Marked Suppression of T Cells by a Benzothiophene Derivative in Patients with Human T-Lymphotropic Virus Type I-Associated Myelopathy/Tropical Spastic Paraparesis

In a search for new anti-autoimmune agents that selectively suppress activation of autoreactive T cells, one such agent, 5-methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide (CI-959-A), was found to be effective. This compound, which is known to suppress tumor necrosis factor alpha (TNF-α)-induced CD54 expression, inhibited the primary proliferative response of the T cell to antigen (Ag)-presenting cells (APCs) including allogenic dendritic cells (DCs), autologous Epstein-Barr virus-infected B cells, and human T lymphotropic virus type I (HTLV-I)-infected T cells. Autoreactive T cells from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) spontaneously proliferate in vitro, and their activation is reported to be associated with CD54 expression. The spontaneous proliferation of T cells from patients with HAM/TSP was entirely blocked by CI-959-A. However, in this study, the T-cell proliferation in 15 patients with HAM/TSP was found to depend more extensively on major histocompatibility complex (MHC) class II and CD86 than on CD54 Ags. Since most important APCs for the development of HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on DC generation and on the expression of surface molecules on activated T cells is examined. CI-959-A suppressed recombinant granulocyte-macrophage colony stimulating factor (GM-CSF)- and recombinant interleukin-4-dependent differentiation of DCs from monocytes and inhibited the expression of CD54 and, more extensively, MHC class II and CD86 Ags. CI-959-A showed little toxicity toward lymphoma or HTLV-I-infected T-cell lines or toward monocytes and cultured DCs. These results suggest that CI-959-A might be a potent anti-HAM/TSP agent.Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is thought to be an autoimmune disease induced by HTLV-I infection (8, 9, 24). The T lymphocytes obtained from patients with HAM/TSP patients produce interleukin-2 (IL-2) in vivo and proliferate spontaneously in vitro without any additional stimuli or cytokines (35). This spontaneous proliferation of T lymphocytes (SPL) depends on the interaction of T cells with antigen (Ag)-presenting cells (APCs) such as dendritic cells (DCs) (17, 25) and HTLV-I-infected CD4⁺ T cells (15, 32). The DCs localized in the blood and nonlymphoid organs are considered to be functionally immature, in that they are optimized for the uptake and processing of Ag but not for the initiation of primary T-cell responses. However, after the uptake of Ag and exposure to inflammatory agents including tumor necrosis factor alpha (TNF-α) and IL-1, the DCs undergo a process of maturation and gain the ability to present Ag to T cells for their priming (22, 26). In addition to DCs, HTLV-I-infected CD4⁺ T cells directly stimulate autologous CD4⁺ T cells in a major histocompatibility complex (MHC) class II- and CD86 molecule-dependent fashion (32). Among the T cells stimulated with these APCs, some might cross-react with self Ags and closely associate with the development of HAM/TSP.We have been searching for compounds that inhibit the cellular interaction between APCs and T cells to suppress the activation of autoreactive and Ag-specific T cells. The molecules associated with the APC-T cell interaction may provide an effective target for therapy for autoimmune diseases. Binding of APCs and T cells is initiated by contact of adhesion molecules, such as CD54 and CD11a/CD18, expressed on both cells, and induction of sustained proliferation of T cells requires two independent signals provided by APCs: a T-cell receptor-mediated Ag-specific signal and a signal mediated by costimulatory molecules (CSMs) (10, 20) including CD86 and CD58 Ags (1, 11, 31). Blocking of their tight binding through adhesion molecules or interaction of the CSMs with CSM ligands effectively suppressed the abnormal expansion of disease-associated T cells in vivo and in vitro (19, 30, 32) and sometimes effectively induced a long-term unresponsiveness of T cells to recall stimuli.5-Methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carbox-amide (CI-959-A) is known to inhibit CD54 expression, and its derivative is reported to inhibit casein kinase II (4). In the present study, we found that CI-959-A markedly suppressed SPL in patients with HAM/TSP. Furthermore, the compound suppressed the primary T-cell proliferative response to stimuli provided by various APCs, the differentiation of immature DCs from monocytes and their subsequent maturation, and the induction of expression of MHC class II, CD54, and CD86 Ags on activated CD4⁺ T cells.     

Severe stenosis of the internal carotid artery presenting as loss of consciousness due to the presence of a primitive hypoglossal artery: a case report

BACKGROUND: Symptoms of ischemic attacks in the internal carotid system usually involve focal cerebral dysfunction, i.e., hemiparesis or aphasia. However, an ischemic attack in the vertebrobasilar artery system usually presents with combined symptoms. The variety of manifestations included in the vertebrobasilar profile makes the potential pattern of symptoms considerably more variable and complex than that in the carotid system. Manifestations can include syncope and also vertigo. METHOD AND RESULTS: A 42-year-old woman experienced frequent attacks of faintness with vertigo. Angiography demonstrated severe stenosis of the left internal carotid artery with a persistent primitive hypoglossal artery just distal to the stenosis. The right internal carotid artery was normal and cross circulation through the anterior communicating artery was not well developed. Both vertebral arteries were hypoplastic. The patient underwent carotid endarterectomy and, thereafter the episodes of syncope completely disappeared. CONCLUSION: It was supposed that global ischemia including the brain stem occurred because of stenosis of the left internal carotid artery attributable to the presence of a primitive hypoglossal artery.     

Molecular epidemiological study on tetracycline resistance R plasmids in enterohaemorrhagic Escherichia coli O157:H7.

Restriction patterns obtained with EcoRI and Southern hybridization were used for the differentiation of tetracycline-resistant (Tet(r)) R plasmids in enterobaemorrhagic Escherichia coli (EHEC) O157:H7 isolates from a mass outbreak at a kindergarten in Obihiro-City, Hokkaido, Japan, 1996. Two kinds of Tet(r) R plasmids of 50 and 95 kb were detected. The 50-kb plasmids were identical to each other, while the 93-kb plasmids were of three types that were very similar to each other. The tet genes of both 50- and 95-kb R plasmids were 100% identical to the tet gene of pSC101 and all plasmids hybridized to a probe for tet. Because food-origin O157 strains were sensitive to tetracycline, we concluded that such Tet(r) R-plasmids might transfer to drug-sensitive O157 strains in the infected individuals.     

Potentiation of the hypotensive effect of adrenomedullin in pregnant rats

The hypotensive effect of adrenomedullin, a potent vasodilator peptide, was examined in conscious pregnant (6, 13 and 20 days of pregnancy) and non-pregnant rats. The intravenous administration of adrenomedullin (0.01-3.0 nmol/kg) produced a dose-dependent depressor response in pregnant and non-pregnant rats. At low doses (0.01-0.1 nmol/kg), the maximum decrease in blood pressure was significantly higher in pregnant rats (20 days pregnant) than in non-pregnant rats. At high doses, no significant difference was observed between the two groups. Furthermore, the administration of adrenomedullin did not significantly affect the basal mean blood pressure (MBP) at any dose when compared to the non-pregnant group at 6 and 13 days of pregnancy. In the ovariectomized rats, the depressor responses in 17beta-estradiol-treated, progesterone-treated and 17beta-estradiol+progesterone-treated rats were not significantly different from that in the control rats, suggesting that the augmented effect on the depressor response to adrenomedullin in pregnant rats may not be due to hormonal changes during pregnancy. The adrenomedullin receptor mRNA level of the descending thoracic aorta was significantly higher in the late-pregnancy rats (20 days of pregnancy). However, the levels did not show any difference between the early-pregnant rats (6 and 13 days of pregnancy) and the non-pregnant rats. These findings suggested that the changes in the depressor response to adrenomedullin which occur at term in pregnant rats may be mediated by changes of adrenomedullin receptor gene expression rather than by sex hormones.     

The possible role of TNF-α and IL-2 in inducing tumor-associated metabolic alterations

This study was conducted to investigate the role of tumor necrosis factor- (TNF-) and interleukin-2 (IL-2) in inducing cancer cachexia, and the results were compared with those obtained from our previous study on Fisher 344 rats with methylcholanthrene-induced sarcoma. Three groups of male Fisher 344 rats received one of the following regimens: 4×10⁴ IU of human recombinant TNF- per rat per day subcutaneously (sc) for 5 consecutive days (n=5), 3.5×10⁵ U human recombinant IL-2 per rat per day sc for 14 consecutive days (n=5), or normal saline (n=5). The activities of both phosphoenolpyruvate carboxykinase (PEPCK) and malic enzyme (ME) were increased slightly in the IL-2 group. Furthermore, LPL activity was significantly increased in the adipose tissue of the TNF group and in the cardiac muscle of the IL-2 group, but not in that of the TNF group. These results show that there is a significant difference between the metabolic alterations seen in the tumor-bearing state and those induced by either TNF- or IL-2 alone. Thus, it is unlikely that IL-2 or TNF- is the sole mediator of cancer cachexia in this tumor and rat model.     

Differential regulation of neuropeptide Y mRNA expression in the arcuate nucleus and locus coeruleus by stress and antidepressants

In rats, circulating corticosterone and insulin are involved in regulation of the hypothalamic neuropeptide Y (NPY) system, which in turn, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Since the HPA axis and stress responsivity is altered in diseases such as depression, we investigated interactions between the effects of stress and antidepressant drug treatment on arcuate nucleus and locus coeruleus NPY mRNA expressions using in-situ hybridization histochemistry. After acute (2 h) and repeated immobilization (2 h daily, for 14 days), plasma concentrations of corticosterone increased, and those of insulin decreased. The expression of NPY mRNA was significantly increased in the arcuate nucleus, but was unchanged in the locus coeruleus following acute and repeated immobilization. Adrenalectomized rats with systemic corticosterone replacement (ADX+CORT), whose corticosterone concentration was maintained at approximately 50-100 ng/ml during repeated stress, showed a decrease in plasma insulin and an increase in arcuate nucleus NPY mRNA similar to that observed in sham rats, suggesting that changes in NPY mRNA levels are more closely tied to circulating insulin than to circulating corticosterone. In contrast, locus coeruleus NPY mRNA expressions in ADX+CORT rats were significantly higher than those in sham rats after repeated stress. Desmethylimipramine (DMI) treatment for 24 days did not affect basal plasma concentrations of corticosterone or insulin, or arcuate nucleus NPY mRNA expressions, but significantly decreased basal levels of locus coeruleus NPY mRNA compared to saline-treated rats. After repeated immobilization (2 h daily, for 4 days), DMI significantly reduced the stress-induced rise in locus coeruleus NPY mRNA levels, but potentiated the stress-induced rise in arcuate nucleus NPY mRNA expression. These results demonstrate that: (1) the increase in arcuate nucleus NPY mRNA expressions in stressed rats closely follows the decrease in plasma concentrations of insulin; (2) increases in NPY mRNA expressions occur in the absence of changes in plasma corticosterone; and (3) desipramine treatment potentiated the effect of stress on arcuate nucleus NPY mRNA expressions, but blocked the repeated stress-induced increase in locus coeruleus NPY mRNA expressions. Thus, NPY mRNA expression in the arcuate nucleus and the locus coeruleus is sensitive to the effects of stress and to the antidepressant drug desipramine, but the arcuate nucleus NPY system is regulated by different mechanisms than the locus coeruleus NPY system. The results provide further evidence for the importance of circulating insulin in the regulation of the arcuate nucleus NPY system.     

Magnetic resonance imaging evaluation and arthroscopic resection of localized pigmented villonodular synovitis of the knee

Diagnosis of localized pigmented villonodular synovitis is clinically difficult, and plain radiographs are usually normal. This article presents five patients with localized pigmented villonodular synovitis of the knee. Symptoms suggested a meniscal lesion in three patients and a loose body in two. Magnetic resonance imaging performed prior to arthroscopic resection revealed a preoperative diagnosis of a tumor in all five patients. Magnetic resonance imaging is a valuable clinical tool for the assessment of intra-articular soft-tissue tumors of the knee that may otherwise be misdiagnosed.     

Exacerbation of renal failure due to hypothyroidism in a patient with ischemic nephropathy

A case of acute-on-chronic renal failure in a 70-year-old woman with ischemic nephropathy and primary hypothyroidism is presented. Her renal function became progressively worse as the level of serum creatinine increased from 283 to 628 micromol/l (3.2-7.1 mg/dl) within 8 months. Her thyroid function had been normal before the exacerbation of renal failure, but it was markedly reduced with a marked elevation of serum thyroid-stimulating hormone. Thyroid hormone replacement therapy resulted in rapid improvement of the renal function to 159 micromol/l (1.8 mg/dl) of serum creatinine. The development of primary hypothyroidism seemed to worsen the already impaired renal function in this case. We suggest the assessment of thyroid function in patients with unexplained deterioration of renal failure.