Peroxiredoxins are involved in the pathogenesis of multiple sclerosis and neuromyelitis optica spectrum disorder.

Peroxiredoxins (PRXs) are intracellular anti-oxidative enzymes but work as inflammatory amplifiers under the extracellular condition. To date, the function of PRXs in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is not fully understood. The aim of this study was to investigate whether PRXs play a role in the pathogenesis of MS and NMOSD. We analyzed levels of PRXs (PRX1, PRX5 and PRX6) in the cerebrospinal fluid (CSF) and serum of 16 patients with MS, 16 patients with NMOSD and 15 patients with other neurological disorders (ONDs). We identified potential correlations between significantly elevated PRXs levels and the clinical variables in patients with MS and NMOSD. Additionally, pathological analyses of PRXs (PRX1-6) in the central nervous system (CNS) were performed using the experimental autoimmune encephalomyelitis (EAE), animal model of MS. We found that serum levels of PRX5 and PRX6 in patients with MS and NMOSD were higher compared with those in patients with ONDs (P < 0·05). Furthermore, high levels of PRX5 and PRX6 were partly associated with blood-brain barrier dysfunction and disease duration in NMOSD patients. No significant elevation was found in CSF PRXs levels of MS and NMOSD. Spinal cords from EAE mice showed remarkable PRX5 staining, especially in CD45+ infiltrating cells. In conclusion, PRX5 and PRX6 may play a role in the pathogeneses of MS and NMOSD.

Comparison of brain atrophy in patients with multiple sclerosis treated with first- versus second-generation disease modifying therapy without clinical relapse.

BACKGROUND AND PURPOSE: The silent progression of patients with multiple sclerosis (MS) has been reported. The aim of this study was to investigate the association between brain atrophy rates and disease-modifying drugs (DMDs) in patients with MS during their relapse-free period. METHODS: Patients with relapsing-remitting MS were classified into two groups on the basis of clinical records, i.e. a first-generation DMD group treated with interferon-beta-1a, interferon-beta-1b or glatiramer acetate and a second-generation DMD group treated with dimethyl fumarate, fingolimod or natalizumab. Brain volume was calculated with SPM12. RESULTS: A total of 45 patients with relapsing-remitting MS were enrolled in the first-generation (n = 22) or second-generation (n = 23) DMD group. The annualized relapse rate was lower in the first-generation than in the second-generation DMD group (median 0.26 vs. 0.59; P < 0.001). The annualized atrophy rate of the normalized brain volume was not different between the first- and second-generation DMD groups after analysis of covariance (median 0.13% vs. 0.59%; P = 0.17). CONCLUSIONS: The median annualized atrophy rate of normalized brain volume in the first-generation DMD group was similar to the previously reported annual brain atrophy rate of healthy controls, which may suggest that treatment with a first-generation DMD need not be changed when patients with MS are clinically inactive.

Recombinant thrombomodulin ameliorates experimental autoimmune encephalomyelitis by suppressing high mobility group box 1 and inflammatory cytokines.

Recombinant thrombomodulin (rTM) has pleiotrophic properties, including anti-coagulation and anti-inflammation; however, its effectiveness as a treatment for multiple sclerosis (MS) has not been evaluated fully. High mobility group box 1 (HMGB1) and proinflammatory cytokines, working as inflammatory mediators, are reportedly involved in the inflammatory pathogenesis of MS. The aim of this study was to determine whether rTM can be a potential therapeutic agent for experimental autoimmune encephalomyelitis (EAE). EAE mice received rTM treatment (1 mg or 0·1 mg/kg/day) from days 11 to 15 after immunization. The clinical variables, plasma levels of inflammatory cytokines and HMGB1 and pathological findings in EAE were evaluated. rTM administration ameliorated the clinical and pathological severity of EAE. An immunohistochemical study of the spinal cord showed weaker cytoplasmic HMGB1 staining in the rTM-treated EAE mice than in the untreated EAE mice. Plasma levels of inflammatory cytokines and HMGB1 were suppressed by rTM treatment. In conclusion, rTM down-regulated inflammatory mediators in the peripheral circulation and prevented HMGB1 release from nuclei in the central nervous system, suppressing EAE-related inflammation. rTM could have a novel therapeutic potential for patients with MS.

Acute hyperglycaemia prevents the protective effect of pre-infarction angina on microvascular function after primary angioplasty for acute myocardial infarction.

BACKGROUND: Acute hyperglycaemia has been associated with impaired microvascular function after acute myocardial infarction (AMI), whereas pre-infarction angina (PIA) occurring shortly before the onset of AMI has been shown to reduce microvascular injury after reperfusion. OBJECTIVE: To examine whether acute hyperglycaemia prevents the protective effect of PIA on microvascular function after AMI. METHODS: We studied 205 patients with a first anterior wall AMI who underwent primary angioplasty within 12 hours of onset. Coronary flow velocity parameters were assessed immediately after reperfusion using a Doppler guidewire. Severe microvascular injury was defined as the presence of systolic flow reversal and diastolic deceleration time <600 ms. Echocardiographic wall motion was analysed before revascularisation and 4 weeks later. RESULTS: Acute hyperglycaemia, defined as a blood glucose level of >or=198 mg/dl on admission, was found in 67 (33%) patients. In patients without acute hyperglycaemia, PIA was associated with a lower incidence of systolic flow reversal, a longer diastolic deceleration time and a higher coronary flow reserve. However, in patients with acute hyperglycaemia there was no significant difference in these same parameters between patients with and without PIA. In the presence of acute hyperglycaemia PIA did not improve the change in wall motion score. In a multivariate model, the absence of PIA was an independent determinant of severe microvascular injury in patients without acute hyperglycaemia (odds ratio 6.28, p = 0.001), but not in patients with acute hyperglycaemia. CONCLUSION: The protective effect of PIA on microvascular function was attenuated in patients with acute hyperglycaemia, resulting in unfavourable functional recovery.

Subinsular vascular lesions: an analysis of 119 consecutive autopsied brains.

The insula of Reil constitutes a functionally intriguing complex of the brain related to multifunctional activities. We examined the subinsular region in 119 consecutively autopsied patients, as T2 hyperintense lesions are frequently observed in magnetic resonance diagnosis of this region. The patients were admitted in neurology wards and were diagnosed as having cerebrovascular disease in 55 patients (46%), other neurological diseases in 57 patients (48%) and non-neurological diseases in seven patients (6%). Demyelination of the white matter was semi-quantified as a fiber density score (percent stained area/total area) with computer-assisted image analysis on Klüver-Barrera-stained sections. Astrogliosis was assessed by immunohistochemistry for glial fibrillary acidic protein. The lesion analysis showed a dilated perivascular space in 29 patients (24%), demyelination (fiber density score less than the mean - 1 SD) in 27 patients (23%), slit-shaped lesion in six patients (5%), lacunar infarction in one patient (1%) and cerebral hemorrhage in one patient (1%). A histologic-radiologic comparison in two patients with subcortical ischemic vascular dementia showed correspondence between subinsular hyperintensities, and demyelination, gliosis and a dilated perivascular space. These results indicate that subinsular lesions rarely signifies focal vascular lesions, and are consisted of demyelination, gliosis and a dilated perivascular space.

Relation between the TIMI frame count and the degree of microvascular injury after primary coronary angioplasty in patients with acute anterior myocardial infarction.

OBJECTIVE: To investigate the relation between thrombolysis in myocardial infarction (TIMI) frame count (TFC) and coronary blood flow velocity (CBFV) parameters reflecting the degree of microvascular injury in patients with acute myocardial infarction. RESULTS: TFC and CBFV were measured after primary coronary angioplasty in 103 consecutive patients with their first anterior wall acute myocardial infarction. TFC correlated inversely with the averaged peak velocity (r = -0.43, p < 0.0001). However, TFC did not correlate significantly with diastolic deceleration time and with the averaged systolic peak velocity (r = -0.16, p = 0.22, and r = -0.23, p = 0.16, respectively). The patients were divided into two groups according to presence (35 patients) or absence (68 patients) of systolic flow reversal. There was no significant difference in TFC between the two groups (29 (16) v 25 (13), p = 0.20). CONCLUSIONS: These findings suggest that the TFC reflects epicardial CBFV. However, it is not accurate enough to assess the degree of microvascular injury after primary coronary angioplasty.

Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis.

Accumulating evidences indicate that ceramide is closely involved in apoptotic cell death in neurodegenerative disorders and aging. We examined ceramide levels in the cerebrospinal fluid (CSF) or brain tissues from patients with neurodegenerative disorders and the mechanism of how intra- and extracellular ceramide was regulated during neuronal apoptosis. We screened the ceramide levels in the CSF of patients with neurodegenerative disorders, and found that ceramide was significantly increased in patients with Alzheimer's disease (AD) than in patients with age-matched amyotrophic lateral sclerosis (ALS) and other neurological controls. With immunohistochemistry in AD brains, ceramide was aberrantly expressed in astroglia in the frontal cortices, but not detected in ALS and control brains. To explore for the regulation of ceramide in astroglia in Alzheimer's disease brains, we examined the metabolism of ceramide during neuronal apoptosis. In retinoic acid (RA)-induced neuronal apoptosis, RA slightly increased de novo synthesis of ceramide, but interestingly, RA dramatically inhibited conversion of [14C] ceramide to glucosylceramide (GlcCer), suggesting that the increase of ceramide mass is mainly due to inhibition of the ceramide-metabolizing enzyme GlcCer synthase. In addition, a significant increase of the [14C] ceramide level in the culture medium was detected by chasing and turnover experiments without alteration of extracellular [14C] sphingomyelin levels. A 2.5-fold increase of ceramide mass in the supernatant was also detected after 48 h of treatment with RA. These results suggest a regulatory mechanism of intracellular ceramide through inhibition of GlcCer synthase and a possible role of ceramide as an extracellular/intercellular mediator for neuronal apoptosis. The increased ceramide level in the CSF from AD patients, which may be derived from astroglia, raises a possibility of neuronal apoptosis by the response to intercellular ceramide in AD.

Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat.

Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52-64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF-alpha and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.

Acute myocardial infarction showing total occlusion of right coronary artery and thrombus formation of left anterior descending artery.

A 33-year-old Japanese man had an attack of chest pain associated with ST-segment elevation in the inferolateral leads on his electrocardiogram. Emergency coronary angiography showed total obstruction in the mid right coronary artery (RCA) and a movable thrombus in the proximal left anterior descending artery (LAD). We performed emergency percutaneous transluminal coronary angioplasty (PTCA) for the RCA lesion. The operation was successful and we then conducted intracoronary thrombolysis (ICT) with tisokinase 6,400,000 IU for the LAD thrombus. Its size was reduced by ICT. He had an uneventful hospital course. After 1 month, repeat coronary angiography showed no significant stenosis in the RCA nor thrombus in the LAD. A coronary spasm provocation test was performed using acetylcholine. Coronary spasm in the LAD was induced by an intracoronary injection of 100 microg acetylcholine. In this case, we observed a unique condition suggesting simultaneous double coronary artery occlusion.

The coagulation-fibrinolysis system in patients with leukoaraiosis and Binswanger disease.

BACKGROUND: Hypercoagulability is observed in vascular dementia, including Binswanger disease. However, the correlation between hypercoagulability, leukoaraiosis, and dementia remains unclear. OBJECTIVE: To examine how activation of the coagulation fibrinolysis correlates with leukoaraiosis and dementia. PATIENTS AND METHODS: Thrombin-antithrombin complex (TAT), prothrombin fragment(1 + 2) (F1 + 2) and cross-linked D-dimer (XDP) were measured consecutively in 18 subjects without dementia and with leukoaraiosis, and in 29 subjects with subcortical vascular dementia and severe leukoaraiosis (Binswanger disease) at either stable or deteriorating stages. They were compared with 19 patients with old lacunar infarctions and 24 patients with other neurological diseases. We also examined the indices of cognitive impairment and brain atrophy. In each group, the ventricular area-cranial space area ratio was measured by an image analyzer. RESULTS: Patients with Binswanger disease who were exclusively at deteriorating stages showed increased TAT and XDP levels and an increased ventricular area-cranial space area ratio, as compared with the patients with other neurological diseases (P<.001). The index of cognitive impairment in patients at a deteriorating stage showed a decreasing trend vs that of patients in the stable stage. Among the variables that were significantly associated with a hypercoagulable condition (ie, age, scores on Mini-Mental State Examination or the Hasegawa Dementia Rating Scale, Revised [MMSE/HDRS], white matter lesions, ventricular area-cranial space area ratio, and C-reactive protein), age (odds ratio [OR], 2.82) and MMSE/HDSR scores (OR, 0.43) survived as predictors for coagulation activation, and C-reactive protein survived for fibrinolysis activation (OR, 4.63) in multivariate analysis. CONCLUSION: Hypercoagulability in a subgroup of patients with Binswanger disease and with more severe cognitive impairment and brain atrophy does not support a triggering role for a coagulation-fibrinolysis system, although it may contribute to worsening of neurological deficits.

Effects of an antithrombin drug in patients with subacute exacerbations of Binswanger disease.

The blood coagulation system has been shown to be activated in subacute exacerbations of Binswanger disease (BD). In our previous study, the antithrombin drug argatroban t ameliorated the neurological exacerbations in a BD patient with antiphospholipid antibody syndrome. We have further examined the therapeutic efficacy of argatroban in 3 BD patients with subacute exacerbations, but without any immune-mediated prothrombotic complications. In 1 out of these 4 patients, treatment with sodium ozagrel, an antiplatelet drug was applied, but was ineffective. In all patients, argatroban treatment reduced the levels of the hemostatic markers, with a corresponding improvement in cognitive dysfunction and gait disorders. These results suggest that the antithrombin effect is true also for BD patients not compromised by the immune-mediated prothrombotic condition.

[Influence of low high-density lipoprotein cholesterolemia induced by probucol on the progression of coronary atherosclerosis].

The influence of probucol-induced low high-density lipoprotein (HDL) cholesterolemia on the progression of coronary atherosclerosis was studied in 320 patients with angina pectoris or myocardial infarction, 32 patients with probucol 500 mg/day, 288 patients without probucol, who underwent follow-up angiography at intervals of at least 2 years. The 288 patients were divided into two groups depending on the serum HDL-cholesterol (HDL-C) level at the follow-up angiography: the low HDL-C group had a serum HDL-C level below 40 mg/dl (152 patients) and the control group had 40 mg/dl or above (136 patients). Coronary sclerosis index was defined as the total products of coronary scores (0-6) by segments according to the American Heart Association reporting system in the branches without angioplasty and was compared between the three groups. In the probucol group, serum HDL-C level was significantly reduced from 43.9 +/- 10.6 (at baseline) to 31.1 +/- 7.6 mg/dl (at follow-up, p < 0.01) and was lower than that in the other two groups (low HDL-C group 33.1 +/- 5.0 mg/dl, p < 0.07; control group 52.6 +/- 9.8 mg/dl, p < 0.01). Coronary sclerosis index was most increased in the low HDL-C group (8.3 +/- 5.4-->11.9 +/- 6.1, p < 0.01), whereas there was no significant change in the probucol group (7.2 +/- 5.9-->9.1 +/- 6.8, p = 0.24). Our results showed that treatment with probucol inhibits the progression of coronary atherosclerosis despite the decrease in HDL-C level. One possible reason may be remarkable improvement in the other lipid factors, especially the low-density lipoprotein cholesterol level (165.7 +/- 33.9-->123.7 +/- 29.0 mg/dl, p < 0.01).

[A case of multiple cerebral arterial thrombosis due to congenital protein C deficiency].

We report a 49-year-old man who had right hemiparesis and motor aphasia. A computed tomography revealed hypodense areas in the left frontal subcortex. A cerebral angiography demonstrated occlusion of the left distal internal carotid artery and both anterior cerebral arteries, as well as stenosis of the left internal carotid artery at the cervical portion. The second angiogram obtained a month later showed no changes. The diagnosis of atherothrombotic cerebral infarction was established on the basis of clinical profile and angiographic findings. Protein C activity and antigen levels were reduced to approximately one half of the normal level in the patient and his brother. The patient had no other risk factors for stroke. Protein C deficiency has been considered one of the risk factors for thrombotic diseases. Venous thrombosis is the most common clinical manifestation, whereas arterial thrombosis is relatively rare. It is generally believed that arterial ischemic stroke associated with protein C deficiency occurs with embolic mechanism, and atherothrombotic infarction is extremely rare. This is the first report suggesting the possibility that protein C deficiency can cause cerebral thrombosis.

Progression of coronary artery disease in patients receiving percutaneous transluminal coronary angioplasty: angiographic comparison of angioplasty and non-angioplasty sites.

Long-term follow-up of coronary artery stenosis was carried out in 81 patients undergoing successful percutaneous transluminal coronary angioplasty (PTCA). Progression of coronary stenosis was observed in 38 patients with 52 sites, and regression was seen in 23 patients with 23 sites during 2 years or more of follow-up. Progressive change occurred in three sites of 97 PTCA lesions and 49 of 1,090 non-PTCA lesions (no significant difference). On the other hand, regressive change was observed in 19 sites of PTCA lesions and four of non-PTCA lesions (p < 0.05). The percentage of narrowing in PTCA lesions was 28.0 +/- 14.4% at 3-6 months after PTCA, and this improved to 22.8 +/- 15.8% at late study angiography. Coronary score changes were -0.16 +/- 0.54 in PTCA lesions, and 0.08 +/- 0.46 in non-PTCA lesions (p < 0.01). We concluded that the progression of obstructive coronary artery disease in sites with previous PTCA is less than in those with non-PTCA.

[Efficacy and safety of percutaneous transluminal coronary angioplasty of other coronary arteries in patients with chronic total occlusion of the left anterior descending artery].

The acute and long-term outcomes of percutaneous transluminal coronary angioplasty (PTCA) of the right coronary artery (RCA) or left circumflex branch (LCS) in patients with chronic occlusion of the left anterior descending branch (LAD) (group A) were compared with those of sex and age matched patients undergoing PTCA of the RCA or LCX with a normal LAD (group B). Before the procedure, group A had more frequent prior myocardial infarction (96% vs 33%, p < 0.001), and a lower left ventricular ejection fraction (LVEF) (49 +/- 14% vs 71 +/- 13%, p < 0.001). The acute results were similar in the two groups with respect to primary success (group A 90%, group B 91%) and major complications (group A 6%, group B 2%). At 3 months, the rate of restenosis was 33% in group A and 27% in group B. In group A, LVEF increased significantly in patients without restenosis (53 +/- 11% vs 62 +/- 11%, p < 0.01). At long-term follow-up, group A had higher rates of persistent angina but there was no difference in outcome between the two groups. In patients with chronic total occlusion of LAD, PTCA for RCA or LCX can be performed with a low complication rate and provides a significant improvement in LVEF at 3 months in the absence of restenosis. However, at short-term follow-up, these patients have a greater incidence of persistent angina.

Restenosis after successful emergency coronary angioplasty for acute myocardial infarction: comparison with elective angioplasty.

We investigated the initial and late restenosis rate after successful emergency coronary angioplasty in 64 patients with acute myocardial infarction, and compared these results with those of 100 patients (110 lesions) who had successful angioplasty on an elective basis. The majority of the baseline clinical and angiographic variables were similar in the myocardial infarction and elective groups. The restenosis rate at 1 month was high in patients undergoing emergency angioplasty for acute myocardial infarction (23 vs. 12%). At 3-6 months, the angiographic restenosis rate was low for the infarction group (26 vs. 37%). The overall restenosis rate was similar in the infarction and elective groups (39 vs. 40%). Lesion regression after coronary angioplasty was more frequent in the infarction than in the elective angioplasty group (27 vs. 14%, P < 0.05). These findings suggest that considering the high restenosis rate at 1 month and the lower, but still 20% or more, rate at 3-6 months, a follow-up angiography should be performed both prior to discharge and at 3-6 months after the procedure, in patients with acute myocardial infarction.

[Clinical features and long-term outcome of non-Q wave myocardial infarction in the elderly: comparison with Q wave myocardial infarction].

The clinical features and long-term outcome of non-Q wave myocardial infarction (NQMI) in the elderly were assessed in 24 patients with NQMI and compared with those in 48 patients with Q wave myocardial infarction (QMI). NQMI patients had a significantly lower maximal peak of serum creatine phosphokinase activity and lower incidence of pump failure during the acute phase. In-hospital mortality did not differ significantly between the NQMI and QMI patients. Evaluation of acute-phase coronary angiographic features within 6 hours of onset found a significantly higher incidence of infarct-related vessels in the NQMI patients, but the frequency of multivessel disease and the level of collateral flow did not differ between the two groups. Fifteen of the 24 NQMI patients and 34 of the 48 QMI patients underwent emergency coronary revascularization procedures of percutaneous transluminal coronary angioplasty (PTCA) or intracoronary thrombolysis. Successful recanalization was more frequent and the time to recanalization was shorter in the NQMI patients. The requirement for coronary revascularization (PTCA or coronary artery bypass graft) in the chronic phase for residual stenosis did not differ significantly between the two groups. Left ventricular ejection fractions were significantly better in the NQMI patients. The short- and long-term outcomes in elderly patients with NQMI and QMI were good and did not differ between the two groups, probably reflecting the active performance of revascularization in the acute and chronic phases.

[A case of life-threatening ventricular arrhythmias probably due to psychotropic drugs].

We present a case provoked life-threatening ventricular arrhythmias probably due to psychotropic drugs. The patient was a 55-year-old man who had previously twice operations of aortic valve replacement (AVR). The signs of cardiac failure were recurrently appeared from the end of 1991, and he had received promethazine and sulpiride for his depressive state. From cardiac catheterization, we planned his third AVR. The electrocardiographic (ECG) QTc interval was prolonged to 0.48 seconds on this admission. In March 1992 syncopal attack appeared suddenly, and his monitor ECG revealed frequent polymorphous ventricular tachycardia (VT) and Torsade de Pointes (Tdp). These arrhythmias stopped by emergent cardiac pacing. After discontinuing these psychotropic drugs, no ventricular arrhythmias appeared. Since the patient complained severe insomnia one month before operation, the diminished dose of psychotropic drugs (promethazine and levomepromazine) was readministered. Ten days after the operation, syncopal attack reappeared and his ECG recorded frequent VT and Tdp. During both syncopal attacks his serum potassium and magnesium were within normal limits. Two days later, he died from multi-organ failure. We concluded that life-threatening arrhythmias such as VT and Tdp might develop under the administration of mild psychotropic drugs (promethazine or levomepromazine), therefore, must better take a care of ECG changes in cases of using any psychotropic drugs.