Transient ischemic attack without self-awareness of symptoms witnessed by bystanders: analysis of the PROMISE-TIA registry.

BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) can occur without self-awareness of symptoms. We aimed to investigate characteristics of patients with a tissue-based diagnosis of TIA but having no self-awareness of their symptoms and whose symptoms were witnessed by bystanders. METHODS: We used data from the multicenter registry of 1414 patients with a clinical diagnosis of TIA. For patients without evidence of ischemic lesions on imaging, clinical characteristics were compared between patients with and without self-awareness of their TIA symptoms. RESULTS: Among 896 patients (559 men, median age of 70 years), 59 (6.6%) were unaware of their TIA symptoms, but had those symptoms witnessed by bystanders. Patients without self-awareness of symptoms were older and more frequently female, and more likely to have previous history of stroke, premorbid disability, and atrial fibrillation, but less likely to have dyslipidemia than those with self-awareness. Patients without self-awareness of symptoms arrive at hospitals earlier than those with self-awareness (P < 0.001). ABCD2 score was higher in patients without self-awareness of symptoms than those with self-awareness (median 5 vs. 4, P = 0.002). Having no self-awareness of symptoms was a significant predictor of ischemic stroke within 1 year after adjustment for sex, ABCD2 score, and onset to arrival time (hazard ratio = 2.44, 95% confidential interval: 1.10-4.83), but was not significant after further adjustment for arterial stenosis or occlusion. CONCLUSIONS: Patients with a TIA but having no self-awareness of their symptoms might have higher risk of subsequent ischemic stroke rather than those with self-awareness, suggesting urgent management is needed even if patients have no self-awareness of symptoms.

Long waiting time before tooth extraction may increase delayed wound healing in elderly Japanese.

In osteoporosis patients receiving antiresorptive medications, stopping the drug and delaying tooth extraction has been suggested to reduce the risk of osteonecrosis of the jaw (ONJ). However, postponing tooth extraction for ≥ 2 months was associated with an increased risk of delayed wound healing beyond 8 weeks after extraction, a risk factor for developing ONJ. INTRODUCTION: A long waiting time before tooth extraction could result from concern about a potential increased risk of osteonecrosis of the jaw (ONJ) in osteoporosis patients. We clarified whether a long waiting time before tooth extraction during the past year may be associated with an increased risk of delayed wound healing beyond 8 weeks after tooth extraction, which may be a risk factor of ONJ. METHODS: Of 5639 patients aged ≥ 60 years who visited our 20 clinics or hospitals and answered a structured questionnaire, 426 patients (151 men, 275 women) aged 60-96 years comprised the final participants in this study. Self-reported kyphosis was used as a surrogate marker of vertebral fractures. Stepwise logistic regression analysis, adjusted for covariates, was used to calculate the odds ratio (OR) and the 95% confidence interval (CI) for the presence of delayed wound healing longer than 8 weeks after tooth extraction during the past year based on the duration before extraction. RESULTS: Subjects who had waited > 2 months for tooth extraction had a significantly higher risk of delayed wound healing compared with those whose tooth was extracted within 1 month (OR = 7.23; 95% CI = 2.19-23.85, p = 0.001) regardless if antiresorptive medications for osteoporosis were used. The presence of self-reported kyphosis was significantly associated with an increased risk of delayed wound healing (OR = 5.08; 95% CI = 1.11-23.32, p = 0.036). CONCLUSIONS: A long waiting time before tooth extraction may be a risk factor for delayed wound healing beyond 8 weeks after extraction in patients aged ≥ 60 years.

Significant improvement of bone mineral density and bone turnover markers by denosumab therapy in bisphosphonate-unresponsive patients.

Bone mineral density (BMD) sometimes cannot be improved by long-term bisphosphonate (BP) therapy in osteoporosis (OP). This study showed that lumbar as well as hip BMD significantly increased after denosumab treatment in patients not responsive to BPs. Thus, denosumab may be a strong OP treatment option for BP-unresponsive patients. INTRODUCTION: BMD sometimes cannot be improved by long-term BP therapy. METHODS: We administered denosumab to osteoporotic patients with a poor response to BPs who had been taking them for 2 years or longer. Ninety-eight women with BP-poor responsive OP were enrolled in this study. Mean (standard deviation [SD]) age was 71.2 (6.9) years and mean (SD) duration of BP treatment was 59.9 (34.3) months. We distinguished BP responders from non-responders based on changes in BMD values at denosumab commencement (baseline) from 2 years beforehand. RESULTS: There were no significant differences in age, duration of BP use, bone turnover markers, or BMD at baseline between the groups. Prior to denosumab, BMD had increased significantly in responders and decreased significantly in non-responders. Bone turnover markers had decreased significantly at 4 months of denosumab treatment (P < 0.001) and lumbar and hip BMD were significantly increased at 1 year of therapy in both groups (P < 0.001). Simple correlation coefficients were -0.337 for lumbar and -0.339 for hip BMD changes (both P = 0.001) before and after denosumab treatment. Both at the lumbar spine and hips, decreased BMD before denosumab therapy was significantly associated with an increase in BMD at 1 year of treatment (spine, t value = -3.502, P = 0.001, R = 0.113; hip, t value = -3.526, P = 0.001, R = 0.115). CONCLUSIONS: These results suggest that denosumab may be a strong OP treatment option for BP-unresponsive patients.

ASURA (PHB2) interacts with Scc1 through chromatin.

Sister chromatid cohesion mediated by the cohesin complex is essential for faithful chromosome segregation. Previously we reported that PHB2 (prohibitin2/ASURA), a multifunctional protein, has a role in sister chromatid cohesion. Nevertheless, how ASURA is involved in sister chromatid cohesion still remains unclear. The present co-immunoprecipitation analysis reveals that ASURA interacts with cohesin subunit Scc1 in vivo. We show that ASURA associates with chromatin in a similar manner as Scc1 throughout the cell cycle. Furthermore, our observation using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system indicates that ASURA is important for cohesin maintenance at early mitosis. We have also identified that the conserved PHB domain is responsible for chromatin targeting of ASURA. Our results suggest that the regulation of sister chromatid cohesion is mediated by ASURA binding to chromatin, where ASURA might be involved in cohesin protection through ASURA-Scc1 interactions.

Taste disorders in myasthenia gravis: a multicenter cooperative study.

BACKGROUND AND PURPOSE: The purpose of the present study was to investigate the prevalence and clinical characteristics of taste disorders in patients with myasthenia gravis (MG). METHODS: We studied 371 Japanese patients with MG (127 men and 244 women; mean age, 56.6±16.9years) consecutively evaluated between May and September 2010 in six neurological centers comprising the East Japan MG Study Group. Ninety-three patients (25%) had thymoma. We interviewed all patients to determine whether they had taste disorders during the clinical course of MG and then further evaluated the patients with MG, who reported having taste disorders, using a questionnaire. RESULTS: Taste disorders were observed in 16 (4.3%) of the 371 patients with MG. We concluded that taste disorders in 2.4% of patients with MG excluding other factors were associated with MG itself. All patients had thymoma with seropositivity for anti-acetylcholine receptor antibodies. Thymoma tended to be advanced, and four patients with Masaoka stage IVa required radiation therapy or chemotherapy. Five patients noticed taste disorders 2-3 months before the onset of MG. Sweet taste loss was more common than salty, bitter, and sour taste loss. CONCLUSIONS: This was the first systematic survey of taste disorders in patients with MG by a multicenter study. Taste disorders were more common in the present sample of patients with MG than in the general population.

Differences in odor identification among clinical subtypes of Parkinson's disease.

OBJECTIVE: Olfactory dysfunction is a non-motor symptom in idiopathic Parkinson's disease (PD). We investigated whether this dysfunction differs among clinical subtypes of PD. METHODS: Participants comprised of 90 patients with idiopathic PD and without dementia. Olfactory function was evaluated using the odor stick identification test for Japanese, which evaluated the detection of 12 odorants familiar to Japanese participants. Patients were divided into tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT) PD subgroups using part III of the Unified Parkinson's Disease Rating Scale. RESULTS: Fifty-five patients were classified as ART, 21 as MXT, and 14 as TDT. There were no differences in age, sex, or duration of illness among the subtypes. Subjective symptoms of impaired sense of smell were significantly higher (P<0.05) in the ART than in the TDT. Mean odor identification score was 4.3 in the ART, 5.2 in MXT, and 6.6 in TDT. It was significantly lower in the ART than in the TDT (P<0.01). CONCLUSION: Olfactory dysfunction differed among the clinical subtypes of PD. This suggests that olfactory function might relate to prognosis of patients with PD.

Riluzole use during pregnancy in a patient with amyotrophic lateral sclerosis: a case report.

Pregnancy with amyotrophic lateral sclerosis (ALS) is rare and generally considered dangerous. Riluzole is the only drug approved for use in ALS, but the effect on maternal and fetal health is unknown. We describe the case of an ALS patient taking riluzole throughout pregnancy. A 34-year old Japanese woman, who had been diagnosed with probable ALS 4 years earlier, visited our hospital for abdominal distension, without knowing that she was pregnant. The patient had been taking riluzole for 2 years, inclusive of her gestational months, and we decided to continue administration of the medication. The patient delivered a normal female infant transvaginally at 38 weeks gestation. The patient's neurological status was stable 1 year after delivery and the baby had developed normally. We found that, in this case, riluzole did not cause any side-effects to the pregnant woman or her fetus.

Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase.

The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.

Clinical-diffusion mismatch defined by NIHSS and ASPECTS in non-lacunar anterior circulation infarction.

OBJECTIVES: Instead of the mismatch in MRI between the perfusion-weighted imaging (PWI) lesion and the smaller diffusion-weighted imaging (DWI) lesion (PWI-DWI mismatch), clinical-DWI mismatch (CDM) has been proposed as a new diagnostic marker of brain tissue at risk of infarction in acute ischemic stroke. The Alberta Stroke Program Early CT Score (ASPECTS) has recently been applied to detect early ischemic change of acute ischemic stroke. The present study applies the CDM concept to DWI data and investigated the utility of the CDM defined by the NIH Stroke Scale (NIHSS) and ASPECTS in patients with non-lacunar anterior circulation infarction. METHODS: Eighty-seven patients with first ever ischemic stroke within 24 hours of onset with symptoms of non-lacunar anterior circulation infarction with the NIHSS score>or=8 were enrolled. Initial lesion extent was measured by the ASPECTS on DWI within 24 hours, and initial neurological score was measured by the NIHSS. As NIHSS>or=8 has been suggested as a clinical indicator of a large volume of ischemic brain tissue, and the majority of patients with non-lacunar anterior infarction with score of NIHSS<8 had lesions with ASPECTS>or=8 on DWI, so CDM was defined as NIHSS>or=8 and DWI-ASPECTS 8>or=. We divided patients into matched and mismatched patient groups, and compared them with respect to background characteristics, neurological findings, laboratory data, radiological findings and outcome. RESULTS: There were 35 CDM-positive patients (P group, 40.2%) and 52 CDM-negative patients (N group , 59.8%). P group patients had a higher risk of early neurological deterioration (END) than N group patients (37.1% vs 13.5%, p<0.05), which were always accompanied by lesion growth defined by 2 or more points decrease on ASPECTS (36 to 72 hours after onset on CT). The NIHSS at entry were significantly lower in the P group, but there was no difference in the outcome at three months measured by the modified Rankin Scale. However, CDM was not an independent predictor of END by multiple logistic regression analysis. CONCLUSIONS: Patients with CDM had high rate of early neurological deterioration and lesion growth. CDM defined as NIHSS>or=8 and DWI-ASPECTS>or=8 can be another marker for detecting patients with tissue at risk of infarction, but more work is needed to clarify whether this CDM method is useful in acute stroke management.

Outcomes of grafting intrasynovial tendons of the toes to the hands in 10 patients: a preliminary report.

Ten patients had intrasynovial tendon grafting harvested from the toes for secondary flexor tendon reconstruction in nine fingers and one thumb in our institutes from 2009 to 2014. These patients were followed for a mean of 15 (range: 8-36) months. The ranges of total active motion of the proximal and distal interphalangeal joints of these nine fingers were 143° (range: 108-175°) and of the metacarpophalangeal and interphalangeal joints of one thumb were 110°. In conclusion, this technique is feasible and gives a good result when successful but with a high complication rate. Level of Evidence IV.

Calreticulin as a new histone binding protein in mitotic chromosomes.

Calreticulin (CRT) is a multifunctional Ca(2+)-binding protein that mainly functions in the endoplasmic reticulum as a molecular chaperone for newly synthesized proteins. Recently we reported the protein composition of human metaphase chromosomes (Uchiyama et al., 2004), which included CRT. Here we describe new characteristics of CRT in vitro as well as its localization on the surface of metaphase chromosomes in vivo. CRT was detected in the chromosomal fraction by Western blotting and its binding partners were identified as core and linker histones by ligand overlay assay. Surface plasmon resonance sensor analyses revealed that CRT is bound to chromatin fibers. Moreover, we found that CRT has both supercoiling activity, which assists core histone assembly into chromatin fibers, and binding ability to histone H2A/H2B dimers and histone H3/H4 tetramers. Unlike the chromosome scaffold proteins, indirect immunofluorescent staining revealed that CRT is located on the surface of metaphase chromosomes. These results suggest that CRT plays a role which involves chromatin dynamics on the surface of mitotic chromosomes.

Measurement of residual platelet thrombogenicity under arterial shear conditions in cerebrovascular disease patients receiving antiplatelet therapy.

UNLABELLED: Essentials A consensus methodology for assessing the effects of antiplatelet agents has not been established. Measuring platelet thrombus formation (PTF) for evaluating antiplatelet effects was assessed. PTF differentially reflected antiplatelet effects compared to other tests. PTF may be associated with the severity of carotid or intracranial arterial stenosis. Click to hear a presentation on platelet function testing in the clinic by Gresele and colleagues SUMMARY: Background A consensus methodology for assessing the effects of antiplatelet agents has not been established. Objective We investigated the usefulness of directly measuring platelet thrombus formation (PTF) using a microchip-based flow chamber system for evaluating antiplatelet therapy. Patients/Methods Platelet thrombus formation in the whole blood of 94 patients with ischemic cerebrovascular disease treated with clopidogrel and/or aspirin was measured in a flow chamber system at a shear rate of 1500 s(-1) and was compared with the results of assays for agonist-induced platelet aggregability, phosphorylation of vasodilator-stimulated phosphoprotein, platelet p-selectin expression (PS), and platelet-monocyte complexes. Results In all patients tested, area under the flow pressure curve (AUC10), which represents platelet thrombogenicity, showed weak correlation with platelet aggregation induced by either adenosine diphosphate or collagen. In addition, AUC10 was lower in patients treated with dual antiplatelet therapy (median 79.4) compared with patients treated with aspirin or clopidogrel alone (217.7 and 301.0, respectively), whereas the parameters evaluated by the other assays did not reflect the combined treatment efficacy. In clopidogrel monotherapy patients, AUC10 was associated with the severity of arterial stenosis (R(2) = 0.127, ß = 1.25), and AUC10 and PS were higher in patients with severe carotid or intracranial arterial stenosis than in those with mild stenosis. Conclusions Platelet thrombus formation measurement using a flow-chamber system was useful for evaluating the efficacy of treatment with aspirin and clopidogrel, both alone and in combination. The present findings indicate that high residual platelet thrombogenicity in patients treated with clopidogrel may be associated with the severity of carotid or intracranial arterial stenosis.

Repression of rRNA synthesis induced by disaggregation in Dictyostelium discoideum.

Cells disaggregated from the slugs of Dictyostelium discoideum continued to incorporate [3H]uridine or [3H]uracil, though at a lower rate than interphase amoebae. Disaggregation brought about a marked increase in the proportion of labeled poly(A)-containing RNA to labeled total RNA. The proportion reached the maximum in disaggregated cells after 1 h of incubation, but remained high even after 5 h of incubation. Reconstruction of slugs from the disaggregated cells did not bring about a decrease but a further increase in the proportion. The real proportion estimated from the minimum period of labeling reached almost 100% in the disaggregated cells, in contrast to about 30% in the interphase amoebae. The increase in the proportion is attributed to the disaggregation-induced repression of rRNA synthesis, which was supported by sucrose density gradient analyses of RNA synthesized in the disaggregated cells. The possibility that rRNA synthesis in this organism is regulated by the loss of cell contact is discussed.

Structural basis of the interaction between IgG and Fcgamma receptors.

The binding of multivalent antigen-antibody complexes to receptors for the Fc portion of IgG (FcgammaR) induces the clustering of the FcgammaR and triggers cell activation leading to defence reactions against pathogens. The Fc portion of IgG consists of two identical polypeptide chains which are related to each other by a 2-fold axis and are folded in two structural domains, the C(H)2 domain, near the flexible hinge region of the IgG molecule, and the C(H)3 domain. We studied the interaction in solution between the Fc fragment of mouse IgG2b and the extracellular region of mouse FcgammaRII. We find that one Fc molecule binds one FcgammaRII molecule only. Using NMR spectroscopy, we show that FcgammaRII binds to a negatively charged area of the C(H)2 domain, corresponding to the lower hinge region, and that the binding of FcgammaRII onto one of the two symmetrically related sites on the Fc induces a conformational change in the other site. We therefore propose a model that explains why IgG molecules are unable to trigger FcgammaR-mediated cellular responses spontaneously in the absence of crosslinking by multivalent antigens.

Arthroscopic assistance does not improve the functional or radiographic outcome of unstable intra-articular distal radial fractures treated with a volar locking plate: a randomised controlled trial.

There is no consensus on the benefit of arthroscopically assisted reduction of the articular surface combined with fixation using a volar locking plate for the treatment of intra-articular distal radial fractures. In this study we compared the functional and radiographic outcomes of fluoroscopically and arthroscopically guided reduction of these fractures. Between February 2009 and May 2013, 74 patients with unilateral unstable intra-articular distal radial fractures were randomised equally into the two groups for treatment. The mean age of these 74 patients was 64 years (24 to 92). We compared functional outcomes including active range of movement of the wrist, grip strength and Disabilities of the Arm, Shoulder, and Hand scores at six and 48 weeks; and radiographic outcomes that included gap, step, radial inclination, volar angulation and ulnar variance. There were no significant differences between the techniques with regard to functional outcomes or radiographic parameters. The mean gap and step in the fluoroscopic and arthroscopic groups were comparable at 0.9 mm (standard deviation (SD) 0.7) and 0.7 mm (SD 0.7) and 0.6 mm (SD 0.6) and 0.4 mm (SD 0.5), respectively; p = 0.18 and p = 0.35). Arthroscopic reduction conferred no advantage over conventional fluoroscopic guidance in achieving anatomical reduction of intra-articular distal radial fractures when using a volar locking plate.

Deteriorating ischemic stroke in 4 clinical categories classified by the Oxfordshire Community Stroke Project.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the frequency, possible predictive factors, and prognosis of deteriorating ischemic stroke in 4 clinical categories according to the classification of the Oxfordshire Community Stroke Project (OCSP). METHODS: A total of 350 patients with first-ever ischemic stroke who presented within 24 hours of onset were enrolled. Based on the OCSP criteria, cerebral infarctions were divided into the following 4 clinical categories: total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), lacunar infarcts (LACI), and posterior circulation infarcts (POCI). Clinical deterioration was defined as a decrease of >/=1 points in the Canadian Neurological Scale (CNS) (in TACI, PACI, and LACI) or Rankin Scale (RS) (in POCI) during 7 days from the onset. In each clinical category, deteriorating (D) and nondeteriorating (ND) patients were compared in terms of their background characteristics, risk factors, vital signs, laboratory data, and cranial CT at the time of hospitalization. The acute-phase mortality and functional outcome were also compared. RESULTS: The subjects comprised 86 patients (24.6%) with TACI, 63 (18.0%) with PACI, 141 (40.3%) with LACI, and 60 (17.1%) with POCI. Overall, 90 patients (25.7%) deteriorated. The frequency was very high in TACI (41.9%), followed by LACI (26.2%) and POCI (21.7%), whereas it was very low in PACI (6. 3%). There were some clinical variables that differed significantly between D and ND groups. In the patients with TACI, early abnormalities of the cranial CT and significant stenoses in corresponding arteries were more frequent in the D than the ND group. In those with LACI, the CNS and hematocrit were lower in the D than the ND group. In those with POCI, cerebral atrophy was more severe and significant stenoses in vertebrobasilar arteries were more frequent in the D than ND group. The mortality of the D groups of patients with TACI and POCI exceeded 35%, and the functional outcome was worse in the D group than in the ND group of patients with TACI, LACI, and POCI. CONCLUSIONS: The frequency of deterioration in acute ischemic stroke significantly differed among the OCSP subgroups, and deterioration worsened the prognosis. There were some factors that could predict deterioration: early CT findings in TACI, large-artery atherosclerosis in TACI and POCI, and stroke severity in LACI. Further research to find sophisticated radiological and chemical markers appears to be needed.

Cloning and sequencing of a 27.8-kb nucleotide sequence of the 79 degrees-81 degrees region of the Bacillus subtilis genome containing the sspE locus.

The nucleotide sequence of a 27830-bp DNA segment in the 79 degrees-81 degrees region of the Bacillus subtilis genome has been determined. This region contains 29 complete ORFs including the sspE gene, which encodes a small acid-soluble spore protein gamma and locates on the one side terminal of our assigned region. A homology search for the products deduced from the 29 ORFs revealed that nine of them exhibit significant similarity to known proteins, e.g. proteins involved in an iron uptake system, a multidrug resistance protein, a chloramphenicol resistance protein, epoxide hydrolase, adenine glycosylase, and a glucose-1-dehydrogenase homolog.