Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor alpha-stimulated vascular endothelial cells

Vascular cell adhesion molecule-1 (VCAM-1) is a mononuclear leukocyte-selective adhesion molecule that is expressed in human vascular endothelial cells at sites of local inflammation. It participates in local endothelial-monocyte interactions during the initiation of atherosclerosis. In the present study, endothelin alone did not induce the surface expression and mRNA accumulation of VCAM-1 in human vascular endothelial cells, but inhibition of endogenous nitric oxide (NO) by N(G)-monomethyl-L-arginine enhanced the surface expression and mRNA accumulation of VCAM-1 stimulated by endothelin-1. It is conceivable that in human vascular endothelial cells, stimulation of an endothelin receptor results in the production of nitric oxide (NO), suppressing the expression of VCAM-1. Endothelin-1 enhanced the surface expression and mRNA accumulation of VCAM-1 in cells treated with tumor necrosis factor alpha (TNF-alpha). The enhancement by endothelin-1 may be explained by the inhibitory effect of TNF-alpha on endothelin-induced NO production. Pretreatment with BQ788 (an endothelin ET(B) receptor antagonist) or inhibitors of nuclear factor kappa B (NF-kappaB) activation completely diminished the synergistic enhancement of VCAM-1 expression by endothelin-1 in TNF-alpha-stimulated vascular endothelial cells, both at the protein and mRNA levels. These findings suggest that the synergistic enhancement of VCAM-1 expression by TNF-alpha and endothelin ET(B) receptor stimulation may be augmented by the induction of NF-kappaB binding activity in human vascular endothelial cells.     

IC202A, a new siderophore with immunosuppressive activity produced by Streptoalloteichus sp. 1454-19. I. Taxonomy, fermentation, isolation and biological activity

IC202A, a new immunosuppressive compound, was isolated from the culture filtrate of Streptoalloteichus sp. 1454-19. It showed a suppressive effect on mixed lymphocyte culture reaction with an IC50 value of 3.6 microg/ml and mitogen induced lymphocyte blastogenesis in vitro.     

Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier

In this study, we investigated the mechanism of the blood-brain barrier (BBB) transport of bunitrolol (BTL), as a model of beta-blocker, in vivo and in vitro. In order to define the contribution of P-glycoprotein (P-gp) to the active efflux of BTL from brain to blood, we examined the in vivo brain distribution of BTL in mdr1a(-/-) mice with a disrupted mdr1a gene. After intravenous administration of BTL to mdr1a(-/-) mice, the brain concentration and Kp value of BTL were significantly increased as compared with those in mdr1a(+/+) mice. Next, the contribution of the mdr1a P-gp to in vitro uptake of BTL was compared in LV500 cells and L cells (mouse mdr1a-expressing cells and host cells, respectively). The intracellular accumulations of [3H]vinblastine and BTL by LV500 cells were lower than those by L cells, but were significantly increased by verapamil, a P-gp inhibitor. Furthermore, the BTL uptake by KB-VJ300 cells, which express human P-gp, was also significantly lower than that by KB host cells, and was increased by verapamil. The steady-state uptake of BTL by LLC-GA5-COL300 cells, expressing human P-gp, was significantly increased in the presence of 20 microM cyclosporin A (another P-gp inhibitor), which had no effect in the LLC-PK1 host cells. On the other hand, the steady-state intracellular accumulation of BTL by MBEC4 cells, which express mdr1b P-gp instead of mdr1a P-gp, was not significantly changed in the presence of verapamil. This finding suggested that BTL is not a good substrate for mdr1b P-gp. In conclusion, our results suggest that BTL is transported from brain to blood by mdr1a P-gp in mice and by MDR1 in humans, and this presumably accounts for the low brain distribution of BTL.     

Kinetics of d-tubocurarine disposition and pharmacologic response in rats

After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of³H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses 0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range 0.15 mg/kg.This work was presented at the First Japanese-American Symposium on Pharmacokinetics and Biopharmaceutics, Tokyo, July 1981, which was held in memory of Dr. Sidney Riegelman.     

Basal expression of c-Fos and Zif268 in the rat basal ganglia: immunohistochemical characterization of striatal Zif268-positive neurons

Basal expression of the protein products of the inducible immediate early genes (IEGs), c-Fos and Zif268, was investigated in five regions of the rat basal ganglia using immunohistochemistry. In particular, high basal levels of Zif268 but very low levels of c-Fos were seen in the caudate-putamen (CPu). Double immunostaining revealed that many of the constitutively expressed Zif268-positive neurons were GABAergic but very few were cholinergic or neuronal nitric oxide synthase (nNOS)-positive, and some of the Zif268-positive neurons were also immunopositive for a glutamate NMDA receptor subunit NR1 or NR2A. No regional difference between the medial and lateral parts of the CPu was observed in the cellular phenotypes of Zif268-positive neurons. Almost no basal levels of Zif268 were seen in the other four regions: the globus pallidus, entopeduncular nucleus, subthalamic nucleus and substantia nigra pars reticulata. As in the CPu, negligible levels of c-Fos were seen in these four regions. Differential expression of these two IEGs may suggest gene-specific and region-specific functions of c-Fos and Zif268 in the basal ganglia. Constitutive expression of Zif268 existing mainly in the GABAergic neurons in the CPu may at least in part be maintained by glutamatergic afferents.     

Dietary sugar beet fiber prevents the increase in aberrant crypt foci induced by gamma-irradiation in the colorectum of rats treated with an immunosuppressant

We demonstrated recently that gamma-irradiation can induce aberrant crypt foci (ACF) in the rat colorectum. The aim of this study was to evaluate the effect of dietary sugar beet fiber (SBF) on the distribution of the CD8(+) intraepithelial lymphocyte (IEL) in the colorectum and on the number of gamma-irradiation-induced ACF of rats administered anti-asialo GM1 (alpha AGM1) as an immunosuppressant. Wistar/ST rats fed a fiber-free diet or the diet supplemented with SBF (100 g/kg diet) were administrated alpha AGM1 or normal rabbit serum as a control during the initiation period with gamma-irradiation. At 5 and 9 wk after the first irradiation, ACF and total aberrant crypts (AC) per area in the colorectum were counted. The numbers of ACF (P = 0.0010) and AC (P = 0.0635) per unit area were lower in the SBF-fed group than in the rats fed the fiber-free diet. alpha AGM1 administration significantly raised the number of ACF (P = 0.0001) and AC (P = 0.0006) per area in the colorectum. Moreover, alpha AGM1 administration during the initiation period reduced the number of CD8(+) IEL per 100 cells in the epithelial layer (P = 0.0001) of the colon. These results demonstrate that reduction of the number of CD8(+) IEL per 100 cells in the epithelial layer as a result of alpha AGM1 administration promotes the formation of irradiation-induced ACF in the colorectum. The number of CD8(+) IEL per 100 cells in epithelial layer was lower in the group fed the fiber-free diet than in the SBF-fed group (P = 0.0522). These results indicated that the ingestion of dietary SBF suppressed gamma-irradiation-induced ACF formation through the immune surveillance in the colorectal mucosa.     

Late onset X-linked hydrocephalus with normal cerebrospinal fluid pressure

A family with X-linked hydrocephalus with normal cerebrospinal fluid (CSF) pressure and in which three brothers and a grandson of case 1, a proband, were affected is reported. The symptoms at onset were epileptic attacks that started in adulthood in the three brothers and at the age of 6 years in the grandson. In the three brothers, from 10 to 27 years after the onset of epileptic episodes, disorganization of intelligence and psychiatric deterioration were gradually noticed by their families. At the same time, they showed occasional urinary incontinence. Brain computed tomography (CT) scans revealed dilatation of the ventricular systems. Based on the results of the measurement of CSF pressure and radioactive-iodinated human serum albumin (RISA)-cysternography, two of the brothers were diagnosed as having normal pressure hydrocephalus (NPH), and they were treated neurosurgically. However, no obvious improvement in clinical symptoms was observed. Although the grandson had shown normal psychomotor development during his early childhood, temporal epilepsy and temper tantrums started at the age of 6 years. Computed tomography-scanning revealed dilatation of the ventricular system similar to the other three cases at the age of 8 years. With the diagnosis of NPH, the patient underwent a shunt operation, which resulted in no obvious effects. As it is reasonable to surmise that the pathological gene would have been transferred via the daughter of the proband to the grandson, it is suggested that the inheritance manner might be X-linked recessive. The cases presented here are different from the cases of hydrocephalus due to stenosis of the aqueduct Sylvius (HSAS) and other types of X-linked hydrocephalus reported previously in terms of the age of onset, course, symptoms, and CT findings. Thus, it is suggested that the present cases might be a new type of X-linked hydrocephalus.     

Nasal septal abscess caused by anaerobic bacteria of oral flora

Although nasal septal abscess (NSA) was formerly common, it has become rare since the development of antibiotics. NSA, if left untreated, can lead to intracranial complications such as meningitis and eventually result in saddle-nose deformity. NSA often occurs after injury, and indigenous skin bacteria such as Staphylococcus aureus are frequently detected. We treated a patient who had injured the upper alveolus in a fall on the stairs and developed NSA two weeks later. Anaerobic bacteria, including Veillonella parvula and Peptostreptococcus sp., were detected. Symptoms were relieved by needle and incisional drainage. Our patient represents a very rare case of NSA in terms of the cause of onset and the detected bacteria. Early drainage can result in good outcomes.     

Neuromuscular electrical stimulation in the intensive care unit prevents muscle atrophy in critically ill older patients: A retrospective cohort study

Critically ill patients in the intensive care unit (ICU) develop muscle atrophy and decreased physical function. Though neuromuscular electrical stimulation (NMES) therapy has been shown to be effective in preventing this, but its effect on older patients is unknown.To examine the course of critically ill older patients treated with NMES in the ICU and to define the impact of its use.A retrospective cohort study was conducted using older ICU patients (≥65 years) categorized into a control group (n = 20) and an NMES group (n = 22). For subgroup analysis, each group was further classified into pre-old age (65–74 years) and old age (≥75 years).The control group showed significant decrease in muscle thickness during ICU and hospital stay. The NMES group showed lower reduction in muscle thickness and showed decrease in muscle echo intensity during hospital stay, compared to the control group. NMES inhibited decrease in muscle thickness in the pre-old age group versus the old age group. The decreasing effect of NMES on echo intensity during hospital stay manifested only in the pre-old age group. We did not find much difference in physical functioning between the NMES and control groups.Lower limb muscle atrophy reduces in critically ill older patients (≥65 years) with NMES and is pronounced in patients aged < 75 years. The impact of NMES on the physical functioning of older patients in ICU needs to be further investigated.