Which factors increase procedural thromboembolic events in patients with unruptured paraclinoid internal carotid artery aneurysm treated by coil embolization?

We analyzed the factors which increase the frequency of procedural thromboembolic events during coil embolization of unruptured paraclinoid internal carotid artery aneurysms. Neurologically symptomatic complications did not occur in our series. Silent hyperintense lesions on postoperative DWI were frequently detected after the coiling procedure in which we needed to withdraw the unreleased coil. Patient's age, sex, aneurysm diameter, packing density, use of balloon-assisted technique, and exchanging maneuver of microcatheter during the procedure did not increase the frequency of silent thromboembolic events.

Soluble interleukin-2 receptor as an indicator of immunological disturbance found in silicosis patients.

Silicosis patients (SILs) possess not only respiratory disorders but also alterations in autoimmunity. To determine an early indicator of immunological disturbance in SILs, the role of serum-soluble interleukin (IL)-2 receptor (sIL-2R) was analyzed. Of ten SILs, immunological clinical parameters such as immunoglobulin (Ig) G, complements, the titer of autoantibodies including anti-nuclear antibodies (ANA), anti-Scl-70 antibody (Ab) and anti-centromere (CM) Ab, and experimental indicators such as serum-soluble Fas, serum IL-2, CD25+ cells in CD4+ or CD8+ fractions, and sIL-2R were divided from respiratory parameters such as percent vital capacity (%VC), percentage of forced expiratory volume in 1 second (FEV1.0%) and v25/Ht (liter/second/m(body height) by a correlation assay. Additionally, a stepwise regression test showed that sIL-2R was correlated with Ig G, ANA and anti-CM Ab. Furthermore, factor analysis revealed that sIL-2R contributed to the subpopulation of SILs with poorer immunological status in the absence of alterations in respiratory status. By defining healthy donors as 1, SILs as 2 and patients with systemic sclerosis as 3 for immunopathological progression status as metric variables, sIL2R and ANA showed a strong positive correlation. This suggests that sIL-2R is a good clinical indicator of immunological disturbance found in SILs without clinical manifestations of any disturbance in autoimmunity. Further analysis using a large-scale number of patients should be performed to confirm these findings.

Reduced function of CD4+25+ regulatory T cell fraction in silicosis patients.

The quality and quantity of CD4+25+ regulatory T cells (Treg) in silicosis patients (SIL) were examined and compared with results from healthy donors (HD) because SIL often develop autoimmune diseases along with pulmonary disorders. Peripheral blood mononuclear cells from 57 SIL and 50 HD were analyzed for Treg. Treg frequency and clinical parameters were subjected to a factor analysis. Treg and CD4+25- T cells (Tneg) from five HD and five SIL, sorted by flow-cytometer, were used for functional assays of Treg, the expression pattern of Treg specific genes (FoxP3, GITR and CTLA-4) and activation-related genes (CD122 and CD123). Although the actual frequency of Treg did not differ between SIL and HD, the age-corrected level was reduced in SIL. The factor analysis showed that Treg frequency was positively associated with the serum level of IL-2. The inhibitory effect of Treg on Tneg activation was decreased when the Treg:Tneg ratio was 1:1/4 to 1/2. In addition, Treg dominancy of FoxP3 and CTLA-4 expression and Tneg dominancy of CD132 expression found in HD were lost in SIL. These results indicated that the Treg fraction in SIL may be substituted with chronically activated T cells due to recurrent exposure to silica, resulting in a reduction in the frequency and function of Treg. Since the reduction of Treg may precede the clinical manifestation, as silicosis may be a pre-clinical status for autoimmune diseases, control of Treg function using cell and/or gene therapy may be a good way to manage autoimmune disease.

Inhibitory effects of anti-oxidants on apoptosis of a human polyclonal T-cell line, MT-2, induced by an asbestos, chrysotile-A.

To clarify the effects of silica and silicates on cellular features of lymphocytes, a human T-lymphotropic virus type-1-immortalized polyclonal T-cell line, MT-2, was exposed to various concentrations of chrysotile-A, an asbestos classified as silicate. MT-2 cells underwent apoptosis in a dose- and time-dependent manner. The mitochondrial apoptotic pathway was activated during chrysotile-A-induced apoptosis of MT-2 cells, because of the phosphorylation of JNK and p38, increase of BAX and release of cytochrome-c from mitochondria to cytoplasma. In addition, anti-oxidants such as hydroxyl-radical excluders and capturers of superoxide and inhibitors of superoxide production effectively reduced the size of the apoptotic fraction in MT-2 cells cultured with chrysotile-A. These results indicate that the activation of reactive oxygen species may play a central role in asbestos-induced T-cell apoptosis, and anti-oxidants may help to prevent complications of pneumoconiosis.

Expression of protein gene product 9.5 (PGP9.5)/ubiquitin-C-terminal hydrolase 1 (UCHL-1) in human myeloma cells.

The neuron cytoplasmic protein gene product 9.5 (PGP9.5)/ubiquitin-C-terminal hydrolase 1 (UCHL-1) protein is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal of ubiquitin, and is involved in the processing of ubiquitin precursors and ubiquinated proteins. Although this molecule is known as a specific tissue marker for the neuroendocrine system, many reports have indicated that PGP9.5 is a marker for certain tumour types, such as cancer of the lung, colon, and pancreas. The expression of PGP9.5 in myeloma cells was examined. PGP9.5 seemed to be expressed specifically in myeloma cells as compared with other haematological malignant cells. In addition, in myeloma cells subjected to growth-factor starvation, the upregulation of PGP9.5 was observed in association with that of p27(Kip1), a cyclin-dependent-kinase inhibitor, although the upregulation caused by irradiation was milder. In contrast, the hypoxic culture of myeloma cells induced down-regulation of PGP9.5. These results suggested that PGP9.5 may be a good marker for myeloma among haematological malignancies. In addition, it may indicate certain cellular features of myeloma cells, such as sensitivity to proteasome inhibitors.

Secretory IgA in saliva and academic stress.

Several reports have proposed that the concentration of secretory immunoglobulin A (S-IgA) in saliva is an indicator of psychological stress. With this in mind, we decided to examine it in 10 second year medical student volunteers at Kawasaki Medical School course between May 4 and July 13, 2000 and discussed the relationship between S-IbA and the stress from academic examinations. Saliva was collected three times (on rising, at forenoon, and at bedtime) every Thursday. During this period, sporadic academic examinations were held twice and term end examination occurred during the last two weeks. Results showed the concentration of S-IgA significantly higher at the on rising time-point than at the other two time-points. There was also a tendency for the S-IgA level in saliva to be higher on the day before academic examinations and during them and lower on the days between these examinations. In addition, daily variations in the S-IgA concentration sometimes seemed to be disturbed by other academic stress. Therefore it may be possible to use this measurement to monitor psychological stress in students and workers.

The contribution of cardiorespiratory fitness and visceral fat to risk factors in Japanese patients with impaired glucose tolerance and type 2 diabetes mellitus.

It is still unclear as to how cardiorespiratory fitness and visceral fat accumulation contribute to coronary heart disease (CHD) risk factors in patients with diabetes mellitus. The purpose of the present study was to investigate whether cardiorespiratory fitness contributes to such risk factors independently of visceral fat accumulation. Two hundred Japanese patients (137 men and 63 women, aged 22 to 81 years) with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (type 2 DM) without any intervention and pharmacological therapy participated in a cross-sectional study. The levels of fasting insulin, triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and resting blood pressure were assessed. Maximal oxygen uptake (V.o(2max)), an index of cardiorespiratory fitness, was predicted by a graded exercise test using a cycle ergometer. Visceral fat area (VFA) was measured by computed tomography scan. The criteria for abnormalities of the risk factors were determined according to the standard values for Japanese. All subjects were divided equally into the following 3 groups according to their fitness level: low-fit (V.o(2max) < 32 mL/kg/min in men, V.o(2max) < 26 mL/kg/min in women), mid-fit (32 < or = V.o(2max) < 36 in men, 26 < or = V.o(2max) < 30 in women), and high-fit (V.o(2max) > or = 36 in men, V.o(2max) > or = 30 in women). The association between fitness level and the prevalence of abnormal values for these parameters was analyzed by a multiple logistic regression model adjusted for age and VFA. The odds ratio (OR) and 95% confidence interval (CI) for the prevalence of hyperinsulinemia were significantly lower in the mid-fit (OR = 0.35, 95% CI, 0.16 to 0.78) and in the high-fit groups (OR = 0.40, 95% CI, 0.16 to 0.98) compared with the low-fit group. In addition, ORs for the prevalence of low HDL-C in the mid-fit and high-fit groups were significantly lower (OR = 0.35, 95% CI, 0.14 to 0.86; and OR = 0.19; 95% CI, 0.08 to 0.60, respectively) than in the low-fit group. These results suggested that cardiorespiratory fitness might be one of the predictors of metabolic abnormalities, especially in patients with hyperinsulinemia and low HDL-C, independent of visceral fat accumulation in Japanese patients with IGT and type 2 DM.

Intramolecular epitope spreading among anti-caspase-8 autoantibodies in patients with silicosis, systemic sclerosis and systemic lupus erythematosus, as well as in healthy individuals.

Dysregulation of apoptosis through the Fas-Fas ligand pathway is relevant in autoimmune disease onset. We recently reported elevated serum levels of sFas in patients with silicosis, systemic sclerosis (SSC) and systemic lupus erythematosus (SLE), and proposed a block of apoptosis in the pathogenesis. The disturbance of apoptosis in lymphocytes including autoreactive clones could induce autoantibody production. Since autoantibodies directed against unknown antigens are present in the sera of these patients, the sera samples were examined for the presence of autoantibodies directed to caspase-8. Using Western blotting, autoantibodies against caspase-8 were detected in healthy individuals and in over 60% of patients. Using epitope mapping employing 12 amino acid polypeptides with SPOTs system, a minimum of 4 epitopes and a maximum of 13 were found, which implied that epitope spreading was in progress. It is noteworthy that two important catalytic cystein residues were included within the epitopes; firstly the active site cystein Cys287, and secondly Cys360 located in the unique pentapeptide motif QACQG. Using recombinant human caspase-8 linked protein chip array, autoantibodies were identified and molecular weight determined. The antibodies were mainly IgG; 80% were subclass IgG1(lambda); 20% were IgG4(kappa). Despite the ratio of human light chain kappa:lambda = 2:1, the predominance of IgG1(lambda) is noticeable. Anti-caspase-8 autoantibodies are detectable in healthy individuals and in patients suffering silicosis, SSc or SLE. A few epitopes were detected in healthy individuals compared to those suffering autoimmune diseases, indicating the intramolecular epitope spreading. Relationship of autoantibodies and the clinical background of the patients requires clarification.

Characteristic changes of stress protein expression in streptozotocin-induced diabetic rats.

Stress proteins (heat shock proteins, HSP) play essential roles in folding, assembly and translocation of polypeptides and also in maintenance of the integrity of polypeptides as molecular chaperones. Since long-lasting hyperglycemia causes modification of cellular proteins, it is possible that expression of molecular chaperones may be altered during the course of diabetes. Here, we examined the cellular levels of stress proteins such as HSP105, HSP90 and HSC70/HSP70 in various tissues of streptozotocin-induced diabetic rats. In comparison to controls, the levels of HSC70 were markedly decreased in the liver but not in the brain, adrenal gland and pancreas of diabetic rats. The levels of HSP105 and HSP90 were not significantly changed in these tissues of diabetic rats. Furthermore, the induction of HSP70 as well as HSC70 by hyperthermia was significantly reduced in the liver and adrenal gland of diabetic rats. These results suggested that the expression and induction of HSC70/HSP70 may be altered during the course of diabetic disease and may result in impairment of the cytoprotective ability of diabetic rats.

Role of hsp105 in protection against stress-induced apoptosis in neuronal PC12 cells.

hsp105alpha is a stress protein characteristically highly expressed in the brain compared with other tissues in mammals. Here, to examine whether hsp105alpha plays a pivotal role in the nervous system, we tested the capability of hsp105alpha to protect against apoptosis in rat neuronal PC12 cells. Various stress treatments such as serum deprivation, heat shock, hydrogen peroxide, etoposide, and actinomycin D induced apoptosis in PC12 cells with characteristic shrinking of nuclei and chromatin. However, PC12 cells that constitutively overexpressed mouse hsp105alpha exhibited a strong protective effect against apoptosis induced by these stress treatments. Cleavage of poly(ADP-ribose) polymerase induced in PC12 cells by these treatments was inhibited in the constitutively overexpressed hsp105alpha cells. Furthermore, c-Jun N-terminal kinase (JNK) was activated in the cells treated with heat shock but not other treatments, and the heat-induced JNK activation was inhibited by the constitutive expression of hsp105alpha.Thus, hsp105alpha prevents not only heat-induced apoptosis by inhibiting JNK activation, but also prevents the apoptosis induced by other stressors through different pathways, and may play important roles in neuronal protection.

[Hemodynamic effects of STA-MCA anastomosis on patients with occlusion of the main cerebral artery].

PURPOSE: We studied cerebral circulation in patients with occlusion of the main cerebral artery and investigated the efficacy of STA-MCA anastomosis. PATIENTS AND METHODS: Thirty-six patients with occlusion of the main cerebral artery were studied. Twenty-three patients had occlusion of the internal carotid artery and 13 had occlusion of the middle cerebral artery. The mean age was 62 years. Cerebral blood flow (CBF) was measured in all patients and cerebrovascular reactivity (CVR) was examined in 11 patients by xenon enhanced CT. Intraoperatively, cortical arterial pressure and anastomotic flow were measured. RESULTS: There was no perioperative mortality or morbidity. There was no ipsilateral stroke recurrence during the follow-up period averaging 35.1 months. Patency of the anastomosis was verified in 91% of the patients by magnetic resonance angiography. Twenty-three (64%) patients showed decreased CBF before the operation and 57% of these patients showed improvement to the normal range after STA-MCA anastomosis. All of the eight patients with decreased CVR showed improvement after the operation. Anastomotic flow correlated significantly with the cortical arterial pressure. CONCLUSION: STA-MCA anastomosis could improve cerebral circulation of patients with low CBF or low CVR due to occlusion of the main cerebral arterial. It was concluded that STA-MCA anastomosis may contribute to the reduction of stroke recurrence, if perioperative complications are reduced.

Methylprednisolone ameliorates cochlear nerve degeneration following mechanical injury.

We investigated whether methylprednisolone sodium succinate can ameliorate cochlear nerve degeneration following compression injury on the cerebellopontine angle portion of the cochlear nerve, using a quantitative animal experimental model that we have developed recently. In this model, cochlear nerve degeneration after compression could be quantitatively evaluated, while cochlear ischemia induced by the compression carefully maintained below the critical limit that causes irreversible damage to the cochlea. Eleven rats were treated with methylprednisolone during the pre- and post-compression period. Two weeks after compression, the numbers of SGC were compared between the rats that received the compression without and with methylprednisolone treatment. Methylprednisolone treatment improved the survival of SGC following cochlear nerve injury statistically highly significantly in the basal turn where the traumatic stress had been less than in the other cochlear turns in our experimental setting. Although it was not statistically significant, greater survival was also observed in the other cochlear turns. The results of this experimental study indicated that at least a portion of injured cochlear nerve had been potentially treatable, and that methylprednisolone might prevent such cochlear neurons from entering into the vicious process of irreversible damaging process.

Intraoperative electrophysiological monitoring of oculomotor nuclei and their intramedullary tracts during midbrain tumor surgery.

OBJECTIVE: During surgery for intrinsic midbrain lesions, we intraoperatively recorded evoked compound muscle action potentials (ECMAPs) from the extraocular muscles and evaluated how this type of intraoperative electrophysiological monitoring could minimize postoperative oculomotor nerve palsy (ptosis and/or diplopia). METHODS: The ECMAPs were recorded through a spring electrode applied to the extraocular muscle (Method 1, seven cases) or a needle electrode inserted into the superior intraorbital space (Method 2, five cases). The surgeon repeated electrical stimulations whenever tissue of unknown origin was encountered intraoperatively, and this information was used to safely guide surgical resection of the tumors. RESULTS: Using these monitoring techniques, the response-free areas were resected and the areas from which ECMAP responses were recorded were avoided. For all 12 patients, ECMAPs were successfully recorded from the extraocular muscles. Ten patients did not exhibit any postoperative deterioration of oculomotor nerve function. Two patients exhibited deterioration of oculomotor nerve function immediately after surgery, which resolved within 1 month. Equally robust ECMAPs could be recorded with Method 2, compared with Method 1. CONCLUSION: Intraoperative ECMAP recordings from the extraocular muscles precisely indicated the locations of the oculomotor nuclei and/or intramedullary oculomotor tracts. Although Method 2 is a more indirect method for recording ECMAPs than is Method 1, Method 2 was equally useful in recording ECMAPs, which seemed to be the summed potentials from the superior rectus muscle and the levator palpebrae superioris muscle. These monitoring techniques are valuable in guiding surgeons to avoid causing inadvertent harm to the oculomotor nuclei and tracts during midbrain surgery, particularly when the neuroanatomic features are distorted by the presence of tumor.

Enhanced phospholipase C activity in the cultured skin fibroblast obtained from patients with coronary spastic angina: possible role for enhanced vasoconstrictor response.

OBJECTIVES: We measured phospholipase C (PLC) activity in the cultured skin fibroblasts obtained from patients with and without coronary spasm and examined its correlation with coronary artery vasomotility. BACKGROUND: Coronary artery vasomotility is enhanced in coronary spastic angina (CSA), but no information is available for the intracellular signaling. In spontaneously hypertensive rats, PLC activity in the skin fibroblasts has been shown to be enhanced. METHODS: Skin fibroblasts obtained from 24 patients with CSA-14 with organic coronary artery disease (CAD) and 12 control subjects--were cultured by the explant method. Activity of PLC was determined by incubating the membrane fraction with 3H-phosphatidyl inositol bisphosphate and by quantifying 3H-inositol trisphosphate. In patients with CSA and control subjects, the relations between PLC activity and coronary artery basal tone and constrictor response to intracoronary acetylcholine (ACh) were examined. RESULTS: Activity of PLC (pmol/protein [mg] per min) was 1.74+/-0.19 in patients with CSA; 0.90+/-0.12 in patients with CAD; and 0.65+/-0.07 in control subjects (p<0.001, patients with CSA vs. patients with CAD and control subjects; p = NS, patients with CAD vs. control subjects). According to the Lineweaver-Burk plot, Michaelis constant (micromol/liter) of PLC was 28+/-4 in patients with CSA; 49+/-14 in patients with CAD; and 56+/-10 in control subjects (p<0.05, patients with CSA vs. control subjects), whereas the maximal velocity was not different between the three groups. There were significant positive correlations between PLC activity and both basal tone (p = 0.0108) and response to ACh (p = 0.0053). Western blot analysis using membrane fraction demonstrated that 89% of PLC isoenzymes detected was of the delta1 isoform. CONCLUSIONS: Because the PLC activity measured was genetically defined and was positively correlated with coronary artery vasomotility, enhanced PLC activity may be involved in the pathogenesis of coronary spasm.

Successful surgical treatment of a large mixed pial-dural arteriovenous malformation.

A large mixed pial-dural arteriovenous malformation was successfully treated by surgical resection and occlusion of the draining veins. Treatment of this type of malformation is discussed.

Cerebellopontine angle cisternal infusion of NGF, BDNF and NT-3: effects on cochlear neurons disconnected from central target, cochlear nucleus. An in vivo quantitative study.

Cochlear neurons need their synaptic contacts with both their peripheral (organ of Corti) and central (cochlear nucleus) targets for survival. We examined the in vivo effectiveness of the neurotrophins (NGF, BDNF and NT-3) on cochlear neuronal survival using our in vivo model, in which the central connection alone was selectively and quantitatively interrupted. The particular neurotrophins evaluated in the present study did not appear to have cochlear nerve rescue potential. However, the experimental model reported here can serve as a useful tool to investigate cochlear neuronal degeneration from the central side, which may lead to identification of effective mediators in the future.

Effectiveness of preoperative administration of an N-methyl-D-aspartate antagonist to enhance cochlear neuron resistance to intraoperative traumatic stress: an experimental study.

OBJECT: Cochlear neurons are inevitably exposed to traumatic stress during surgical removal of an acoustic neuroma; that event is an important cause of postoperative cochlear neuronal degeneration, with subsequent loss of spiral ganglion cells (SGCs). The object of this study was to investigate whether preoperative pharmacological treatment can enhance the resistance of cochlear neurons to the traumatic stress of surgery. METHODS: Cochlear neuronal degeneration was induced in 17 rats by controlled compression of the cerebellopontine angle portion of the cochlear nerve. Dizocilpine maleate (MK-801; 10 mg/kg), an N-methyl-D-aspartate (NMDA) antagonist, was administered intraperitoneally to six of the 17 rats 30 minutes before compression occurred. Two weeks after compression, each rat was killed, and the numbers of SGCs in histological preparations of temporal bones were counted. CONCLUSIONS: Spiral ganglion cells were more numerous in rats administered dizocilpine maleate (p < 0.03) than in rats that did not receive treatment, indicating that receptor-mediated glutamate neurotoxicity may participate in the pathogenesis of trauma-induced cochlear neuron death and that administration of an NMDA antagonist before surgery may protect the nerve from injury leading to hearing loss.

A comprehensive classification system of vestibular schwannomas.

Because traditional classifications of vestibular schwannomas (according to relative size) cannot comprehensively describe lesions that grow in different patterns after arising in regions as diverse as the cerebellopontine (CP) angle, the internal auditory canal, and the region lateral to the fundus of the internal auditory canal (labyrinth), we developed a new system to classify vestibular schwannomas, a system that describes the anatomical structures involved by the tumour, rather than size alone. The vestibular schwannoma is classified first by location and then by extent. Our system provides surgeons information helpful in choosing the surgical approach, in estimating the difficulty of tumour excision, and in determining whether hearing might be preserved. Our system also avoids confusion and misunderstanding in discussions of treatment results because it reflects the diverse biological characteristics of vestibular schwannomas.

Coil embolisation for ruptured vertebral artery dissection distal to the origin of the posterior inferior cerebellar artery.

Although many surgical or endovascular treatments for ruptured vertebral artery dissection have been reported, the best treatment is controversial. We treated five cases of ruptured vertebral artery dissection distal to the origin of the posterior inferior cerebellar artery (PICA), using retrievable platinum coils packed in the dissection site and the immediately proximal vertebral artery. All patients had a contralateral vertebral artery of the same calibre or larger. All dissections were occluded completely, together with the portion of the vertebral artery distal to the PICA origin. No complications related to the procedure were seen. The purpose of the treatment is to isolate the dissection from the cerebral circulation. Occlusion of the rupture site, preserving perforating arteries arising from the vertebral artery, would be ideal. Short-segment occlusion by retrievable platinum coils is close to the ideal.

Modulation of the chaperone activities of Hsc70/Hsp40 by Hsp105alpha and Hsp105beta.

Hsp105alpha and Hsp105beta are stress proteins found in various mammals including human, mouse, and rat, which belong to the Hsp105/Hsp110 protein family. To elucidate their physiological functions, we examined here the chaperone activity of these stress proteins. Hsp105alpha and Hsp105beta prevented the aggregation of firefly luciferase during thermal denaturation, whereas the thermally denatured luciferase was not reactivated by itself or by rabbit reticulocyte lysate (RRL). On the other hand, Hsp105alpha and Hsp105beta suppressed the reactivation of thermally denatured luciferase by RRL and of chemically denatured luciferase by Hsc70/Hsp40 or RRL. Furthermore, although Hsp105alpha and Hsp105beta did not show ATPase activity, the addition of Hsp105alpha or Hsp105beta to Hsc70/Hsp40 enhanced the amount of hydrolysis of ATP greater than that of the Hsp40-stimulated Hsc70 ATPase activity. These findings suggest that Hsp105alpha and Hsp105beta are not only chaperones that prevent thermal aggregation of proteins, but also regulators of the Hsc70 chaperone system in mammalian cells.