Excitation of the Isovector Spin Monopole Resonance via the Exothermic

The (^{12}N, ^{12}C) charge-exchange reaction at 175 MeV/u was developed as a novel probe for studying the isovector spin giant monopole resonance (IVSMR), whose properties are important for better understanding the bulk properties of nuclei and asymmetric nuclear matter. This probe, now available through the production of ^{12}N as a secondary rare-isotope beam, is exothermic, is strongly absorbed at the surface of the target nucleus, and provides selectivity for spin-transfer excitations. All three properties enhance the excitation of the IVSMR compared to other, primarily light-ion, probes, which have been used to study the IVSMR thus far. The ^{90}Zr(^{12}N,^{12}C) reaction was measured and the excitation energy spectra up to about 70 MeV for both the spin-transfer and non-spin-transfer channels were deduced separately by tagging the decay by γ emission from the ^{12}C ejectile. Besides the well-known Gamow-Teller and isobaric analog transitions, a clear signature of the IVSMR was identified. By comparing with the results from light-ion reactions on the same target nucleus and theoretical predictions, the suitability of this new probe for studying the IVSMR was confirmed.

Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells.

BACKGROUND: Thromboembolic events are a major complication in ovarian cancer patients. Tissue factor (TF) is frequently overexpressed in ovarian cancer tissue and correlates with intravascular thrombosis. TF binds to coagulation factor VII (fVII), changing it to its active form, fVIIa. This leads to activation of the extrinsic coagulation cascade. fVII is produced by the liver and believed to be supplied from blood plasma at the site of coagulation. However, we recently showed that ovarian cancer cells express fVII transcripts under normoxia and that this transcription is inducible under hypoxia. These findings led us to hypothesise that ovarian cancer cells are intrinsically associated with TF-fVIIa coagulation activity, which could result in thrombosis. METHODS: In this study, we examined whether ectopically expressed fVII could cause thrombosis by means of immunohistochemistry, RT-PCR, western blotting and flow cytometry. RESULTS: Ectopic fVII expression occurs frequently in ovarian cancers, particularly in clear cell carcinoma. We further showed that ovarian cancer cells express TF-fVIIa on the cell surface under normoxia and that this procoagulant activity is enhanced by hypoxic stimuli. Moreover, we showed that ovarian cancer cells secrete microparticles (MPs) with TF-fVIIa activity. Production of this procoagulant secretion is enhanced under hypoxia. CONCLUSION: These results raise the possibility that cancer cell-derived TF-fVIIa could cause thrombotic events in ovarian cancer patients.

Atrial natriuretic factor significantly contributes to the mineralocorticoid escape phenomenon. Evidence for a guanylate cyclase-mediated pathway.

The mechanism underlying the mineralocorticoid escape phenomenon remains unknown. To assess the possible contribution of natriuretic peptides to mineralocorticoid escape, rats were injected with 5 mg deoxycorticosterone acetate for 3 d. Plasma atrial natriuretic factor (ANF) rose to twice basal levels and atrial ANF content decreased significantly by 24 h of treatment. This coincided with renal escape and with a significant increase in urinary cGMP excretion. Plasma ANF remained elevated and atrial ANF content continued to decline by 48 and 72 h while atrial ANF mRNA levels increased significantly only at 72 h. Plasma brain natriuretic peptide did not increase during escape although atrial brain natriuretic peptide mRNA levels increased significantly. Chronically administered HS-142-1 (HS), a specific antagonist of the guanylate cyclase-coupled natriuretic peptide receptors, significantly and dose-dependently impaired the escape phenomenon. The highest dose of HS completely suppressed the increase in urinary cGMP. Despite the continued suppression, partial escape was observed by the end of the observation period. HS alone influenced neither plasma nor tissue or urine parameters. These findings show that despite activation of atrial ANF, blockade of the guanylate cyclase-coupled natriuretic peptide receptors impairs the ability of the kidney to escape the Na+ retaining effect of excess mineralocorticoid in a dose-dependent fashion. Later-acting, unknown mechanisms eventually come into play to mediate the escape phenomenon through a guanylate cyclase-independent pathway. Therefore, ANF of cardiac origin appears to be a major factor initiating mineralocorticoid escape through a guanylate cyclase-dependent pathway.

Effects of Hydroxychloroquine in Patients With Cutaneous Lupus Erythematosus: A Multicenter, Double-Blind, Randomized, Parallel-Group Trial.

OBJECTIVE: To assess the efficacy and tolerability of hydroxychloroquine (HCQ) in patients with cutaneous lupus erythematosus (CLE), in a phase III clinical trial conducted in Japan. METHODS: We conducted a double-blind, randomized, parallel-group clinical trial. This was a baseline-controlled study, and the group differences were evaluated in an exploratory analysis. A total of 103 patients with active CLE (according to a Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] activity score of ≥4) were included. Patients were randomized 3:1 to receive HCQ or placebo during the 16-week double-blind period, and all patients were given HCQ during the following 36-week single-blind period. The primary efficacy end point was a reduction in the CLASI activity score at week 16. The secondary end points included the central photo evaluation (5-point scale), patient's global assessment (7-point scale), the Skindex-29 score, and investigator's global assessment (7-point scale, based on the other 3 secondary end points). In patients with systemic lupus erythematosus, fatigue and musculoskeletal pain were assessed. Safety was assessed up to week 55. RESULTS: The mean CLASI score at week 16 was significantly improved from baseline in both the HCQ group and the placebo group: mean change -4.6 (95% confidence interval [95% CI] -6.1, -3.1) (P < 0.0001), and mean change -3.2 (95% CI -5.1, -1.3) (P = 0.002), respectively, without between-group difference (P = 0.197). The investigator's global assessment demonstrated a greater proportion of "improved" and "remarkably improved" patients in the HCQ group (51.4% versus 8.7% in the placebo group [P = 0.0002 between groups]). The other secondary end points supported the efficacy of HCQ. Cellulitis, drug eruption, hepatic dysfunction, and Stevens-Johnson syndrome were shown to be serious adverse events related to HCQ use. CONCLUSION: The results of this randomized clinical trial support the efficacy and tolerability of HCQ in patients with CLE.

Predictive models for conversion of prediabetes to diabetes.

AIM: To clarify the natural course of prediabetes and develop predictive models for conversion to diabetes. METHODS: A retrospective longitudinal study of 2105 adults with prediabetes was carried out with a mean observation period of 4.7years. Models were developed using multivariate logistic regression analysis and verified by 10-fold cross-validation. The relationship between [final BMI minus baseline BMI] (δBMI) and incident diabetes was analyzed post hoc by comparing the diabetes conversion rate for low (< -0.31kg/m2) and high δBMI (≥ -0.31kg/m2) subjects after matching the two groups for the covariates. RESULTS: Diabetes developed in 252 (2.5%/year), and positive family history, male sex, higher systolic blood pressure, plasma glucose (fasting and 1h- and 2h-values during 75g OGTT), hemoglobin A1c (HbA1c) and alanine aminotransferase were significant, independent predictors for the conversion. By using a risk score (RS) that took account of all these variables, incident diabetes was predicted with an area under the ROC curve (95% CI) of 0.80 (0.70-0.87) and a specificity of prediction of 61.8% at 80% sensitivity. On division of the participants into high- (n=248), intermediate- (n=336) and low-risk (n=1521) populations, the conversion rates were 40.1%, 18.5% and 5.9%, respectively. The conversion rate was lower in subjects with low than high δBMI (9.2% vs 14.4%, p=0.003). CONCLUSIONS: Prediabetes conversion to diabetes could be predicted with accuracy, and weight reduction during the observation was associated with lowered conversion rate.

Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma.

Zic is a novel zinc finger protein which displays a highly restricted expression pattern in the adult and developing mouse cerebellum and is highly homologous to the recently cloned Drosophila pair-rule gene Opa. To clarify the mechanism for the development of the human cerebellum and its involvement in human nervous system diseases, we have isolated human Zic cDNA and examined its expression by using monoclonal antibody against recombinant Zic protein. The nucleotide sequence of human Zic cDNA is 85% homologous to that of mouse Zic cDNA. Its putative amino acid sequence is highly conserved (> 99%) except for substitution of only two amino acid residues. In situ chromosome hybridization localized the human Zic gene to chromosome band 3q24. Human Zic protein was immunohistochemically detected in the nuclei of the cerebellar granule cell lineage from the progenitor cells of the external germinal layer to the postmigrated cells of the internal granular layer. Furthermore, Zic protein was detected in medulloblastoma (26/29 cases), whereas no other tumors examined (over 70 cases including primitive neuroectodermal tumors) expressed this protein. These findings suggest that Zic is a potential biomarker for medulloblastoma as well as the human cerebellar granule cell lineage.

Alterations in circulating and cardiac tissue concentrations of brain natriuretic peptide in spontaneously hypertensive rats.

OBJECTIVE: This study was designed to investigate the modification of plasma and cardiac tissue brain natriuretic peptide concentrations in spontaneously hypertensive rats and Wistar-Kyoto rats in relation to those of atrial natriuretic peptide during the development of hypertension. METHODS: Blood pressure, tissue weight, and plasma and cardiac tissue atrial natriuretic peptide and brain natriuretic peptide concentrations were measured in conscious 5, 10, and 18 week old, spontaneously hypertensive, and in corresponding normotensive rats. Pharmacokinetics of atrial natriuretic peptide and brain natriuretic peptide were also examined. RESULTS: Plasma concentrations of both atrial natriuretic peptide and brain natriuretic peptide in hypertensive rats increased significantly with development of hypertension. The pattern was not in parallel, so that the brain natriuretic peptide/atrial natriuretic peptide ratio was high in spontaneously hypertensive rats. Concentrations of brain natriuretic peptide in the cardiac ventricle were already higher in hypertensive rats than in controls as early as 5 weeks of age, whereas atrial natriuretic peptide concentrations in the ventricle, predominantly in the left ventricles, and the highest brain natriuretic peptide/atrial natriuretic peptide ratio was in the left ventricles from 18 week old spontaneously hypertensive rats. Pharmacokinetics showed that the plasma half lives of atrial natriuretic peptide and brain natriuretic peptide were not different between the two strains. CONCLUSIONS: Although raised blood pressure stimulates both atrial natriuretic peptide and brain natriuretic peptide, production of brain natriuretic peptide in the ventricles is already increased in the prehypertensive stage, and in older hypertensive rats, it is more responsive to progression of hypertension than atrial natriuretic peptide. It is suggested that regulation of production and secretion of the two natriuretic peptides is not temporally coordinated during development of hypertension in this model.

Identification of differentially expressed genes in rat hippocampus after transient global cerebral ischemia using subtractive cDNA cloning based on polymerase chain reaction.

BACKGROUND AND PURPOSE: The purpose of this study is to identify new molecules that play important roles in the phenomena that occur in the hippocampus after transient global cerebral ischemia, as clues to better understanding of the mechanisms. METHODS: A subtractive cDNA library was established by suppression subtractive hybridization of rat hippocampal tissues after transient global cerebral ischemia. With differential screening of the library, upregulated fragments were identified. The mRNA expression levels of selected genes were measured with semiquantitative reverse transcriptase polymerase chain reaction (PCR). RESULTS: Among more than 100 isolated fragments, approximately half were determined to be identical to known sequences. The rest showed high homology to known sequences, and only 2 did not exhibit homology to any known sequences. The expression of 5 genes identified in this study increased in 24 hours after ischemia to a level twice as high as that in sham-operated controls. These included furin, prosaposin, synaptotagmin IV, heat shock protein 105, and the neutral and basic amino acid transporter (NBAT). The increases in the mRNA expression levels of the genes except NBAT, as revealed by semiquantitative reverse transcription PCR, were statistically significant at both 6 and 24 hours after ischemia. CONCLUSIONS: Genes isolated are thought to be associated with production of proteins necessary for degeneration, neuroprotection, and reconstruction of neurons. How the expression of these genes relates to functional changes after ischemia remains to be determined. PCR-based subtractive cDNA cloning is demonstrated to be a useful tool for analyzing in vivo gene expression in animal ischemia models.

Tissue-specific regulation of renal and cardiac atrial natriuretic factor gene expression in deoxycorticosterone acetate-salt rats.

Atrial natriuretic factor (ANF) is expressed in several noncardiac tissues where it may have an autocrine or paracrine function. Such function may be expected of locally synthesized ANF in the renal parenchyma. Previous investigations of the existence of ANF mRNA in the renal parenchyma have yielded conflicting results. The investigations reported here were designed to detect and measure ANF mRNA in normal rats and in rats subjected to a deoxycorticosterone acetate (DOCA)-salt treatment schedule known to strongly activate cardiac ANF gene expression. The expression of the renal ANF gene was measured using a newly developed quantitative competitive reverse transcription-polymerase chain reaction (QC-RT-PCR). This method uses an internal competitor that serves as an internal standard and makes the procedure independent of measurement relative to housekeeping genes. It was found that renal ANF mRNA levels were 10(7) times lower than those found in left or right atria, but immunoreactive (ir) renal ANF concentration by specific radioimmunoassay was 10(4) times lower than that of atrial irANF levels. Reverse-phase high-performance liquid chromatography analysis revealed that more than 99% of renal irANF is processed ANF(99-126). This finding suggests that most of the irANF measured in kidney extracts likely originates from atrial sources. Left atrial ANF mRNA levels after 1 week of DOCA-salt treatment was significantly higher than that of control rats ([21.06+/-2.99] x 10(-l5) mol/microg total RNAversus [8.59 +/-1.26] x 10(-5) mol/microg total RNA, P<.05). However, renal ANF mRNA levels in DOCA-salt rats were significantly decreased compared with those of control rats ([1.64+/-0.34] x 10(-22) mol/microg total RNA versus [3.96+/-0.61]x 10(-22) mol/microg total RNA, P<.05). These results indicate that (1) renal ANF mRNA can be consistently and specifically demonstrated after reverse transcription and PCR amplification; (2) renal and cardiac ANF synthesis are regulated in a tissue-specific, opposite manner during DOCA-salt treatment; and (3) the finding that renal ANF mRNA is downregulated by DOCA-salt treatment together with previous findings suggest the need for further investigation into the role of renal ANF mRNA downregulation in the pathogenetic mechanism that leads to volume expansion and hypertension after chronic DOCA-salt treatment.

Genetic analyses of the in vivo function of LolA, a periplasmic chaperone involved in the outer membrane localization of Escherichia coli lipoproteins.

The major outer membrane lipoprotein (Lpp) of Escherichia coli is released from the cytoplasmic membrane into the periplasm as a complex with LolA, a periplasmic chaperone, prior to the localization in the outer membrane. To determine whether or not LolA is generally involved in the outer membrane localization of lipoproteins in vivo, the chromosomal lolA gene was manipulated so as to be controlled by the lac promoter-operator. Depletion of LolA caused a severe growth defect, and impaired the outer membrane localization of Lpp and Pal, another outer membrane lipoprotein. Although LolA depletion did not immediately arrest the growth of cells lacking Lpp, disruption of the chromosomal lolA gene was lethal to the lpp strain, indicating that LolA is generally required for the outer membrane localization of lipoproteins, and therefore essential irrespective of the presence or absence of Lpp.

Absence of Carp's agent in sera of patients with multiple sclerosis in Japan.

A study was devised to test for Carp's agent in the sera of Japanese patients with multiple sclerosis (MS). The sera were obtained from 17 patients with definite MS and six patients with possible MS. Strain C3H mice were given an intraperitoneal injection of 0.1 mL of each serum. One week before and 1, 3, and 6 weeks after inoculation, blood drops from tail tip were smeared and polymorphonuclear leukocytes (PMNLs) were counted. Although the experimental animals were kept under careful control, substantial fluctuation in the number of PMNLs occurred, and the variations of PMNL count in the experimental groups were all within the normal range. We conclude that there is no Carp's agent in the sera of patients with MS in Japan.

Incidental Lewy body disease in a patient with REM sleep behavior disorder.

We studied an 84-year-old man with a 20-year history of nocturnal violent behavior during sleep, but no other clinically evident neuropsychiatric disorders. Polysomnographic investigations confirmed that he suffered from REM sleep behavior disorder (RBD). Histopathologic examination revealed he had Lewy body disease with a marked decrease of pigmented neurons in the locus ceruleus and substantia nigra. These histologic findings represent the first documented evidence of a loss of brainstem monoaminergic neurons in clinically idiopathic RBD and suggest that Lewy body disease might provide an explanation for idiopathic RBD in the aged.

Plasma and urine levels of adrenomedullin and proadrenomedullin N-terminal 20 peptide in chronic glomerulonephritis.

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. We examined the plasma and urinary levels of these peptides in patients with chronic glomerulonephritis (CGN). The mean plasma AM concentration of the patients with CGN did not differ from that of control subjects (4.17 +/- 0.17 v 3.87 +/- 0.21 fmol/mL, respectively), whereas urinary AM excretion was significantly less in the patients with CGN (5.96 +/- 0.95 v control, 8.93 +/- 1.02 fmol/mg of creatinine; P < 0.05). Plasma concentrations and urinary excretion of PAMP were significantly less for the patients with CGN compared with control subjects (0.91 +/- 0.08 v 1.23 +/- 0.20 fmol/mL; P < 0.05 and 25.0 +/- 3.0 v 35.0 +/- 3.6 fmol/mg of creatinine, respectively; P < 0. 05). The plasma AM concentration was negatively correlated with plasma renin activity (r = -0.58; P < 0.01) and aldosterone concentration (r = -0.40; P < 0.05). Urinary excretions of AM and PAMP showed significant correlations with urine excretion of sodium (r = 0.39; P < 0.05 and r = 0.49; P < 0.01, respectively). These findings suggest that AM and PAMP may have roles in the regulation of sodium in patients with CGN.

Dissociation of cardiac hypertrophy, myosin heavy chain isoform expression, and natriuretic peptide production in DOCA-salt rats.

We examined the relationship between cardiac hypertrophy, myosin heavy chain (MHC) isoform expression, and production of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) before and after the development of DOCA-salt hypertension. DOCA-salt rats exhibited significant left ventricular hypertrophy at the prehypertensive stage (1 week of treatment), without MHC isoform switch or change in natriuretic peptide gene expression. In the hypertensive stage (5 weeks of treatment), pronounced left ventricular hypertrophy was observed, and this was characterized by an increase in beta-MHC protein, resulting in a switch from 90% alpha-MHC to 51% alpha-MHC and 49% beta-MHC. ANF and BNP mRNA levels and peptide content were significantly increased at this stage. Unexpectedly, the MHC isoform switch was evident in the non-hypertrophied right ventricle to the same degree as in the left ventricle. Natriuretic peptide production was also increased in the right ventricle at 5 weeks of treatment, but to a lesser degree than in the left ventricle. In contrast, in the hypertrophied left atrium there was no MHC isoform switch, while ANF and BNP mRNA levels were augmented. Plasma ANF was significantly increased in the prehypertensive stage; this was accompanied by a partial depletion of atrial ANF stores. Plasma BNP was increased only in the hypertensive stage, reflecting an increase in ventricular BNP synthesis and secretion. These results suggest that 1) cardiac hypertrophy, MHC isoform expression, and stimulation of natriuretic peptide production are processes that may be dissociated from each other; 2) increases in plasma ANF without a concomitant increase in plasma BNP reflect atrial hemodynamic overload, while increases in both ANF and BNP in plasma are associated with ventricular hypertrophy; and 3) there exist differences in the storage, secretion, and processing patterns of ANF and BNP in the atria.

Effect of dantrolene on K(+)- and caffeine-induced dopamine release in rat striatum assessed by in vivo microdialysis.

Recently, dantrolene has been reported to affect the central nervous system in addition to peripheral targets such as skeletal muscle. We examined effects of dantrolene on K(+)- and caffeine-induced dopamine release in rat striatum using in vivo microdialysis. Perfusion with KCl via the dialysis probe for 20 min induced immediate increase in DA release. Either chelation of extracellular calcium or addition of dantrolene for 120 min preceded reapplication of 100 mM KCl for 20 min. Calcium chelation attenuated the increase in DA release induced by KCl. Application of dantrolene enhanced the KCl-induced increase in DA release, but this effect disappeared at 100 microM. Caffeine caused a dose-dependent increase in dopamine release, independently of extracellular calcium. Treatment with 100 microM dantrolene for 120 min reduced the increase in DA release induced by caffeine. These findings that dantrolene modulates dopamine release in rat striatum indicate that conventionally administered dantrolene is likely to act on the central nervous system.

Differential regulation by pregnenolone sulfate of intracellular Ca2+ increase by amino acids in primary cultured rat cortical neurons.

We investigated the effects of pregnenolone sulfate (PS) on the [Ca2+]i increase induced by gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) using fluorescence imaging. PS inhibited the 50 microM GABA-induced increase in [Ca2+]i in a dose-dependent manner with an IC50 of 30 microM. The inhibitory effect of PS was apparent within 5 min and was in a non-competitive manner, suggesting that PS may act directly to the membrane level but indirectly to the GABA binding sites. Our previous study has already shown that the GABA-induced Ca2+ increase involves GABAA receptors and the similar pathway to a high K(+)-induced Ca2+ response (Takebayashi et al., 1996). Because 50 microM of PS could not inhibit a 25 mM K(+)-induced Ca2+ increase, it seems likely that the site of the inhibitory action of PS on the GABA-induced Ca2+ increase may be independent of the pathway of the high K(+)-induced Ca2+ response, but rather at GABAA receptor complex. In contrast, PS potentiated the 50 microM NMDA-induced increase in [Ca2+]i in a dose-dependent manner. The magnitude of the NMDA response was approximately doubled in the presence of 100 microM of PS. However, PS did not affect the acetylcholine(Ach)-induced increase in [Ca2+]i. Furthermore, corticosterone had little effect on the GABA- and NMDA-induced Ca2+ increases, indicating that the alteration of the Ca2+ response is specific for PS. In conclusion, it is suggested that PS modulates differentially [Ca2+]i increase induced by GABA and NMDA.

Effect of simvastatin on proliferative nephritis and cell-cycle protein expression.

BACKGROUND: Mesangial cell proliferation is important in subsequent mesangial matrix expansion in glomerular injury. Therefore, the regulation of mesangial cell proliferation may be critical in the treatment of glomerulonephritis. Inhibition of 3-hydro-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibits the production of mevalonate and has been shown to suppress proliferation in many cell types, including mesangial cells in vitro. It is expected that HMG-CoA reductase inhibitor may suppress mesangial cell proliferation and subsequent progression of glomerulonephritis. Recently, the tight relationship between cell-cycle regulatory protein expression and mesangial cell proliferation in experimental glomerulonephritis was demonstrated. The aim of the present study is to examine the effect of simvastatin, one of the HMG-CoA reductase inhibitors, on the glomerular cell proliferation and on the expression of CDK2 or p27Kip1 in mesangial cells in experimental glomerulonephritis in vivo. METHODS: The effect of simvastatin on a rat mesangial proliferative glomerulonephritis induced by antithymocyte antibody (anti-Thy 1.1 GN) was studied. Administration of simvastatin or vehicle (for control GN) were started from two days before disease induction, and was continued to the day of nephrectomy. Nephrectomy was done at days 0, 2, 4, 7, 12 and 20 after disease induction. Immunohistochemistry for proliferating cells, macrophages, alpha-smooth muscle actin, type IV collagen and PDGF-B chain was performed, respectively, in addition to conventional periodic-acid Schiff staining. Double immunostaining for CDK2/OX-7 or p27Kip1/OX-7 was also done, respectively. RESULTS: There was no difference in the degree of the initial injuries between simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell proliferation (about 70% of proliferation was suppressed at day 4). At day 4, alpha-smooth muscle actin expression was also decreased in simvastatin-treated GN rats. Inhibition of macrophage recruitment into glomeruli by simvastatin was also a prominent feature (about 30% decrease in the number of glomerular macrophages at day 2). Simvastatin significantly suppressed subsequent mesangial matrix expansion and type IV collagen accumulation in glomeruli. Although it might simply reflect the reduction in mesangial cells, glomerular PDGF-B chain expression was reduced. There was no significant difference in plasma lipids levels at day 2 and day 4. In vehicle-treated GN rats, the number of CDK2+/OX-7+ cells (CDK2-expressed mesangial cells) in glomeruli increased significantly from day 4 to day 7. Although simvastatin suppressed mesangial cell proliferation, the increase in the number of glomerular CDK2+/OX-7+ cells was also attenuated by simvastatin treatment. There was no difference in the number of p27Kip1+/OX-7+ cells (p27Kip1-expressed mesangial cells) in the glomerulus between vehicle-treated and simvastatin-treated GN rats. CONCLUSION: Simvastatin suppressed mesangial cell proliferation and subsequent matrix expansion, and macrophage infiltration into glomeruli in anti-Thy 1.1 GN rats. The antiproliferative effect of simvastatin in this model was also associated with the reduction of CDK2 expression in mesangial cells.

Effects of brain natriuretic peptide-45, a circulating form of rat brain natriuretic peptide, in spontaneously hypertensive rats.

Rat brain natriuretic peptide-45 (rat BNP-45) has recently been isolated from rat heart and shown to be a circulating form of rat BNP. We investigated the effects of rat BNP-45 in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and compared them with those of rat alpha-atrial natriuretic peptide (alpha-ANP). BNP-45 was a potent natriuretic and hypotensive agent in both strains. The effects were comparable with those of alpha-ANP and were far greater than those of porcine BNP-26 reported previously. In SHR blood pressure decreased more than in WKY following injection of the highest dose (2.0 nmol/kg) of BNP-45 or alpha-ANP. However, WKY were more susceptible than SHR to BNP-45 for diuresis, natriuresis and urinary cGMP excretion. Moreover, a high dose of BNP-45 led to a prolonged lowering of blood pressure and urinary cGMP excretion compared to alpha-ANP, and these features were prominent in WKY. BNP-45 disappeared more slowly than alpha-ANP when the two peptide (2.0 micrograms) were injected i.v. in WKY. Thus, rat BNP-45 and alpha-ANP had comparable hypotensive and natriuretic potency; however, the action and plasma half-life of rat BNP-45 were more prolonged.

Protein kinase cdelta and alpha are involved in the development of vasospasm after subarachnoid hemorrhage.

We have previously shown the enhanced activity of protein kinase C in the membrane fraction of the canine vasospastic artery after subarachnoid hemorrhage, which increased with progression of angiographic vasospasm. This study examined identification of protein kinase C isoforms in the canine basilar artery, and the changes in expression and/or translocation of each isoform during the development of vasospasm. Vasospasm was produced by using the "two-hemorrhage" canine model in the basilar artery, and angiographic progression of vasospasm was assessed consecutively. Two isoforms, protein kinase Calpha and delta were identified in basilar arteries by Western blotting. Densitometric analysis showed that the expression of protein kinase Cdelta in the membrane fraction was significantly increased in the earlier stage, and protein kinase Calpha was increased later as vasospasm progressed. These results indicate that protein kinase Cdelta and alpha isoforms may play a significant role in the development and maintenance of vasospasm.

Serum neuroleptic activities required to inhibit relapse in schizophrenic patients--a study by radioreceptor assay.

1. The serum levels of antidopaminergic (anti-D2), anti-alpha-adrenergic (anti-NA) and antiserotonergic (anti-5HT2) activities of neuroleptics were determined in schizophrenic patients on maintenance treatment. 2. The patients whose conditions remained stable had significantly higher serum levels of anti-D2 and anti-5HT2 activities than those who were considered to be in unstable conditions after a period of remission. 3. However, the serum levels of anti-5HT2 activity in patients whose conditions remained stable varied as much as those of anti-NA activities did, so it appeared that from a pharmacological viewpoint anti-D2 activity of neuroleptics was the most important in preventing a relapse in schizophrenic patient. 4. The serum levels of anti-D2 activity required to prevent relapses differed for each neuroleptic. 5. The frequency of side effects increased concordant with increasing serum levels of anti-D2, anti-NA and anti-5HT2 activities, and unfortunately even minimum effective serum levels of anti-D2 activity elicited slight side effects in the majority patients.