an antagonist of angiotensin receptor (AT1), losartan, could be safely used in a patient treated by DSC-LDL apheresis. Losartan (50 mg/day) was given to a patient with coronary heart disease who had been treated by DSC-LDL apheresis and had experienced an anaphylactoid reaction by administration of an angiotensin converting enzyme inhibitor. The effects of losartan on blood pressures and humoral factors were examined by comparing these parameters between apheresis with and without losartan. Blood pressures and plasma levels of bradykinin, renin, and aldosterone were measured before and at 1,000, 2,000, and 3,000 ml of plasma treatment. Bradykinin levels during LDL apheresis tended to be higher with losartan than without losartan (without versus with, 529 +/- 121 [n = 4, mean +/- SE] pg/ml vs. 1,058 +/- 49 at the 2,000 ml stage, p < 0.01). The rise of plasma renin activity with losartan (221 +/- 26% at the 3,000 ml stage) was significantly greater than that without losartan (144 +/- 2.4%). Mean blood pressure decreased by 7% during apheresis with losartan, but blood pressure reduction was not accompanied by any complaints. These results suggest that AT1 receptor antagonists are safely used in patients treated by DSC-LDL apheresis.