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Biomedical subjects

T Nishimura

Publications and source records attributed to T Nishimura.

At least 379 records · Page 21Linked to original sources
PubMed1997

Enhancement of [123I]beta-CIT binding in the striatum with clomipramine: is there a serotonin-dopamine interaction?

Many reports support the concept of serotonergic-dopaminergic interaction in the brain. However, at present, there are few methods to study this relationship in vivo. The purpose of this study was to investigate the effect of serotonin (5-HT) uptake inhibitor, clomipramine, on a dopamine (DA) transporter ligand, [123I]beta-CIT (RTI-55), in rat brain. Dose-dependent changes in [123I]beta-CIT specific binding induced by clomipramine were studied in the striatum (rich in DA transporter) and the hypothalamus (rich in 5-HT transporter). The changes in the time-activity curves of [123I]beta-CIT specific binding after clomipramine injection were also examined in these two regions. Using the cerebellum as the reference region, k3 and k4 values with and without clomipramine administration were estimated by a two-compartment kinetic analysis. Clomipramine inhibited [123I]beta-CIT specific binding in the hypothalamus, but enhanced its specific binding in the striatum in a dose-dependent manner. Kinetic analysis showed that k3 in the striatum was increased by 55%. In conclusion, enhancement of [123I]beta-CIT binding in the striatum after clomipramine administration indicated the possibility of 5-HT-DA interaction.

Animals↗
PubMed1997

Hypothermia inhibits the alveolar epithelial injury caused by hyposmotic albumin solution during preservation of the resected human lung.

This study was conducted to determine whether hypothermia inhibited alveolar epithelial injury in the resected human lung during preservation. Hyposmotic albumin solution, 248 mOsm/kg, was instilled into the alveolar spaces of resected human lungs which were inflated with an airway pressure of 7 cmH2O and stored at either 37 degrees C or 8 degrees C for 4 h. Alveolar fluid was aspirated and the influx of lactate dehydrogenase (LDH) and globulin into the alveolar spaces, as markers of alveolar epithelial injury, was measured. Ion transport and fluid clearance across the alveolar epithelium were calculated by the changes in electrolyte and albumin concentrations in the alveolar fluid, respectively. While the LDH levels and globulin concentrations increased significantly in the hyposmotic experiments at 37 degrees C, hypothermia inhibited these increases. Alveolar fluid clearance at 37 degrees C increased to 20% in the hyposmotic experiments compared with 12% in the control isosmotic experiments; however, sodium and chloride transport in the hyposmotic experiments was not significantly different from that in the isosmotic experiments. Thus, we conclude that hypothermia at 8 degrees C inhibits alveolar epithelial injury caused by the hyposmotic solution in resected human lungs. Moreover, alveolar ion and fluid clearance mechanisms were preserved across the injured alveolar epithelial cells.

Epithelium↗
PubMed1997

Evaluation of left ventricular ejection fraction from radial long-axis tomography: a new reconstruction algorithm for ECG-gated technetium-99m sestamibi SPECT.

UNLABELLED: Radial long-axis tomography can provide views similar to contrast left ventriculography (LVG) including the basal and apical areas of the left ventricle, not possible in routine short-axis tomography. We applied this method to ECG-gated Tc-99m Sestamibi (MIBI) myocardial SPECT images to estimate the left ventricular ejection fraction (LVEF). METHODS: ECG-gated Tc-99m MIBI SPECT was performed with a temporal resolution of 10 frames per R-R interval. LVEF was calculated on the basis of left ventricular volume estimates at end diastole (ED) and end systole (ES) with using an ellipsoid body model. To validate this method, LVEF's derived from ECG-gated Tc-99m MIBI SPECT were compared with those from LVG in 11 patients with coronary artery disease. RESULTS: There was a close linear correlation between LVEF values calculated from Tc-99m MIBI SPECT and those from LVG (r = 0.89, p < 0.001), although the gated SPECT underestimated LVEF compared to LVG. The technique showed excellent reproducibility (intra-observer variability, r = 0.96, p < 0.001; inter-observer variability, r = 0.71, p < 0.005). CONCLUSION: The radial long-axis tomography technique gives a good estimate of LVEF, in agreement with estimates based on LVG. ECG-gated Tc-99m MIBI SPECT can, therefore, be applicable to assess myocardial perfusion and ventricular function at the same time.

Adult↗
PubMed1997

Detection of impaired fatty acid metabolism in right ventricular hypertrophy: assessment by I-123 beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial single-photon emission computed tomography.

Fatty acid metabolism has been reported to be impaired earlier than myocardial blood flow in left ventricular hypertrophic myocardium, e.g., in hypertrophic cardiomyopathy or hypertensive heart disease. The purpose of this study was to determine whether impaired fatty acid metabolism also occurs in right ventricular (RV) hypertrophy. The subjects consisted of 6 patients with chronic obstructive pulmonary disease, 4 with primary pulmonary hypertension, 2 each with refractory pulmonary tuberculosis, tricuspid insufficiency, pulmonary embolism, 1 each with atrial septal defect, ventricular septal defect (Eisenmenger complex), Ebstein anomaly, and endocardial defect, and 7 healthy controls. SPECT imaging with Tl-201 (Tl) and I-123 beta-methyliodophenyl pentadecanoic acid (BMIPP), and Tc-99m RBC first pass and gated blood pool scintigraphy were performed. Based on Tl planar images, the subjects were classified into 3 groups: 7 patients with no RV visualization (Group A), 11 with moderate RV visualization (Group B) and 9 with marked RV visualization (Group C). As a semi-quantitative evaluation by Tl myocardial SPECT, 3 regions in 3 representative short axial images were divided into 9 segments, each of which was graded from 0 to +3, and their sum was calculated as the RV score. The right ventricular ejection fraction (RVEF) and the left ventricular ejection fraction were obtained by Tc-99m RBC cardiac scintigraphy. The groups with marked visualization of the right ventricle had lower RVEF (p < 0.01), and there was a good correlation between the RVEF and the RV score with both Tl and BMIPP (Tl: r = -0.79, BMIPP: r = -0.70). Although a good correlation was demonstrated between the RV score with Tl and BMIPP in Groups A and B (r = 0.86, p < 0.001), in Group C, in which there was marked RV T1 visualization, the RV score with BMIPP was significantly smaller than with Tl (BMIPP vs. Tl: 11.5 +/- 3.7 vs. 16.4 +/- 3.8, p < 0.01). These findings suggest that impaired fatty acid metabolism may exist in severely hypertrophic right ventricle due to RV overload.

Aged↗
PubMed1997

Hepatotoxicity of diisopropyl ester of malonic acid and chloromalonic acids, disinfection by-products of the fungicide isoprothiolane.

The fungicide isoprothiolane (diisopropyl 1,3-dithiolane-2-ylidenemalonate) decomposes to the diisopropyl esters of malonic acid (DM), chloromalonic acid (DCM) and dichloromalonic acid (DDCM) upon aqueous chlorination. In this study, the cytotoxicity of these compounds was examined using rat hepatocytes cultured on Matrigel. DCM and DDCM caused hepatocellular death at concentrations > 0.5 mM, while DM had no effect on the cell viability even at the maximum concentration examined (4 mM). Significant lipid peroxidation, measured as 2-thiobarbituric acid reactive substances, was observed in both DCM- and DDCM-treated hepatocyte cultures, and was significantly enhanced by pretreatment with 0.1 mM bis(p-nitrophenyl)phosphate (BNPP), a carboxylesterase inhibitor. When both BNPP and SKF-525A, a cytochrome P450 inhibitor, were present in the medium, DCM-induced cytotoxicity and lipid peroxidation were significantly suppressed compared to cultures with BNPP-treatment alone. By contrast, the DDCM-induced cytotoxicity was not affected by the combined pretreatment of SKF-525A and BNPP. These results indicate that DCM is metabolically activated by cytochrome P450 in an ester form, while DDCM is activated by a mechanism other than one involving cytochrome P450. To further elucidate the cytochrome P450 isozyme involved in the metabolic activation of DCM, microsomal lipid peroxidation was studied in vitro using microsomes from rats treated with beta-naphthoflavone, musk xylene, phenobarbital, pyrazole, or dexamethasone. Among these preparations, the microsomes from dexamethasone-treated rats showed the most extensive lipid peroxidation in the presence of DCM, and the lipid peroxidation was enhanced by BNPP as observed in hepatocyte cultures. These findings suggest the possible involvement of cytochrome P450 3A in the metabolic activation of DCM.

Animals↗
PubMed1997

Changes in cytochrome P450 enzymes by 1,1-dichloroethylene in rat liver and kidney.

We examined the effect of 1,1-dichloroethylene (1,1-DCE) on microsomal cytochrome P450 (P450) enzymes in rat liver and kidney. Rats were treated intraperitoneally with 1,1-DCE daily for 4 days, at doses of 200, 400, and 800 mg/kg. Among the P450-dependent monooxygenase activities in liver microsomes, testosterone 2alpha-hydroxylase (T2AH), which is associated with CYP2C11 activity, was remarkably decreased by 800 mg/kg 1,1-DCE. The level relative to control activity was < 10%. Furthermore, immunoblotting showed that 1,1-DCE (> or = 400 mg/kg) significantly decreased CYP2C11/6 protein levels in liver microsomes. In addition, 7-methoxyresorufin O-demethylase (MROD), 7-ethoxycoumarin O-deethylase (ECOD), benzphetamine N-demethylase (BZND), chlorzoxazone 6-hydroxylase (CZ6H), and testosterone 6beta-hydroxylase (T6BH) activities were significantly decreased by the highest dose of 1,1-DCE (by 40-70%). However, the activities of other P450-dependent monooxygenases, namely 7-ethoxyresorufin O-deethylase (EROD), 7-benzyloxyresorufin O-debenzylase (BROD), aminopyrine N-demethylase (APND), erythromycin N-demethylase (EMND), lauric acid omega-hydroxylase (LAOH), and testosterone 7alpha-hydroxylase (T7AH) were not affected by 1,1-DCE at any dose. Immunoblotting showed CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A2/1 protein levels were significantly decreased by 60-66% by 1,1-DCE (800 mg/kg), whereas that of CYP4A1/2 was not affected by any dose of 1,1-DCE. By contrast, among the P450-dependent monooxygenase activities in kidney microsomes, only CZ6H activity was increased by 1,1-DCE (1.6-fold at 800 mg/kg). Also, it was observed that 1,1-DCE (800 mg/kg) significantly increased CYP2E1 protein levels by immunoblotting (approximately 1.5-fold). These results suggest that 1,1-DCE changes the constitutive P450 isoforms in the rat liver and kidney, and that these changes closely relate to the toxicity of 1,1-DCE.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1997

Ocular manifestations in adult T-cell leukemia/lymphoma.

Ocular manifestations of adult T-cell leukemia/lymphoma (ATL) are rare events. However, several ocular lesions which resulted from human T-cell leukemia virus type I (HTLV-I) infection have been reported, including direct infiltration of ATL cells, cytomegalovirus retinitis, and HTLV-I-associated uveitis (HAU). The aim of this study was to characterize ocular involvement in ATL and to correlate these lesions with HTLV-I proviral DNA integration. Three patients with acute-type ATL and ocular lesions were evaluated hematologically and ophthalmologically. Analysis of HTLV-I proviral DNA was carried out with a standard Southern blot technique using DNA from abnormal lymphocytes in peripheral blood. Two patients developed intraocular lesions located within intermediate and/or posterior segments which were caused by infiltration of ATL cells. Ocular lesions in one patient, which were localized to the anterior-intermediate segment, closely resembled those of HAU. Analysis of HTLV-I proviral DNA revealed multiple integrations in all three patients. The present study indicated heterogeneity in ocular manifestations of ATL. Multiple HTLV-I proviral DNA integrations may be associated with intraocular involvement in this disease.

Adult↗
PubMed1997

A clinicopathological study of a patient with familial amyotrophic lateral sclerosis associated with a two base pair deletion in the copper/zinc superoxide dismutase (SOD1) gene.

The recognition of mutations in the copper/zinc superoxide dismutase (SOD1) gene in familial amyotrophic lateral sclerosis (FALS) has been a landmark in ALS research. We report a clinicopathological study of a female patient with FALS showing a two base pair deletion in exon 5 of the SOD1 gene. Her clinical course was rapid and she died 2 years after the onset. The SOD1 activity was down to 30% of the normal level. Western blot analysis did not reveal the mutant protein which was expected to be approximately 2.4 kDa smaller than normal SOD1 protein in molecular mass. In contrast to the neuropathological findings of the previously reported cases showing the same mutation, our case was characterized by sparing of the dorsal column and the presence of only a modest number of intracytoplasmic eosinophilic inclusions showing weak or partial immunoreaction for neurofilament and negative reaction for SOD1. Thus, the same mutation in the SOD1 gene does not necessarily induce consistent pathological changes in the central nervous system.

Adult↗
PubMed1997

Developmental expression of extracellular matrix components in intramuscular connective tissue of bovine semitendinosus muscle.

We have investigated the expression patterns of extracellular matrix components in intramuscular connective tissue during the development of bovine semitendinosus muscle by means of indirect immunofluorescence techniques. Types I, III, V, and VI collagen and fibronectin were located in the endomysium and the perimysium. Type IV collagen, laminin, and heparan sulfate proteoglycans (PGs) were exclusively located in the endomysium, and dermatan sulfate PGs existed only in the perimysium. The localization of these components in the intramuscular connective tissue of semitendinosus muscle remained unchanged throughout prenatal and postnatal growth of cattle, suggesting that they are essential for forming and maintaining structures of the endomysium and perimysium in bovine semitendinosus muscle. On the other hand, decorin was undetectable in the endomysium of neonates, although other matrix components were already expressed. It was expressed slightly in the endomysium of 2-month-old calves, and clearly detectable in the endomysium of cattle more than 6 months old. Chondroitin sulfate PGs were barely detectable in the perimysium of fetuses and neonatal calves, and progressively appeared during postnatal development of the muscle. It seems likely that these PGs are closely related to the postnatal development of the endomysium and perimysium.

Aging↗
PubMed1997

Locations of crossover breakpoints within the CMT1A-REP repeat in Japanese patients with CMT1A and HNPP.

The crossover breakpoints for Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are located in the CMT1A-REP repeat flanking a 1.5-Mb region of chromosome 17p11.2-12. The precise locations of the breakpoints are heterogeneous, and we analyzed the relative frequency distribution of breakpoints in 33 unrelated Japanese CMT1A and 3 unrelated HNPP families. The CMT1A-REP repeat region was divided into five regions, A, B, C, D and E, based on restriction site differences between the proximal and distal CMT1A-REP repeats. The frequency distribution of breakpoints within the CMT1A-REP repeat in the Japanese patients was 3% in region A, .78% in B/C and 19% in D, which is similar to that in Caucasian patients. This result also indicates that an 8-kb region defined by region B/C is a recombinational hotspot within the CMT1A-REP repeat in Japanese patients.

Asian People↗
PubMed1997

Contribution of hypoxia to the development of cardiomyopathy in hamsters.

OBJECTIVE: It has been hypothesized that microvascular spasms cause cardiomyopathy. To elucidate the contribution of hypoxia to the development of cardiomyopathy, the newly-developed hypoxia tracer, Tc-99m nitroimidazole, was applied to detect myocardial hypoxia in a hamster model. METHODS: Tc-99m nitroimidazole (180 MBq) and I-125 iodoantipyrine (370 kBq) were injected into cardiomyopathic Syrian hamsters or control hamsters at age 10, 25, and 40 weeks (n = 6 in each group). The myocardial uptake of Tc-99m nitroimidazole was measured and dual tracer autoradiography was performed. RESULTS: Histologic study revealed that the cardiomyopathic hamsters at age 10, 25 and 40 weeks were in the myocytolytic stage, the fibrotic and healing stage, and the hypertrophy and dilatation stage, respectively. Tc-99m nitroimidazole uptake was significantly greater in the cardiomyopathic hamsters than in the controls at age 25 weeks (cardiomyopathic hamsters, 33.3 +/- 4.7% g dose/g; control, 25.2 +/- 3.1), whereas there were no significant differences between both strains at age 10 and 40 weeks. The quantified concentration of I-125 iodoantipyrine in the cardiomyopathic hamster at age 40 weeks was significantly lower than that in the controls. When the Tc-99m nitroimidazole uptake was normalized by I-125 iodoantipyrine concentrations, the cardiomyopathic hamsters at age 25 and 40 weeks showed significantly greater uptake than the controls. CONCLUSION: The myocardium in cardiomyopathic hamsters was hypoxic at the fibrotic and healing stage and may be hypoxic at the hypertrophy and dilatation stage. This may contribute to the development of cardiomyopathy.

Animals↗
PubMed1997

Differentiation between benign and metastatic cervical lymph nodes with ultrasound.

OBJECTIVE: The differentiation between benign and metastatic lymph nodes with ultrasound (US) is based primarily on the evaluation of size, shape, margin and internal echo structure. The aim of this study is to determine whether these parameters are reliable indicators and to correlate internal echo structure and histopathological findings. MATERIALS AND METHODS: Seventy-one nodes in 21 patients with pathologically proven oral squamous cell carcinoma were examined. The shortest diameter, the short/long diameter ratio (S/L ratio), margins and internal echo structure of the lymph node were evaluated by US. The internal echo structure was divided into six patterns: homogeneous hypoechoic, homogeneous hyperechoic, heterogeneous, eccentric hyperechoic, centric hyperechoic and anechoic pattern. In addition, internal echo structure was correlated with histopathological findings. RESULTS: In 71.4% of the metastatic nodes, the shortest diameter was more than 10 mm and the S/L ratio was higher than that of benign nodes (average 0.71). Eleven (84.6%) of the 13 lymph nodes with irregular margins were metastatic. Heterogeneous and anechoic patterns were observed in metastatic nodes, whereas homogeneous hypoechoic and eccentric hyperechoic patterns were present in benign nodes. On ultrasonography with the corresponding histopathological findings, echogenic areas in the homogeneous hyperechoic, heterogeneous and centric hyperechoic patterns of metastatic nodes proved to be necrosis or fibrosis. Eccentric hyperechoic areas in benign nodes corresponded to the hilus and surrounding fatty tissue. CONCLUSIONS: The shortest diameter, S/L ratio, margin and internal echo structure were considered to be critical indicators to differentiate between benign and metastatic nodes. Secondary changes caused by tumour infiltration, necrosis, or fibrosis should be assessed when metastatic lymph nodes are differentiated from benign ones by internal echo structure.

Adult↗
PubMed1997

Paradoxical positive nitrogen balance in burn patients receiving high-dose administration of insulin for nutritional care.

BACKGROUND: Nitrogen balance in patients who need high-dose administration of insulin has not been evaluated clinically. The purpose of this study was to compare the difference in nitrogen balance between burn patients who received high-dose administration of insulin and those who did not. METHODS: This study was performed in 19 severely burned adults with no liver or kidney failure. Patients were divided into two groups on the basis of the mean ratio of administered insulin and calorie intake (I/C) for the initial 4 weeks, a high I/C group (n = 9) and a low I/C group (n = 10). There were no significant differences between the two groups regarding age, percentage of area burned, and body weight. Nitrogen balance, blood urea nitrogen, and urine urea nitrogen were measured in all patients. Plasma concentrations of glucose, insulin, glucagon, cortisol, and urinary excretion of 3-methyl-histidine were measured in 12 patients (six in each group). RESULTS: Until day 10 both groups exhibited similar changes in plasma concentrations of glucose, insulin, glucagon, and cortisol. Subsequently, plasma concentrations of insulin and glucagon began to decrease in the low I/C group, whereas a high level was sustained in the high I/C group (p < 0.05). Plasma glucose and cortisol measurements showed no significant differences between the two groups. Blood urea nitrogen levels and urinary excretion of 3-methyl-histidine were not different between the two groups. Urine urea nitrogen excretion in the high I/C group, however, was significantly lower than that in the low I/C group from day 8 (p < 0.05). Thus the high I/C group achieved positive nitrogen balance more quickly than the low I/C group. Paradoxically, however, the high I/C group was at higher risk of septic complications and exhibited higher mortality than the low I/C group (p < 0.05). CONCLUSIONS: These results indicate that an improvement in nitrogen balance, which is accepted as a good thing in the management of critically ill patients, is not necessarily good in the high I/C group and that residual nitrogen was retained within the body in the high I/C group.

Adult↗
PubMed1997

Effect of 2,4,4'-trichloro-2'-hydroxydiphenyl ether on cytochrome P450 enzymes in the rat liver.

We examined the effect of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) on microsomal cytochrome P450 (P450) enzymes in rat liver. Rats were treated intraperitoneally with Irgasan DP300 daily for 4 days, at doses of 0.2, 0.4 and 0.8 mmol/kg. Among the P450-dependent monooxygenase activities, 7-benzyloxyresorufin O-debenzylase (BROD) and 7-pentoxyresorufin O-depentylase (PROD) in rats, which are associated with CYP2B1, were remarkably induced by all doses of Irgasan DP300. The relative induction to each control activity were from 5.6- to 22.3-fold and 4.9- to 20.2-fold, respectively. Furthermore, immunoblotting showed that CYP2B1/2 protein level in rat liver microsomes was increased from 10.8- to 34.4-fold by Irgasan DP300. In addition, 7-ethoxycoumarin O-deethylase (ECOD) and p-nitrophenol hydroxylase (PNPH) activities were significantly increased by Irgasan DP300 at all doses (from 1.4- to 4.9-fold). Although the activities of other P450-dependent monooxygenases, namely aminopyrine N-demethylase (APND), aniline p-hydroxylase (ANPH), erythromycin N-demethylase (EMND), lauric acid omega-hydroxylase (LAOH) and testosterone 6 beta-hydroxylase (TS6BH) were increased at high doses (> or = 0.4 mmol/kg) of Irgasan DP300, the relative level was lower than those of the CYP2B1-dependent monooxygenases such as BROD and PROD. However, 7-ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD), testosterone 2 alpha-hydroxylase (TS2AH) and testosterone 7 alpha-hydroxylase (TS7AH) activities were not affected by any doses of Irgsan DP300. Immunoblotting showed that CYP3A2/1 and CYP4A1 protein levels were significantly induced from 1.3- to 2.2-fold by Irgasan DP300 (> or = 0.4 mmol/kg), whereas those of CYP1A1/2, CYP2C11/6 and CYP2E1 were not affected by any doses of Irgasan DP300. These results suggest that Irgasan DP300 induces the P450 isoforms of CYP2B subfamily in the rat liver, and that the induced P450 isozymes closely relates to the toxicity of Irgasan DP300 or its chlorinated derivatives.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1997

The origin of bone formed by heterotopic periosteal autografts.

PURPOSE: This study tested the hypothesis that a significant amount of the new bone produced by heterotopic periosteal autografts is derived osteoinductively because proliferating periosteal cells express the bone morphogenetic protein (BMP). MATERIALS AND METHODS: Rabbit ulnar and radial periosteum were autografted as free grafts (FGs) to the forelimb musculature, and as millipore diffusion chambers grafts (MDCGs) to the rectus abdominus muscle. The grafts were recovered at 3, 5, 7, 14, and 28 days postoperation, fixed in 4% paraformaldehyde, demineralized in 0.6N HCL, and 4.0 microns paraffin-embedded sections were immunostained with monoclonal antibody against recombinant human (rh) BMP-2. RESULTS: Sections from FGs recovered 5 to 28 days postoperatively exhibited cartilage and bone; fibrous tissue, cartilage, bone, and osteochondroid differentiated within MDCGs. Although BMP-2 was expressed by mesenchymal cells, osteoblasts, osteocytes, and osteoclasts, none of the MDCGs produced the osteoinductive signature of transmembrane bone formation. CONCLUSIONS: These observations indicated that the larger fraction of the new bone produced by heterotopic periosteal autografts is derived from the graft cells.

Animals↗
PubMed1997

Reduction of plasma cholesterol levels and induction of hepatic LDL receptor by cerivastatin sodium (CAS 143201-11-0, BAY w 6228), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in dogs.

The effects of cerivastatin sodium (BAY w 6228), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma cholesterol concentrations and the induction of hepatic LDL receptors were investigated with beagle dogs and Hep G2 cells. Oral administration of cerivastatin (0.01, 0.03, and 0.1 mg/kg per day) for 3 weeks reduced plasma total and very low-density lipoprotein plus low-density lipoprotein (VLDL + LDL) cholesterol concentrations and increased hepatic LDL receptor binding activity in dogs. Scatchard plot analysis revealed a 1.9-fold increase in the maximum binding capacity of hepatic LDL receptors in cerivastatin-treated animals. Similar results were obtained by administration of pravastatin (1.0 and 5.0 mg/kg/day) for 3 weeks. Binding activity of the LDL receptor, as well as receptor mRNA and protein concentrations, were increased in a dose-dependent manner (0.01-1.0 microM) by exposure of Hep G2 cells to cerivastatin. The results suggest that cerivastatin reduces plasma cholesterol concentrations by increasing hepatic LDL receptor expression. The mechanism of lowering cholesterol concentration by cerivastatin was the same as with the other previously examined HMG-CoA reductase inhibitors, but the effects with cerivastatin were apparent at doses much lower than the effective doses of the other drugs. Cerivastatin, therefore, shows potential for clinical use as a potent and efficacious plasma cholesterol-lowering drug.

Animals↗
PubMed1997

Variable deposition of amyloid beta-protein (A beta) with the carboxy-terminus that ends at residue valine40 (A beta 40) in the cerebral cortex of patients with Alzheimer's disease: a double-labeling immunohistochemical study with antibodies specific for A beta 40 and the A beta that ends at residues alanine42/threonine43 (A beta 42).

Amyloid beta-protein (A beta) deposits in the cerebral cortices of patients with Alzheimer's disease (AD) were investigated immunohistochemically to determine their carboxy terminal sequences. Antibodies specific for A beta terminating at residue valine40 (A beta 40) and at residues alanine42/threonine43 (A beta 42) were used. Virtually all parenchymal A beta deposits were positive for A beta 42. Many of these deposits were also partially or completely labeled for A beta 40. The degree of A beta 40 labeling varied from area to area within a given brain and from AD case to AD case. In contrast to parenchymal deposits, A beta 40 labeled essentially all the vascular deposits which constitute amyloid angiopathy (AA), with A beta 42 occurring variably in some of these deposits. Occasional AA was found, however, in which A beta 42 predominated or was exclusively deposited. Such a diversity of A beta species, both in brain parenchyma and in AA, suggests that multiple C-terminal processing mechanisms occur in the cell types responsible for these deposits.

Aged↗