[Immune reconstitution inflammatory syndrome in the central nervous system].

The prognosis of HIV-related disorders have markedly improved after highly active antiretroviral therapy was introduced, however, following initiation of the therapy, some patients with severe immunodeficiency develop a paradoxical clinical deterioration despite decreased HIV viral load and increased CD4+ T-cell counts. These phenomena are recently recognized as immune reconstitution inflammatory syndrome (IRIS). It is considered that the rapid restoration of the immune system leads to exuberant inflammatory responses to antigenic stimuli. Although the disorders are sometimes life-threatening, the definition and the management of IRIS have not been established yet. We review the current knowledge of IRIS, especially in the area of HIV-related CNS disorders. Cryptococcal meningitis and progressive multifocal leukoencephalopathy (PML) are common disorders which cause CNS IRIS. HIV encephalopathy is also reported to develope IRIS. Infiltration of cytotoxic CD8+ T lymphocytes is observed in the suffered brain tissue of PML and HIV encephalopathy, and it may be one of the pathogenic factors.

[Prevalence of neurological complications in Japanese patients with AIDS after the introduction of HAART].

We investigated trends in neurological complications of infection with human immunodeficiency virus (HIV) in Japan after the introduction of highly active antiretroviral therapy (HAART). Two questionnaire surveys were performed in hospitals treating acquired immunodeficiency syndrome (AIDS) to compare two periods: immediately after the introduction of HAART (1999-2001); and a few years later (2002-3). Neurological complications accompanied 15.9% in 1999-2001 and 9.8% in 2002-3. Neurological complications developed without HAART in about 80% of cases. Neurological complications developed as the first AIDS-defining disease for 8.3% of AIDS patients in 1999-2001 and for 5.4% in 2002-3. Prevalences of HIV encephalopathy and myelopathy decreased markedly over the study period, as reported in other developed nations. However, prevalences of cytomegalovirus encephalitis, PML and primary brain lymphoma did not decrease. PML and primary brain lymphoma occurred in patients who received HAART and whose CD4 counts were relatively high during the study period. This is probably related to the extended survival of HIV-infected individuals after the introduction of HAART as a worldwide therapy, and the reactivation of viremia or latent infection persisting within the central nervous system.

Immune-mediated myelopathy following allogeneic stem cell transplantation.

We report a case of immune-mediated myelopathy occurring 4 months after unrelated bone marrow transplantation for myelodysplastic syndrome. After the tapering of cyclosporine for graft-versus-host disease prophylaxis, the patient developed several neurological symptoms mimicking the clinical features of multiple sclerosis (MS). Although neurological exacerbation was well stabilized with a bulk dose of corticosteroid, sustained improvement of neurological deficits occurred after the patient developed hematopoietic mixed chimerism (HMC). This experience may provide clinical evidence supporting the current therapeutic concept, in which HMC induction can potentially cure several immune diseases, including MS.

Herpetic lumbosacral radiculoneuropathy in patients with human immunodeficiency virus infection.

We report 4 cases of human immunodeficiency virus infection associated with lumbosacral radicular dysfunction and urinary retention. Three of these cases had the so-called Elsberg syndrome in that their symptoms were associated with genital herpes. In 1 case, different herpes simplex virus types were isolated from the cerebrospinal fluid and genital swabs. Lumbosacral radiculoneuropathy with urinary retention caused by herpes viruses can develop not only with an initial genital herpes infection, but also due to reactivation of a latent herpes virus.

[Clinical investigation of the 8 cases with AIDS (acquired immunodeficiency syndrome)-associated progressive multifocal leukoencephalopathy (PML)].

We experienced 8 cases of progressive multifocal leukoencephalopathy (PML) complicated by human immunodeficiency virus (HIV) type-1 infection from 1985 to 1999. These cases showed dementia, bradykinesia, dysarthria, hemiparesis, and so on. All of the cases were severely immunocompromised hosts, because none had more than 150/mm3 CD4 + lymphocytes; indeed, 5 of the cases were below 20/mm3. Other neurological complications except PML were primary CNS lymphoma, HIV encephalitis, and CMV encephalitis. The mean life durations was 7.6 months after the first symptom appeared, for all but one of the patients; the exceptional patient lived for 24 months after. Autopsy studies of the central nervous systems were performed for 7 cases, all of which showed extensive demyelinating lesions of the white matter, and in some cases these extended into the spinal cord. In contrast to Western countries, in Japan there have been few reports of AIDS-associated PML. Thus, this report was thought to be important here.

Delayed ischemic stroke associated with methamphetamine use.

A 19-year-old woman had right occipital infarction 3 months after she had injected methamphetamine. No other possible causes of stroke could be found in this case. Magnetic resonance angiography revealed beading of the right posterior cerebral artery, which suggested vasculitis. Her symptoms were right-sided headache, left superior quadrant hemianopia, and left hypesthesia, which gradually improved without any treatment. Methamphetamine has been known to cause hemorrhagic and ischemic stroke relatively soon after administration. We report here that methamphetamine may also cause chronic cerebral vasculitis and delayed ischemic stroke.

[A case of Crow-Fukase syndrome showing improvement following excision and irradiation of bone lesions].

A 57-year-old woman suffering from pleural and pericardial effusion, pulmonary hypertention, lymphadenopathy, hepatosplenomegaly, edema, hypertrichosis, small hemangioma and polyneuropathy was diagnosed as Crow-Fukase syndrome. Osteoctomy of the left second rib and irradiation of this rib and the left iliac bone were performed. Serum vascular endothelial growth factor (VEGF) level decreased to less than one-half the level before the operation (from 5,180 to 2,150 pg/ml). Immediately after the operation, pleural and pericardial effusions due to hyperpenetration improved, and polyneuropathy and hypertrichosis due to hypervasularity also gradually improved. The resected lesion was histopathologically found to be of a plasmacytoma of the IgG lambda type. Since the level of VEGF in the tissue specimen was much lower (116 pg/ml) than that in the serum, VEGF could not have been produced by the plasmacytoma.

Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, plays an important role in the earliest events of atherogenesis. However, direct evidence of the effects of MCP-1 on atherosclerosis in chronic hemodialysis (HD) patients has not been reported. METHODS AND RESULTS: The serum MCP-1 concentrations and the intimal - medial thickness (IMT) in the carotid arteries were measured in 42 non-diabetic chronic HD patients and 20 age-matched controls. The expression of MCP-1 was examined immunohistochemically in radial arterial tissues obtained from the HD patients. IMT and the serum concentration of MCP-1 in the HD patients were both significantly greater than in controls. Multiple regression analysis revealed that the serum concentration of MCP-1 was an independent factor influencing IMT. Tissue immunostaining showed that MCP-1 is expressed in both endothelial and smooth muscle cells and that its level of expression correlates with the serum concentration of MCP-1. CONCLUSIONS: An increase in MCP-1 may be an important factor in the progression of atherosclerosis in non-diabetic HD patients.

[Immunosuppressive-associated encephalopathy in bone marrow transplant recipients].

We studied clinical features of immunosuppressive (cyclosporine, tacrolimus) associated encephalopathy in bone marrow transplant patients. 378 cases of allogeneic bone marrow transplant recipients over fifteen years old of chronic and acute leukemia (CML, ANLL, ALL) (n = 311), myelodysplastic syndrome (MDS) (n = 42) and severe aplastic anemia (SAA) (n = 25) were investigated. Immunosuppressive associated encephalopathy occurred in 12 cases. The rate of incidence was significantly higher in SAA and MDS (7 cases) than in leukemia. The cases which showed typical radiological abnormality in MRI were limited in SAA and hypoplastic MDS. 10 cases died, which revealed worse than an overall survival rate of recipients without immunosupressive-associated encephalopathy. 5 of 7 cases in SAA and MDS had taken cyclosporine as treatment of the disease before bone marrow transplantation and that might influence the incidence of encephalopathy.

Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis.

INTRODUCTION: Tissue factor plays a key role in the extrinsic coagulation pathway and is induced by inflammatory cytokines. Atrial myocarditis has been detected recently in some patients with lone atrial fibrillation. Virchow's triad of low blood flow, hypercoagulability, and endothelial dysfunction, enhances thrombus formation. The present study was designed to elucidate the role of endothelial dysfunction in thrombogenesis associated with nonvalvular atrial fibrillation. MATERIAL AND METHODS: We investigated tissue factor expression in the endothelia of left atrial appendages obtained from seven patients with nonvalvular atrial fibrillation and cardiogenic thromboembolism. Tissues were divided into 7-13 sections and compared with control specimens from four patients who died of noncardiac events. Expression of tissue factor, von Willebrand factor and tissue factor pathway inhibitor was evaluated by immunohistochemistry. RESULTS: Histopathologically, inflammatory cells infiltrated the endocardium and all seven patients showed features of persistent myocarditis. Activated T cells [15.3+/-9.4 cells/high power field (HPF, mean+/-S.D.) vs. control 2.2+/-4.4/HPF (P=0.0294)] and a few macrophages [5.1+/-8.4 cells/HPF vs. control 2.4+/-3.5 cells/HPF (P=NS)] infiltrated the endocardium. Tissue factor was overexpressed in the endothelia particularly in tissues containing inflammatory cells and denuded matrix of the endocardium, compared with the control group. Von Willebrand factor, but not tissue factor pathway inhibitor, was also overexpressed in these tissues. CONCLUSION: Tissue factor expression induced by local inflammation is involved in the pathogenesis of thrombosis in patients with nonvalvular atrial fibrillation.

Clusters of ventricular fibrillation in a patient with an implantable cardioverter difibrillator treated with amiodarone.

A 44 year-old man with severe left ventricular dysfunction resulting from an old myocardial infarction developed clusters of ventricular fibrillation (VF). Although coronary bypass surgery was performed and heart failure was well controlled, the VF recurred during amiodarone therapy. Despite multiple deliveries of shocks by an implantable cardioverter defibrillator, the electrical storm could not be terminated. Some substrate for rapid ventricular tachyarrhythmias, refractory to class III drugs, can lead to death from arrhythmia.

Carvedilol decreases elevated oxidative stress in human failing myocardium.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating beta-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results- Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P<0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9+/-4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22+/-8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P<0.005) along with amelioration of heart failure. CONCLUSIONS: Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.

Anti-inflammatory effects of long-lasting locally-delivered human recombinant tissue factor pathway inhibitor after balloon angioplasty.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) has anti-proliferative and anti-migratory effects on cultured smooth muscle cells (SMC) in addition to its anti-thrombotic activity. Here, we assess how long locally delivered recombinant TFPI (rTFPI) remains detectable at the delivery sites and clarify the main mechanism by which rTFPI blocks neointimal growth in vivo. METHODS: The iliac arteries of 85 Japanese white rabbits were injured using a Cutting Balloon. First, to establish the efficacy of local delivery of rTFPI, 5 groups of 3 rabbits each were examined immediately or 1, 2, 4 or 7 days after delivery. They were treated locally with a total amount of 200 microg of rTFPI given at 40 microg per pulse per minute by means of a Pulse Spray catheter. Thereafter, 34 rabbits which had received 200 microg of rTFPI after cutting angioplasty were compared to the same number of controls regarding thrombosis, inhibition of neointimal proliferation and inflammation. RESULTS: A total of 2.6+/-1.6 ng rTFPI persisted on the injured vessel 4 days after delivery. rTFPI was still present on 48 % of the cut sites 7 days after delivery, despite its short half-life in plasma. Thrombosis in the rTFPI-treated group was significantly reduced compared to the controls. The number of macrophages present within the media and intima was significantly decreased at day 7 after delivery of rTFPI. Furthermore, the number of Ki-67-positive cells 14 days after rTFPI delivery was significantly lower than in controls although there were no significant differences between them after 2 days. CONCLUSIONS: Local delivery of rTFPI decreased the degree of neointimal formation 4 weeks after TFPI delivery because of anti-inflammatory and anti-proliferative effects in addition to, or rather than, via anti-thrombosis.

[A clinical study of pachymeningitis].

We report five patients with cranial and spinal pachymeningitis not associated infections or tumors. The underlying causes of pachymeningitis in four patients were Sjögren syndrome, Wegener's granulomatosis, microscopic polyangitis, and dermatomyositis, respectively. In one patient, the cause was unknown. Cerebrospinal fluid analysis showed an increase in cells in only one patient and elevated protein levels in three patients. Blood test revealed an inflammatory disease except in one patient. The anti-nuclear antibody was present in four of five patients examined, and P-ANCA was present in two out of four patients. The prognosis was good except in one patient of Wegener's granulomatosis. We reviewed 48 previously reported cases of pachymeningitis were not associated infections or tumors. The lesions of pachymeningitis were more localized in the cranial dura than the spinal dura, and many cases had immunological abnormalities.