Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

Neuromelanin or DaT-SPECT: which is the better marker for discriminating advanced Parkinson's disease?

BACKGROUND AND PURPOSE: Whether the neuromelanin-positive substantia nigra pars compacta area (NM-SNc) on neuromelanin magnetic resonance imaging (NM-MRI) and the specific binding ratio (SBR) on 123 I-N-v-fluoropropyl-2b-carbomethoxy3b-(4-iodophenyl)nortropane single photon emission computed tomography (DaT-SPECT) can be correlated with motor fluctuations (MFs) in advanced Parkinson's disease (PD) was investigated. METHODS: Thirty-five PD patients (60 ± 13 years) and 23 healthy individuals as controls (59 ± 19 years) were enrolled. The relationships between NM-MRI and DaT-SPECT were prospectively examined in two subgroups divided according to the presence or absence of MFs. Multivariate analysis was performed using the Cox proportional hazard model to screen for association factors. RESULTS: The NM-SNc size was correlated with the SBR (Spearman's ρ = 0.43, P < 0.05). The NM-SNc size was significantly reduced in PD with MFs compared with the subgroup without (P < 0.001), whereas the SBR did not significantly differ between the groups. NM-SNc size was a significant association factor for MFs (hazard ratio 0.94, P = 0.04). In receiver operating characteristic analysis of the factors for MF occurrence, the area under the receiver operating characteristic curve of the NM-SNc size showed a significant difference of 0.89 (P < 0.05) but no significant difference was found in the SBR. CONCLUSIONS: NM-SNc size was significantly correlated with the SBR in PD, but several factors in advanced PD were more closely associated with NM-SNc size than the SBR. NM-MRI might reflect the status of advanced PD more accurately than DaT-SPECT. Therefore, NM-MRI appears to provide a better marker for discriminating advanced PD than DaT-SPECT.

KPT-330 has antitumour activity against non-small cell lung cancer.

BACKGROUND: We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. METHODS: The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed. RESULTS: KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation. CONCLUSIONS: Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.

Visceral fat accumulation is associated with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Obesity is associated with the risk of coronary artery disease and stroke. Visceral fat plays a significant role in the atherogenic effects of obesity. Whether visceral fat accumulation, as measured by computed tomography (CT), is an independent risk factor for the presence of cerebral small vessel disease (SVD) was investigated. METHODS: This study comprised 506 Japanese subjects 35-74 years of age (mean 55.3 years) without a history of symptomatic cerebrovascular disease who underwent health screening tests, including brain magnetic resonance imaging, carotid echography and measurements of the visceral fat area (VFA) and subcutaneous fat area (SFA) on abdominal CT. Visceral fat accumulation was defined as VFA ≥ 100 cm(2) . Logistic regression analysis was performed to examine the associations between visceral fat accumulation and cerebral SVD such as white matter lesions (WMLs) and silent lacunar infarction (SLI). RESULTS: The prevalence of WMLs and SLI but not carotid plaque were significantly higher in subjects with VFA ≥ 100 cm(2) than those with VFA < 100 cm(2) . A VFA ≥ 100 cm(2) was associated with WMLs and SLI independent of age, cardiovascular risk factors and other measurements of obesity, such as waist circumference and body mass index. A large waist circumference was independently associated with SLI. SFA, the combination of VFA and SFA, and body mass index were not associated with WMLs or SLI. CONCLUSIONS: Visceral fat accumulation was independently associated with the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease.

Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase.

Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.

Comparison of prognosis of separated and non-separated tooth autotransplantation.

The aim of this study was to compare the prognosis of separated and non-separated tooth autotransplantation of the upper first and second molars with complete root formation undertaken at dental clinics. The participating dentists were requested to provide information on transplantations they had undertaken from 1 January 1990 to 31 December 2010. Data on a total of 708 teeth from 637 patients were collected. This study analysed 35 separated teeth and 22 non-separated teeth of 47 participants ranging from 27 to 76 years of age (mean age: 55·0 years) after data screening and elimination. The cumulative post-transplantation survival rate at 10 years was 77·1% for separated teeth and 63·6% for non-separated teeth as calculated with the Kaplan-Meier method. There were no significant differences between separated teeth and non-separated teeth in a log rank test (P = 0·687). Separated-tooth autotransplantation can help fill narrow recipient sites and increase occlusal supporting zones, but the clinical success rate was only 48·6%. Although transplantation of teeth with complete root formation has limited prognosis, transplantation of upper first and second molars, whether separated or non-separated, is a viable option to replace missing teeth.

Gender difference in tooth autotransplantation with complete root formation: a retrospective survey.

Gender-related risk factors in the survival of transplanted teeth with complete root formation have not yet been identified. The purpose of this study was to investigate gender differences in tooth autotransplantation at dental clinics. We asked participating dentists to provide information on transplantations they had undertaken from 1 January 1990 to 1931 December 2010. The data were screened to exclude patients who underwent more than one transplantation, smokers or those whose smoking habits were unknown, patients under 30 or who were 70 years old and over, cases where the transplanted teeth had incomplete root formation or multiple roots and those with fewer than 20 present teeth post-operation. We analysed 73 teeth of 73 males (mean age, 47.2 years) and 106 teeth of 106 females (mean age, 45.3 years) in this study. The cumulative survival rate and mean survival time were calculated using the Kaplan-Meier method. The cumulative survival rate for males was 88.3% at the 5-year mark, 64.8% at 10 years and 48.6% at 15 years; for females, it was 97.2% at the 5-year mark, 85.9% at 10 years and 85.9% at 15 years. A log-rank test indicated the difference between males and females to be significant (P = 0.011). There was also a significant difference in the main causes for the loss of transplanted teeth: males lost more transplanted teeth due to attachment loss than females (P < 0.05). These results indicate that males require more attention during the autotransplantation process, particularly at the stage of pre-operation evaluation and that of follow-up maintenance.

Influence of age on tooth autotransplantation with complete root formation.

The aim of this study was to investigate risk factors with age in the long-term prognosis of autotransplantation of teeth with complete root formation at dental clinics. Participating dentists were asked to provide information on transplantations they had undertaken from 1 January 1990 to 31 December 2010. Data on a total of 708 teeth from 637 patients were collected. The data were screened to exclude patients who were under 25 or 70 years of age and over, those who were smokers or whose smoking habits were unknown, those whose transplanted teeth had incomplete root formation or multiple roots and those with fewer than 25 present teeth post-operation. The participants in this study were 71 men (74 teeth) and 100 women (107 teeth) ranging from 25 to 69 years of age. Third molars were used as donor teeth in 89·0% of the cases. The participants were divided into three age groups of 25-39, 40-54 and 55-69. Survival analysis was conducted using the Kaplan-Meier method, and a log-rank test revealed that there were no significant differences in age groups for men or women. Cox regression analysis indicated that the survival of transplanted teeth was not influenced by age. However, although not statistically significant, the clinical success rate was lower in the 55-69-year-old group than that in the younger groups. These results indicate that if suitable donor teeth are available and the conditions are right, autotransplantation is a viable treatment for missing teeth regardless of the age of the patient.

Pharmacokinetics and effect of food after oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with Parkinson's disease.

WHAT IS KNOWN AND OBJECTIVES: Ropinirole hydrochloride, a dopamine receptor agonist with a non-ergot alkaloid structure, is highly selective for the dopamine D(2) /D(3) receptors. This study was conducted to evaluate the steady-state pharmacokinetics, safety and efficacy after repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with Parkinson's disease (PD). METHODS: This was a multicenter, open-label, uncontrolled study. The total duration of participation in the study ranged from 56 to 63 weeks. In the study, the plasma concentrations of ropinirole, its major metabolite SK&F104557 (N-depropyl ropinirole) and another metabolite SK&F89124 (ropinirole hydroxylated at the seventh position of the indole ring) were assessed. Safety based on adverse events, haematology, biochemistry, urinalysis and electrocardiography (ECG) (standard 12-lead ECG) were evaluated, and vital signs (blood pressure/pulse rate) were measured. Efficacy based on the Japanese version of Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (motor) and II [activities of daily living (ADL)] as well as tolerability was evaluated. RESULTS: After repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with PD, ropinirole, SK&F104557 and low levels of SK&F89124 were detected in plasma. The trough concentrations of ropinirole and the two metabolites increased in proportion to the dose when ropinirole hydrochloride prolonged-release tablets were administered at doses ranging from 2 to 16 mg/day. The plasma exposure to ropinirole and its two metabolites after intake of normal diet was comparable to that in the fasting state. The most common adverse events (10% or more) were somnolence, nausea, constipation, hallucination and nasopharyngitis. Most adverse events were mild or moderate in severity, and with no death. During the treatment period, serious adverse events were reported in five patients. Efficacy analysis (LOCF) at the final endpoint up to week 16 demonstrated a mean (SD) change from baseline in the Japanese UPDRS III (motor) and II (ADL) scores of -11·3 (8·21) and -3·9 (3·22), respectively, and thereafter remained at similar levels until week 52. WHAT IS NEW AND CONCLUSIONS: After administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with PD, the plasma pharmacokinetics of ropinirole and its metabolites was linear and not affected by food. Compared with the immediate-release (IR) tablet, the prolonged-release tablet can be administered to Japanese patients with PD at a reduced daily dose frequency and adjusted to the maintenance dose after fewer dose changes with a smaller diurnal variation in the plasma ropinirole concentration.

A retrospective survey of autotransplantation of teeth in dental clinics.

The aim of this study was to investigate the usage of tooth autotransplantation in dental clinics which offer the treatment and evaluate its practicality. Participating dentists were requested to provide information on transplantations they had undertaken from 1 January 1990 to 31 December 2010. A total of 614 teeth from 552 patients (37 dentists) ranging in age from 17 to 79 (mean age: 44·1) were examined. Cumulative survival rate and mean survival time were calculated using the Kaplan-Meier method, and log rank test was used for analysis of factors. The mean number of autotransplantation patients per clinic per year was 1·4. Upper third molars constituted 36·8% of donor teeth, while 37·1% were lower third molars. The lower first molar region was the most common recipient site at 32·6%, followed by the lower second molar region (28·0%). Prosthodontic treatment of transplanted teeth involved coverage with a single crown (72·5%) and abutment of bridge (18·9%). A total of 102 transplanted teeth were lost owing to complications such as attachment loss (54·9%) and root resorption (25·7%). The cumulative survival rate in cases where donor teeth had complete root formation was 90·1% at 5 years, 70·5% at 10 years and 55·6% at 15 years. The mean survival time was 165·6 months. Older age was a significant risk factor (P < 0·05) for survival. In cases where suitable donor teeth are available, autotransplantation of teeth may be a plausible treatment option for dealing with missing teeth in dental clinics.

Risk factors affecting third molar autotransplantation in males: a retrospective survey in dental clinics.

The aim of this study was to investigate the risk factors affecting long-term prognosis of autotransplantation of third molars with complete root formation in males at dental clinics. Participating dentists were requested to provide information on transplantations they had undertaken from 1 January 1990 to 31 December 2010. Data on a total of 708 teeth from 637 patients were collected. After data screening and elimination, participants of this study consisted of 183 teeth of 171 males ranging from 20 to 72 years of age (mean age, 44·8 years). The cumulative survival rate was 86·0% at the 5-year mark, 59·1% at 10 years and 28·0% at 15 years. The mean survival time was 134·5 months, as calculated by the Kaplan-Meier method. Single factor analysis using the log-rank test showed that the following factors had significant influence (P < 0·05) on survival of transplanted teeth: periodontal disease as the reason for recipient site tooth extraction, fewer than 25 present teeth and Eichner index Groups B1 to C. Cox regression analysis examined five factors: age, smoking habit, recipient site extraction caused by periodontal disease, fewer than 25 present teeth and Eichner index. This analysis showed that two of these factors were significant: fewer than 25 present teeth was 2·63 (95% CI, 1·03-6·69) and recipient site extraction caused by periodontal disease was 3·80 (95% CI, 1·61-9·01). The results of this study suggest that long-term survival of transplanted teeth in males is influenced not only by oral bacterium but also by occlusal status.

Correlation of foetal body weight by coronet width measurement using ultrasonography in prepartum cows: a pilot study.

This study aimed to clarify the effectiveness of foetal body weight estimation by measuring foetal coronet width using transrectal ultrasonography in beef cows during near-term pregnancy. A characteristic 'gull wing' pattern was obtained from the foetal coronet cross-section from the dewclaw side using ultrasonography. This pattern was matched to the bone surface of the distal part of the middle phalanx. Then, the relationship between coronet width and body weight at birth of 22 Japanese Brown calves was analysed and a high correlation coefficient of 0.8965 (P < 0.001) was obtained. In conclusion, the coronet width of the fetus is depicted as a 'gull wing' hyperechoic structure and can be measured by ultrasonography per rectum during near-term pregnancy. This technique may be a useful tool to identify high-risk cows with dystocia before calving. High foetal coronet values may predispose cattle to dystocia.

3D Quantitative Synthetic MRI in the Evaluation of Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: Synthetic MR imaging creates multiple contrast-weighted images based on a single time-efficient quantitative scan, which has been mostly performed for 2D acquisition. We assessed the utility of 3D synthetic MR imaging in patients with MS by comparing its diagnostic image quality and lesion volumetry with conventional MR imaging. MATERIALS AND METHODS: Twenty-four patients with MS prospectively underwent 3D quantitative synthetic MR imaging and conventional T1-weighted, T2-weighted, FLAIR, and double inversion recovery imaging, with acquisition times of 9 minutes 3 seconds and 18 minutes 27 seconds for the synthetic MR imaging and conventional MR imaging sequences, respectively. Synthetic phase-sensitive inversion recovery images and those corresponding to conventional MR imaging contrasts were created for synthetic MR imaging. Two neuroradiologists independently assessed the image quality on a 5-point Likert scale. The numbers of cortical lesions and lesion volumes were quantified using both synthetic and conventional image sets. RESULTS: The overall diagnostic image quality of synthetic T1WI and double inversion recovery images was noninferior to that of conventional images (P = .23 and .20, respectively), whereas that of synthetic T2WI and FLAIR was inferior to that of conventional images (both Ps < .001). There were no significant differences in the number of cortical lesions (P = .17 and .53 for each rater) or segmented lesion volumes (P = .61) between the synthetic and conventional image sets. CONCLUSIONS: Three-dimensional synthetic MR imaging could serve as an alternative to conventional MR imaging in evaluating MS with a reduced scan time.

Isolation of the most immature population of murine fetal thymocytes that includes progenitors capable of generating T, B, and myeloid cells.

Thymus cells of murine fetuses at day 12 of gestation are exclusively of the CD3-CD4-CD8-CD44+CD25- phenotype, which is known as a hallmark of the most immature subset of thymus cells. In the present study, we show that day 12 fetal thymus (FT) cells express Fc gamma RII/ III (FcR) at a broad range of levels on their surface. The FcR+ FT cells seem to represent T lineage cells, because a large majority of them express the T lineage specific transcription factors TCF-1 and GATA-3 as well as CD3 epsilon in the cytoplasm. Also shown is that the FcR- population contains progenitors capable of developing into not only T cells but also B and myeloid cells, whereas FcR+ progenitors are mostly committed to the T lineage. These findings indicate that thymic T lineage cells express FcR on their surface at the earliest stage of differentiation, and thus FcR is a useful marker in isolating the most immature population of murine FT cells.

Involvement of transcription factors TCF-1 and GATA-3 in the initiation of the earliest step of T cell development in the thymus.

Flow cytometric and immunocytochemical analyses of murine fetal thymus (FT) cells with antibodies to various surface markers and transcription factors reveal that the synthesis of TCF-1 and GATA-3 protein begins simultaneously in a fraction of the most immature population of FT cells, which have the phenotype of CD4-CD8-CD44+CD25-. No TCF-1-producing cells is found in the fetal liver (FL). In CD44+CD25- FT cells, the production of TCF-1 is immediately followed by intracellular expression of CD3 epsilon. It is also found that the T cell development from FL, but not FT, progenitors in the FT organ culture system is severely inhibited by the addition of antisense oligonucleotides for either TCF-1 or GATA-3. These results strongly suggest that TCF-1 and GATA-3 play essential roles in the initiation of the earliest steps of T cell development in the thymus.

Gesture subtype-dependent left lateralization of praxis planning: an event-related fMRI study.

Ideomotor apraxia is a disorder mainly of praxis planning, and the deficit is typically more evident in pantomiming transitive (tool related) than intransitive (communicative) gestures. The goal of the present study was to assess differential hemispheric lateralization of praxis production using event-related functional magnetic resonance imaging. Voxel-based analysis demonstrated significant activations in posterior parietal cortex (PPC) and premotor cortex (PMC) association areas, which were predominantly left hemispheric, regardless of whether planning occurred for right or left hand transitive or intransitive pantomimes. Furthermore, region of interest-based calculation of mean laterality index (LI) revealed a significantly stronger left lateralization in PPC/PMC clusters for planning intransitive (LI = -0.49 + 0.10, mean + standard deviation [SD]) than transitive gestures (-0.37 + 0.08, P = 0.02, paired t-tests) irrespective of the hand involved. This differential left lateralization for planning remained significant in PMC (LI = -0.47 + 0.14 and -0.36 + 0.13, mean + SD, P = 0.04), but not in PPC (-0.56 + 0.11 and -0.45 + 0.12, P = 0.11), when both regions were analyzed separately. In conclusion, the findings point to a left-hemispheric specialization for praxis planning, being more pronounced for intransitive gestures in PMC, possibly due to their communicative nature.

A LRRK2 G2019S mutation carrier from Turkey shares the Japanese haplotype.

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is recognized as the most common cause of familial autosomal dominant and also sporadic forms of Parkinson disease (PD). A common founder has been described for most Europeans and all North Africans and Jews; besides, two distinct G2019S LRRK2 haplotypes were found in a small proportion of European families and in Japanese PD patients. This study revealed a Turkish patient heterozygous for the G2019S mutation sharing the Japanese haplotype. To the best of our knowledge, it is the first time that the G2019S-associated Japanese haplotype has been reported in a different population.

Activation of tyrosine hydroxylase prevents pneumonia in a rat chronic cerebral hypoperfusion model.

Pneumonia is a common complication with the highest attributable proportion of deaths in patients with stroke. Cilostazol is a potent type III phosphodiesterase inhibitor, approved as an anti-platelet aggregation agent. The present study was designed to determine the protective mechanism of cilostazol against post-stroke pneumonia using a rat chronic cerebral hypoperfusion model. Rats were subjected to bilateral common carotid artery ligation (LBCCA) and divided randomly into the vehicle group (n=72) and cilostazol group (n=72). Rats of each group were sacrificed at baseline and at days 14, 28 and 42 after LBCCA. Cilostazol significantly improved the swallowing reflex by shortening the latency to elicited swallowing and increasing the numbers of swallows (P<0.05) at 14 days of hypoperfusion. It also decreased the numbers of bacterial colonies grown in cultures from homogenized lungs. Cilostazol markedly upregulated cyclic AMP responsive element binding protein (CREB) phosphorylation, increased tyrosine hydroxylase (TH) expression in the substantial nigra, and maintained dopamine (84.7+/-2.3 vs. 79.2+/-4.1% control; P=0.0512) and substance P levels (86.6+/-7.9 vs. 73.9+/-6.5% control; P<0.05) in the striatum, compared with the vehicle group. Our results indicate that cilostazol improves the swallowing reflex by enhancing the expression of TH through the CREB phosphorylation signaling pathway, and suggest that cilostazol could be useful in preventing pneumonia in the chronic stage of stroke.