Both a Calcium Antagonist and ACE Inhibitor Reverse Hypertrophy in Hypertension But a Calcium Antagonist also Depresses Contractility

The aim of this study was to compare the effects of a calcium antagonist, nicardipine SR, with an angiotensin-converting enzyme (ACE) inhibitor, alacepril, on the regression of left ventricular hypertrophy (LVH) and function. Twenty patients with LVH, aged 42–73 years, were treated with nicardipine SR or alacepril. Ten patients were treated with nicardipine SR (40–80 mg) for 21 months, and the other 10 patients were treated with alacepril (25–100 mg) for 18 months. All patients underwent echocardiography to assess left ventricular structure and function before and after the treatment. After nicardipine SR or alacepril treatment, blood pressure was decreased significantly from 176.0 ± 13.9/97.0 ± 5.3 mmHg to 140.0 ± 14.0/77.4 ± 7.2 mmHg and from 168.2 ± 22.3/99.0 ± 5.5 mmHg to 138.4 ± 12.5/85.2 ± 9.7 mmHg, respectively (both p < 0.01), whereas heart rate did not change (73.8 ± 14.6 beats/min vs. 69.9 ± 13.5 beats/min and 71.6 ± 9.7 vs. 65.8 ± 8.1 beats/min, respectively). The left ventricular mass index decreased significantly from 133.2 ± 11.7 g/m2 to 114.4 ± 15.7 g/m2 with nicardipine SR and from 137.1 ± 14.8 g/m2 to 99.3 ± 23.0 g/m2 with alacepril (both p < 0.01). The fractional shortening, peak shortening rate, and peak lengthening rate all improved significantly after each treatment. The end-systolic wall stress/left ventricular end-systolic volume index, as an index of left ventricular contractility, was decreased significantly after treatment with nicardipine SR but was not changed after treatment with alacepril. In conclusion, both nicardipine SR and alacepril similarly reduced LVH and improved left ventricular systolic and diastolic function. However, alacepril did not alter left ventricular contractility, whereas nicardi-pine SR decreased left ventricular contractility.     

Chronic estrogen supplementation following ovariectomy improves the emotional stress-induced cardiovascular responses by indirect action on the nervous system and by direct action on the heart.

BACKGROUND: Takotsubo cardiomyopathy is triggered by emotional or physical stress especially in post-menopausal women. A reduction in estrogen levels following menopause might underlie the high incidence of takotsubo cardiomyopathy. METHODS AND RESULTS: The left ventricular contraction between ovariectomized rats (OVX) and OVX with estrogen supplementation (OVX + E) while subjected to immobilization stress (IMO) was compared. The IMO in combination with general anesthesia impaired the left ventricular contraction in both OVX and OVX + E. Estrogen supplementation tended to improve the IMO-induced cardiac dysfunction and significantly attenuated the increase of blood pressure and heart rate. To understand the protective mechanism of estrogen, the expression of c-fos mRNA, a marker of cellular activation was compared. The mRNA expression of cardioprotective substances in the heart was also investigated. In the OVX + E, the levels of c-fos mRNA were significantly decreased in the paraventricular hypothalamic nucleus, adrenal gland and left ventricle, suggesting that an increase of estrogen attenuates the emotional stress-induced hypothalamo-sympatho-adrenal outflow from the central nervous system to the target organs. An expression of heat shock protein 70 and atrial natriuretic peptide was significantly augmented in the OVX + E. CONCLUSIONS: These data suggest that estrogen supplementation partially prevents emotional stress-induced cardiovascular responses both by indirect action on the nervous system and by direct action on the heart.     

Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells

Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (P<0.05) or cells exposed to mannitol (33 mmol/L). Overexpression of HO-1 was coupled with an increase in HO activity and carbon monoxide synthesis, decreased cellular heme, and acceleration in all phases of the cell cycle (P<0.001). The rate of cell cycle or cell birth rate was increased by 29% (P<0.05) in cells overexpressing HO-1 but decreased by 23% (P<0.05) in cells underexpressing HO-1 compared with control cells. Exposure to high glucose significantly decreased cell-cycle progression in control cells and in cells underexpressing HO-1 but did not decrease cell-cycle progression in cells overexpressing HO-1. High glucose induced p21 and p27 in control cells but not in cells overexpressing HO-1. The addition of tin-mesoporphyrin (SnMP), an inhibitor of HO activity, reversed the HO-1-mediated decrease of p21 and p27 in cells overexpressing HO-1. These findings identify a novel effect of HO-1 on endothelial cell growth and indicate that heme metabolism and HO-1 expression regulate signaling systems in cells exposed to high glucose, which controls cell-cycle progression.     

High concentration simvastatin induces apoptosis in fibroblast-like synoviocytes from patients with rheumatoid arthritis

OBJECTIVE: We previously reported that 10 mg/day of simvastatin significantly reduced clinical scores of rheumatoid arthritis (RA) in patients with active RA with hypercholesterolemia. We have also reported that a certain pharmacological concentration of simvastatin, i.e., 0.05-0.1 microM, inhibits the production of interleukin 6 (IL-6) and IL-8 and the cell proliferation induced by tumor necrosis factor-alpha (TNF-alpha) in fibroblast-like synoviocytes (FLS) derived from patients with RA in vitro. We investigated other effects of simvastatin on FLS from the standpoint of cell viability and apoptosis. METHODS: RA FLS were cultured with or without 0.05-50 microM simvastatin for 48 h. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured by flow cytometric analysis using propidium iodide and annexin-V. Caspase-3 and -9 activities were analyzed by colorimetric assays. RESULTS: High concentrations of simvastatin, i.e., 1.0-50 microM, reduced cell viability and induced prominent apoptosis in FLS in a dose-dependent manner. The apoptosis induced by simvastatin was caspase-3- and caspase-9-dependent. These effects were completely reversed in the presence of mevalonic acid or geranylgeranyl-pyrophosphate, but not in the presence of farnesyl-pyrophosphate. Further, a geranylgeranyl transferase inhibitor and a RhoA kinase inhibitor mimicked the effect of simvastatin. CONCLUSION: These data, together with our previous report, suggest that low (pharmacological range) and high concentrations of simvastatin affect FLS differently: (1) at a low concentration, it inhibits IL-6 and IL-8 production and the cell proliferation of FLS induced by TNF-alpha (2) at high concentrations, it induces apoptosis in FLS. Understanding this dose-dependent biphasic effect of simvastatin may prove important for its clinical applications in the treatment of RA.     

The neurotoxicity of psychoactive phenethylamines “2C series” in cultured monoaminergic neuronal cell lines

Forensic Toxicology - The aim of this study was to evaluate the neurotoxicity of psychoactive abused 2,5-dimethoxy-substituted phenethylamines “2C series” in monoaminergic neurons....     

Strength estimation of a moving 125Iodine source during implantation in brachytherapy: application to linked sources

This study sought to demonstrate the feasibility of estimating the source strength during implantation in brachytherapy. The requirement for measuring the strengths of the linked sources was investigated. The utilized sources were ¹²⁵I with air kerma strengths of 8.38–8.63 U (μGy m² h^–1). Measurements were performed with a plastic scintillator (80 mm × 50 mm × 20 mm in thickness). For a source-to-source distance of 10.5 mm and at source speeds of up to 200 mm s^–1, a counting time of 10 ms and a detector-to-needle distance of 5 mm were found to be the appropriate measurement conditions. The combined standard uncertainty (CSU) with the coverage factor of 1 (k = 1) was ∼15% when using a grid to decrease the interference by the neighboring sources. Without the grid, the CSU (k = 1) was ∼5%, and an 8% overestimation due to the neighboring sources was found to potentially cause additional uncertainty. In order to improve the accuracy in estimating source strength, it is recommended that the measurment conditions should be optimized by considering the tradeoff between the overestimation due to the neighboring sources and the intensity of the measured value, which influences the random error.     

The physiological identification of pyramidal tract neurons within transplants in the rostral cortex taken from the occipital cortex during development

Axons from neurons in the occipital cortex transiently extend to the pyramidal tract (PT) during the early postnatal development of rats. Normally, these axons are eliminated by the end of the third postnatal week. However, if a portion of fetal occipital cortex is transplanted to the parietofrontal region in newborn hosts then some neurons in the transplant will extend pyramidal tract axons and maintain them. Intracortical microstimulation and electrophysiological recording techniques were used to identify the physiological characteristics of the transplanted pyramidal tract cells and to determine if motor effects could be elicited from the occipital transplant. Microstimulation of the transplant did not reliably evoke movement but the low density and disarray of PT cells within the transplant might account for this. Recording from within the transplant revealed that the overall cell activity was depressed. We were able to identify neurons within the transplant which responded antidromically to stimulation of the pyramidal tract, indicating that their axons have the capacity to conduct impulses and are therefore likely to have developed some viable connections. The functional significance of such projections remains uncertain.     

The distribution of GABA and glycine response in the mouse brain using Xenopus oocytes

Injection of mRNA from different regions of the central nervous system (CNS) of the mouse into the Xenopus oocyte caused a difference in the relative glycine to gamma-aminobutyric acid (GABA) response of the oocyte. Glycine caused the response in oocytes injected with brainstem mRNA but hardly in oocytes injected with cerebrum mRNA and in oocytes injected with cerebellum mRNA. In contrast, GABA caused the response in oocytes injected with mRNA from each of the 3 parts of the CNS. These obvious regional differences may reflect the distribution of the receptors to each plausible neurotransmitter in the CNS.     

An appraisal of segmental pancreatectomy for benign tumors of the pancreatic body: A report of two cases

To preserve pancreatic and splenic function, segmental pancreatectomy with pancreatojejunostomy was performed on two patients with benign pancreatic tumors, and a 3-year follow-up study was conducted. The pancreatic endocrine functions assessed by 75 g oral glucose tolerance test were normal 3 years after surgery, and the exocrine functions returned to within the normal range 1 month after surgery according to a pancreatic function diagnostant (PFD) test. The platelet count increased transiently to 48.9×10⁴/mm³, and 70.5×10⁴/mm³, in the two patients, respectively, but returned to the preoperative value 1 month postoperatively. The operative times were 7 h 51 min and 5 h 3 min, which included the time taken for intraoperative ultrasonography and frozen section diagnosis, and the blood losses were 183 ml and 212 ml. The postoperative hospitalization period averaged 39 days and no complications developed in either patient. The method of performing segmental pancreatectomy, initially reported by Letton and Wilson for cases of pancreatic trauma, was evaluated and successfully applied to benign pancreatic tumors.     

Intraductal papillary mucinous neoplasms of the pancreas: an analysis of protein expression and clinical features

Background/Purpose The molecular pathology of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas has not been well characterized, and there are no reliable markers to predict the presence of associated invasive carcinoma in patients with IPMNs. We investigated the clinicopathologic characteristics of 37 IPMNs and the immunohistochemical findings of these tumors to investigate the malignancy of IPMNs. Methods Between May 1992 and September 2003, 37 patients with IPMNs, 24 with adenoma and 13 with carcinoma, underwent pancreatic resections at Sapporo Medical University Hospital, Japan. In tumor specimens from these patients, we immunohistochemically analyzed the expression of p53 protein, proliferating-cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), matrix metalloproteinase-7 (MMP-7), and E-cadherin. Clinical features and follow-up after resection were recorded. Results Aberrant expression of the proteins examined was frequently observed. Namely, there were significant differences in the expression of MMP-7 according to clinicopathological characteristics. Positive expression of MMP-7 was found in all of nine patients with infiltrating ductal pancreatic adenocarcinoma (IDC) and in all of seven patients with invasive intraductal papillary mucinous adenocarcinoma (IC-IPMC); however, 33.3% of patients with noninvasive IPMA, 58.3% of patients with intraductal papillary mucinous adenoma (IPMA), and all normal pancreatic tissues were negative for MMP-7; differences which were statistically significant (P < 0.05). Conclusions Our current results indicate that MMP-7 may play a significant role in the progression of noninvasive to invasive IPMC.