Effect of VA-045, a novel apovincaminic acid derivative,on closed head injury-induced neurological dysfunction in aged rats

Abstract

Objective: The strength–duration time constant (SDTC) is a measure of axonal excitability and it can provide information about Na⁺ channel function. In this study, we sought to examine the changes in the SDTCs of motor and sensory fibers of the median nerve in patients taking colchicine, which affects axoplasmic flow and may result in axonal neuropathy.

Methods and results: The SDTCs of motor and sensory fibers of 29 patients who had been taking colchicine were measured following stimulation of the right median nerve at the wrist. The results were compared with ten healthy age-matched subjects. No significant differences were found between the groups.

Conclusions: The lack of any effect on the SDTC by colchicine might have been due to the fact that axonal degeneration caused by colchicine affects the Na⁺–K⁺ ATP pump or that it affects internodal channels other than nodal channels.     

Pulmonary leiomyosarcoma presenting as a pancoast tumor

A patient presenting with Pancoast syndrome was definitely diagnosed to have pulmonary leiomyosarcoma. The patient underwent a right upper lobectomy combined with resection of the chest wall, including the 1st to 3rd ribs. The disease recurred rapidly at the local and distant sites. No previous reports about pulmonary sarcoma presenting as a Pancoast tumor were found in the literature. The possibility of primary pulmonary leiomyosarcoma should be considered, and early detection and surgical resection are necessary when a round or oval tumor with necrosis is observed in the apex of the lung.     

Leukocyte angiotensin II levels inpatients with essential hypertension:relation to insulin resistance

Insulin resistance is involved in the pathogenesis of type 2 diabetes, hypertension, and atherosclerosis. Angiotensin (Ang) converting enzyme inhibitors and Ang II type 1 receptor antagonists improve insulin resistance in patients with essential hypertension, which suggest that tissue Ang II is involved in insulin resistance in patients with hypertension. To investigate the participation of tissue Ang II in insulin resistance associated with hypertension, we evaluated the Ang II-generating system in leukocytes and its relation to insulin resistance in patients with essential hypertension. Eighteen patients with essential hypertension participated in this study. Ang II was separated from leukocytes by reversed-phase high-performance liquid chromatography and measured by radioimmunoassay. Insulin resistance was evaluated by determining the steady-state of plasma glucose (SSPG) concentration. The Ang I- and Ang II-generating activities were evaluated in human leukocytes. Human leukocytes have Ang I- and Ang II-generating activities. The Ang II-generating activity was significantly inhibited by pepstatin A. Leukocyte Ang II level does not correlate with BP or plasma Ang II level in patients with essential hypertension. Leukocyte Ang II level strongly correlates with SSPG concentration, and significantly correlates with body mass index and plasma insulin, and with leptin levels in patients with essential hypertension. Leukocyte Ang II may be directly associated with insulin resistance.     

Nasal glioma: An immunohistochemical and ultrastructural study

A case of a 14 month old Japanese female infant presenting with nasal glioma Is reported. The tumor had been noticed at the nasal radix since birth and had slowly and progressively enlarged. There was no communication between the tumor and the cranial cavity on radiological examination. The tumor was macroscopically anchored to the nasal septum by a fibrous stalk, and histologically consisted of nests or trabeculae of either polygonal or spindle cells with plump eosinophilic cytoplasm and oval nuclei, separated by vascular-rich connective tissue intermingled with multinu-cleated giant cells. These tumor cells were immunohisto-chemically positive for glial fibrillary acidic protein as well as for S-100 protein and vimentin. An electron microscopic examination revealed collagen fibers and basal lamina between the tumor cells and the fibroblasts. Tumor cells possessed abundant intermediate filaments, which showed occasional Rosenthal fiber-like structures, in their cytoplasm and processes. A few oligodendrocytes and cilia of 9 micro-tubule doublets either with or without 2 central microtubules were also noted. These clinicopathological findings suggested that this tumor was once an encephalo(meningo)cele, which probably degenerated as a result of the loss of intracranial communication and then appeared to be isolated from the intracranial tissue.     

Effects of estrogen on the excitability of neurons projecting from the noradrenergic A1 region to the preoptic and anterior hypothalamic area

Estradiol benzoate administered to ovariectomized female rats significantly elevated the mean spontaneous firing rate and frequency of successful antidromic propagation into the somatodendritic spike and significantly reduced the strength of post-stimulus inhibition in presumed A1 noradrenergic neurons projecting directly to the preoptic and anterior hypothalamic area. The occurrence of both antidromic spikes and post-stimulus inhibition of the majority of these neurons was completely abolished by the injection of 6-hydroxydopamine but not by 5, 7-dihydroxytryptamine directly into the medial forebrain bundle.     

Subfornical organ neurons with efferent projections to the hypothalamic paraventricular nucleus: an electrophysiological study in the rat

Seventeen neurons in the subfornical organ (SFO) were antidromically activated by electrical stimulation of the paraventricular nucleus (PVN) in the rat. The activity of all identified SFO neurons was excited by microiontophoretically (MIPh) applied angiotensin II (AII) and the effect of AII was blocked by MIPh-applied saralasin (Sar), an AII antagonist, but not by atropine (Atr), a muscarinic antagonist. In these identified SFO neurons, 9 were also excited and 8 were not affected by MIPh-applied acetylcholine (ACh) and the effect of ACh was attenuated by not only MIPh-applied Atr but also by Sar. These results suggest that there are specific AII- and both AII- and ACh-sensitive types of SFO neurons with efferent projections to the PVN.     

Role of apoptosis controlled by cytochrome c released from mitochondria for luteal function in human granulosa cells

PROBLEM: The aim of this study was to investigate the relationship between apoptosis by the mitochondrial pathway and luteal function in human granulosa cells. METHOD OF STUDY: Granulosa cells were obtained by ultrasound-guided follicular aspiration from patients undergoing in vitro fertilization and embryo transfer. After the addition of RU486, cells were stained with a mitochondria-specific fluorescent dye, MitoTracker Red CM x Ros. Using flow cytometry and National Institute of Health image, the mitochondrial fluorescent area was measured. After staining with Hoechst 33258 dye, the number of apoptotic bodies per 1000 cells were counted at random on photomicrographs. Homogenates were used for sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blot analysis using antibodies against cytochrome c or caspase-3. RESULTS: The incidence of apoptotic bodies increased and the mitochondrial membrane potential decreased time dependently. The opposite effect was observed dose dependently with RU486 treatment. Western blot analysis showed increased cytochrome c expression, after treatment with 1-2 microg/mL of RU486 which then decreased with 5-10 microg/mL of RU486. Caspase-3 expression increased dose dependently with RU486. CONCLUSIONS: These results suggest that the activation of caspase-3 caused by cytochrome c released from mitochondria plays an important role in apoptosis-related luteal function in human granulosa cells.     

Effects of dual-action genistein derivatives on relaxation in rat aorta.

Protein tyrosine kinases and nitric oxide (NO) play important roles in several cardiovascular diseases. In this study, we examined the actions of two compounds, each has structure of genistein (a tyrosine kinase inhibitor) and an NO donor, on endothelium-independent relaxation responses in the isolated rat aorta. By rational drug design, genistein was modified to acquire an NO donor, and we synthesized two such compounds (G-II, G-VI). These compounds and genistein induced dose-dependent relaxation responses in endothelium-denuded aortic strips, the rank order of potencies being G-VI > G-II > genistein. Incubation of endothelium-denuded strips with 1H-[1,2,4] oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ, 10 microM), a guanylyl cyclase inhibitor, inhibited both the G-II- and G-VI-induced relaxations, but not the genistein-induced relaxation. The residual relaxations induced by these two compounds were similar to the genistein-induced relaxation. Incubation of endothelium-denuded strips with lysophosphatidylcholine (LPC, 20 microM)-which is a major atherogenic lysophospholipid component of oxidized low-density lipoprotein and is known to activate tyrosine kinase-caused a significant rightward shift in the dose-response curve for genistein. LPC also shifted the G-II- and G-VI-induced relaxation curves to the right; however, these relaxations in the presence of LPC were greater than that induced by genistein. The sodium nitroprusside-induced relaxation in endothelium-denuded strips was similar between in the absence and presence of LPC. These results suggest that each of our newly developed G-II and G-VI compounds has a dual action, as an NO donor and a tyrosine kinase inhibitor. These compounds may be useful against certain cardiovascular diseases.