Assessment of atherosclerotic lesions and distensibility of the thoracic aorta in familial hypercholesterolemia by biplane transesophageal echocardiography]

Atherosclerosis involving the thoracic aorta frequently occurs in patients with familial hypercholesterolemia (FH). In this study, we employed two-dimensional (2-D) transesophageal echocardiography (TEE: 5 MHz) to assess atherosclerotic lesions of the thoracic aorta in 9 patients with FH (47.8 +/- 10.3 yrs) and 11 age-matched normal control subjects. Biplane TEE probe (i.e., transverse or sagittal scan transducer) was used to permit direct imaging of the distal half of the ascending aorta. The atherosclerotic lesions were classified based on the severity of the aortic wall sclerosis as intimal thickening (I.), atheromatous plaque, (II.) and calcification (III.). In all of the patients with FH, atherosclerotic lesions of grade I. or greater were observed particularly in the aortic arch and descending aorta, while, lesions more severe than grade I. in the thoracic aorta were not observed in any of the control subjects. In 6 FH patients (67%), atherosclerotic lesions more severe than grade II. were frequently observed, which were more frequent in the aortic arch and descending aorta than in the ascending aorta.     

Lipolytic activities of p-aminophenol and n-decylamine in endogenous lipid droplets from rat adipocytes

Lipolytic agents such as adrenaline (epinephrine), dibutyryl cyclic AMP (DBcAMP) and theophylline possess common structural characteristics, the existence of a positive charge and a hydrophobic area. p-Aminophenol, which has the same structural characteristics, was found to induce lipolysis in the endogenous lipid droplets from rat adipocytes. It was demonstrated that the positive group and the hydrophobic area of p-aminophenol are essential requirements for its lipolytic activity. Among various amine derivatives, only n-decylamine was found to induce lipolysis in the endogenous lipid droplets. Although the lipolytic action of n-decylamine is fairly low, it possesses remarkable inhibitory effects on both adrenaline- and DBcAMP-induced lipolytic activities. Furthermore, n-decylamine is found to inhibit competitively the DBcAMP-induced lipolysis.     

Cardiac arrest episodes by cardiomyopathy following total pancreatectomy, a case report

A 47-year-old man with advanced pancreatic carcinoma underwent total pancreatectomy with resection of the involved portal vein. His postoperative course was complicated by a couple of cardiac arrest episodes. The first episode occurred seven weeks after surgery during drip infusion of CDDP, and later on during the thirteenth week after surgery. There was no apparent cause for those episodes. On both occasions resuscitation was performed adequately. The second arrest was followed by deep inverted T waves on ECG, however, not by elevation of serum CPK-MB. Because of this, myocardial infarction was ruled out. The diagnosis of cardiomyopathy was made possible through the discovery on the echocardiogram of a hypertrophied left ventricle with thick interventricular septum. Then, on catheterization, myocardial squeezing in the left anterior descending coronary artery was noticed. Finally, histological findings concerning the biopsied cardiac muscle led to the same diagnosis. Cardiac arrest in this case seemed to be due to arrhythmia caused by cardiomyopathy. Echo cardiography should be routinely used as part of the examination prior to extended major surgery.     

Autoradiographic demonstration of the distribution of vagal afferent nerve fibers in the epiglottis of the rabbit

After injection of [3H]leucine into the nodose ganglion of a rabbit autoradiographic examination of the distribution of vagal afferent fibers in the epiglottal wall revealed many nerve bundles of labeled afferent fibers present in the submucosal plexus between the cartilage tissue and the mucosa. The labeled afferent fibers, most of which were myelinated (while a few were unmyelinated), descended towards the mucosa, and then appeared to demyelinate at the subepithelial layer of the mucosa. The labeled afferent fibers entered the mucosal epithelium, terminated as free endings in the intercellular space among the epithelial cells, and extended near the mucosal surface. Grains were also observed near the taste buds in the epithelium, which suggests that some vagal afferent fibers innervated the epiglottal taste buds.     

Synthesis and in vitro degradations of low-molecular-weight copolyesters composed of L-lactic acid and aromatic hydroxy acids

L -lactic acid (LA) was copolycondensed with various aromatic hydroxy acids such as p-hydroxybenzoic acid (HBA), p-hydroxyphenylacetic acid (HPAA), and p-3-(hydroxyphenyl)propionic acid (HPPA) in the absence of catalysts, in order to investigate the copolymerizability and in vitro degradation. The results of ¹H NMR spectroscopy and gel permeation chromatography (GPC) showed that the reaction proceeds quantitatively, but the molecular weight of the copolyesters is relatively low. The in vitro degradation pattern of copoly(LA/HPPA) was changed into an S-type from a parabolic-type with increasing HPPA content in the copolyester, in contrast to only parabolic-type for both copoly(LA/HBA) and copoly(LA/HPAA).     

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.     

Expression of macrophage inflammatory protein-1α (MIP-1α) in human endometrium throughout the menstrual cycle

Objective To investigate the distribution and the role of macrophage inflammatory protein-la (MIP- 1α) in human endometrium during cyclic changes.
Setting Department of Obstetrics and Gynaecology, Shiga University of Medical Science and University Hospital.
Materials Eighteen endometrial tissue specimens surgically resected or biopsied from women with normal menstrual cycles, without hormonal disorder or endometrial diseases.
Methods By immunohistochemistry, using monoclonalantibodies (lambda delta 78 for MIP-la and CR3/43 for human leukocyte antigen-DR (HLA-DR)).
Results Immunoreactivity for anti-MIP-lα was distributed diffusely in epithelial cells throughout the proliferative and secretory phases but was absent during menstruation due to degenerative or necrotic changes. HLA-DR was expressed in epithelial cells only in the late secretory phase and was not expressed in stromal cells.
Conclusion Immunohistochemicalanalysis showed the presence of MIP- lα in the endometrial epithelium. Expression of HLA-DR in epithelial cells was observed only in the late secretory phase, suggesting that accumulation of MIP-lα in epithelium occurred by self production and not via a receptor mediated pathway. MIP-lα was released from the denuded epithelium during menstruation and appeared to contribute to the accumulation of monocytes/macrophages into the endometrial cavity. MIP-la has a number of biological effects other than monocytic chemotaxis, and some of these effects may be exerted in the endometrial tissue.     

Reactive oxygen species mediate compensatory glomerular hypertrophy in rat uninephrectomized kidney

Hyperfiltration in glomeruli is the most common pathway to progressive renal dysfunction. Moreover, reduction of renal mass by unilateral nephrectomy results in an immediate increase in glomerular flow to the remnant kidney, followed by compensatory glomerular hypertrophy. Reactive oxygen species (ROS) are involved in renal hypertrophic responses; however, the role of ROS in compensatory glomerular hypertrophy remains unclear. Therefore, this role was investigated in the present study. Wistar rats were randomly placed into two groups: uninephrectomized rats (Nx) and uninephrectomized rats treated with tempol (Nx + TP). The glomerular volume increased in the Nx 1 week after surgery, but was significantly suppressed in the Nx + TP. Levels of phospho-Akt and phospho-ribosomal protein S6, which are critical for cell growth and hypertrophy, were markedly increased in the glomeruli of the Nx, while tempol treatment almost abolished the activation of these proteins. These results suggest that ROS have important roles in compensatory hypertrophy in glomeruli. M. Ozeki and H. Nagasu have contributed equally to this study.