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Background/purpose A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort. Methods We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020. Results Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P = 0.04). Conclusion Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.

Dysnatremia and dyskalemia are common problems in acutely hospitalized elderly patients. These disorders are associated with an increased risk of mortality and functional complications that often occur concomitantly with acute kidney injury in addition to multiple comorbidities. In a single-center prospective observational study, we recruited 401 acute geriatric inpatients. In-hospital outcomes included all-cause mortality, length of stay, and changes in functional status as determined by the Activities of Daily Living (ADL) scale, Eastern Cooperative Oncology Group (ECOG) performance, and Clinical Frailty Scale (CFS). The prevalence of dysnatremia alone, dyskalemia alone, and dysnatremia plus dyskalemia during initial hospitalization were 28.4%, 14.7% and 32.4%, respectively. Patients with electrolyte imbalance exhibited higher mortality rates and longer hospital stays than those without electrolyte imbalance. Those with initial dysnatremia, or dysnatremia plus dyskalemia were associated with worse ADL scores, ECOG performance and CFS scores at discharge. Subgroup analyses showed that resolution of dysnatremia was related to reduced mortality risk and improved CFS score, whereas recovery of renal function was associated with decreased mortality and better ECOG and CFS ratings. Our data suggest that restoration of initial dysnatremia and acute kidney injury during acute geriatric care may benefit in-hospital survival and functional status at discharge.

Background Identification of frailty is crucial to guide patient care for the elderly. The Clinical Frailty Scale (CFS) is a reliable, synthesis and clinical judgment-based tool. However, a validated Chinese version of CFS (CFS-C) is lacking. The aim of this study is to describe the translation process of CFS into traditional Chinese and to evaluate its reliability and validity in a geriatric study population in Taiwan. Methods This cross-sectional study recruited 221 geriatric outpatients aged 65 years or older at a medical center in Taipei, Taiwan. The Chinese version of CFS was produced following Brislin’s translation model. Weighted kappa for agreement and Kendall’s tau for correlation were used to assess inter-rater reliability (a subgroup of 52 outpatients) between geriatricians and one research assistant, and validity tests (221 outpatients) by comparing CFS-C with Fried frailty phenotype and Frailty Index based on Comprehensive Geriatric Assessment (FI-CGA). Correlation between CFS-C and other geriatric conditions were also assessed. Results The inter-rater reliability revealed moderate agreement (weighted kappa = 0.60) and strong correlation (Kendall’s tau = 0.67). For criterion validity, CFS-C categorisation showed fair agreement (weighted kappa = 0.37) and significant correlation (Kendall’s tau = 0.46) with Fried frailty phenotype, and higher agreement (weighted kappa = 0.51) and correlation (Kendall’s tau = 0.63) with FI-CGA categorisation. CFS-C was significantly correlated with various geriatric assessments, including functional disability, physical performance, hand grip, comorbidity, cognition, depression, and nutrition status. No significant correlation was found between CFS-C and appendicular muscle mass. Conclusions The CFS-C demonstrated acceptable validity and reliability in Chinese older adults in Taiwan. Development of CFS-C enhanced consistency and accuracy of frailty assessment, both in research and clinical practice.

Chlorophyll turns over in green organs during photosystem repair and is salvaged via de- and rephytylation, but the enzyme involved in dephytylation is unknown. We have identified an Arabidopsis thaliana thylakoid protein with a putative hydrolase domain that can dephytylate chlorophyll in vitro and in vivo. The corresponding locus, CHLOROPHYLL DEPHYTYLASE1 (CLD1), was identified by mapping a semidominant, heat-sensitive, missense allele (cld1-1). CLD1 is conserved in oxygenic photosynthetic organisms, sharing structural similarity with pheophytinase, which functions in chlorophyll breakdown during leaf senescence. Unlike pheophytinase, CLD1 is predominantly expressed in green organs and can dephytylate chlorophyll in vitro. The specific activity is significantly higher for the mutant protein encoded by cld1-1 than the wild-type enzyme, consistent with the semidominant nature of the cld1-1 mutation. Supraoptimal CLD1 activities in cld1-1 mutants and transgenic seedlings led to the proportional accumulation of chlorophyllides derived from chlorophyll dephytylation after heat shock, which resulted in light-dependent cotyledon bleaching. Reducing CLD1 expression diminished thermotolerance and the photochemical efficiency of photosystem II under prolonged moderate heat stress. Taken together, our results suggest that CLD1 is the long-sought enzyme for removing the phytol chain from chlorophyll during its turnover at steady state within the chloroplast.

PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2’s activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention., Tsan-Jan Chen, Hung-Jung Wang et al. report the crystal structures of tumor-related mutant forms of pyruvate kinase M2 (PKM2). They show that these mutations lead to increased interaction with the PKM2 binding partner KDM8, suggesting a mechanism for their oncogenic action.

KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A–D) constitute an important class of epigenetic modulators in the transcriptional activation of cellular processes and genome stability. Interleukin-8 (IL-8) is overexpressed in gastric cancer, but the mechanisms and particularly the role of the epigenetic regulation of IL-8, are unclear. Here, we report that KDM4B, but not KDM4A/4C, upregulated IL-8 production in the absence or presence of Helicobacter pylori. Moreover, KDM4B physically interacts with c-Jun on IL-8, MMP1, and ITGAV promoters via its demethylation activity. The depletion of KDM4B leads to the decreased expression of integrin αV, which is exploited by H. pylori carrying the type IV secretion system, reducing IL-8 production and cell migration. Elevated KDM4B expression is significantly associated with the abundance of p-c-Jun in gastric cancer and is linked to a poor clinical outcome. Together, our results suggest that KDM4B is a key regulator of JNK/c-Jun-induced processes and is a valuable therapeutic target.

Cholesterol-α-glucosyltransferase (CGT) encoded by the type 1 capsular polysaccharide biosynthesis protein J (capJ) gene of Helicobacter pylori converts cellular cholesterol into cholesteryl glucosides. H. pylori infection induces autophagy that may increase bacterial survival in epithelial cells. However, the role of H. pylori CGT that exploits lipid rafts in interfering with autophagy for bacterial survival in macrophages has not been investigated. Here, we show that wild-type H. pylori carrying CGT modulates cholesterol to trigger autophagy and restrain autophagosome fusion with lysosomes, permitting a significantly higher bacterial burden in macrophages than that in a capJ-knockout (∆CapJ) mutant. Knockdown of autophagy-related protein 12 impairs autophagosome maturation and decreases the survival of internalised H. pylori in macrophages. These results demonstrate that CGT plays a crucial role in the manipulation of the autophagy process to impair macrophage clearance of H. pylori.

Background Large anterior choroidal artery (AChA) infarcts are frequently associated with stroke evolution. This study aimed to investigate the major determinants for stroke evolution in patients with large AChA infarcts. Methods We studied 118 consecutive adult patients with acute large AChA infarcts. The diagnosis was confirmed as abnormal hyperintensities in 3 or more rostracaudal magnetic resonance imaging slices (5 mm thickness) using diffusion-weighted imaging within typical AChA vascular regions. Stroke evolution was defined as neurologic deterioration with an increase in National Institutes of Health Stroke Scale (NIHSS) score by at least 4 or an increase of NIHSS score in motor function by at least 2 in 7 days after stroke onset. Results Forty-seven (39.8%) patients developed stroke evolution. Thrombolytic therapy was inversely associated with the occurrence of stroke evolution ( P = .004). Using multivariate analysis, thrombolytic therapy was the only protective determinant for stroke evolution (adjusted odds ratio, .08; 95% confidence interval, .01 to .67). Patients with large AChA infarcts receiving thrombolytic therapy had less unfavorable long-term functional outcome than those not receiving thrombolytic therapy (adjusted odds ratio, .11; 95% confidence interval, .02-.75). Conclusions Thrombolytic therapy is an only determinant factor for stroke evolution in large AChA infarcts, which reduced the risk of stroke evolution and improved functional outcome.

Carthamus yellow (CY) is the major component of the yellow pigments of Carthamus tinctorius L. CY has been extensively used as a natural color additive for food and cosmetics. Here, our results demonstrate that carthamus yellow reduced the activity of mushroom tyrosinase in a dose-dependent manner with a half maximal inhibitory concentration (IC(50)) value of approximately 1.01 ± 0.03 mg/mL. A kinetic study of carthamus yellow on tyrosinase exhibited a mode of competitive inhibition with a Ki of 0.607 mg/mL. Moreover, cell viability analysis indicated that carthamus yellow used at concentrations of 1.0-4.0 mg/mL had no cytotoxicity in B16F10 melanoma cells. Melanin content analysis showed that melanin production in B16F10 melanoma cells treated with 4 mg/mL carthamus yellow can decrease to 82.3 ± 0.4% of the levels of melanin production of untreated cells. Thus, carthamus yellow has the potential to become a useful skin-whitening agent in the future.

Purpose This prospective study aims to determine predictive factors for patients to be discharged to home after receiving post-acute care (PAC) services and to improve the case-finding criteria for PAC services in Taiwan. Methods Elder patients admitted to Taichung Veterans General Hospital for treatment of an acute illness were assessed by simplified comprehensive geriatric assessment (CGA) and clinical evaluation. Patients with functional recovery potential were transferred to community hospitals for further PAC service. Discharging status from a PAC unit to a home or long-term care facility was recorded. Results From January 2009 to September 2010, 123 patients were recruited. 40 patients didn’t receive complete PAC service and the remaining 83 patients completed the program. Among the 83 patients that completed the program, 56 patients (67.5%) were discharged to home and 27 patients (32.5%) were transferred to long-term care facilities. The Barthel index (BI) before receiving PAC was low (35.0 ± 21.34) and all patients had below average nutrition. Using multiple logistic regression analysis, patients receiving prior orthopedic surgery, living with other people and in a malnourished state were more likely to be discharged to home after receiving PAC service. Conclusion Two-thirds of PAC patients can be safely discharged to home after receiving PAC services. Patients who live with other people, have prior orthopedic surgeries, and have good nutritional status represented predictive factors for returning home safely.

Using voltage island methodology to reduce power consumption for System-on-a-Chip (SoC) designs has become more and more popular recently. Currently this approach has been considered either in system-level architecture or postplacement stage. Since hierarchical design and reusable intellectual property (IP) are widely used, it is necessary to optimize floorplanning/placement methodology considering voltage islands generation to solve power and critical path delay problems. In this article, we propose a floorplanning methodology considering voltage islands generation and performance constraints. Our method is flexible and can be extended to hierarchical design. The experimental results on some MCNC benchmarks show that our method is effective in meeting performance constraints and can simultaneously consider the tradeoff between power routing cost and total power dissipation.

Background: Although eradication of Helicobacter pylori infection can decrease the risk of gastric cancer, the optimal regimen for treating the general population remains unclear. We report the eradication rate (intention-to-treat and per protocol) of a community-based H. pylori therapy using the strategy of test, treat, retest, and re-treat initial treatment failures. Materials and methods: In 2004, a total of 2658 residents were recruited for 13 C-urea breath testing. Participants with positive results for infection received a standard 7-day triple therapy (esomeprazole 40 mg once daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily), and a 10-day re-treatment (esomeprazole 40 mg once daily, amoxicillin 1 g twice daily, and levofloxacin 500 mg once daily) if the follow-up tests remained positive. Both H. pylori status and side-effects were assessed 6 weeks after treatment. Results: Among 886 valid reporters, eradication rates with initial therapy were 86.9% (95% confidence interval [CI]: 84.7-89.1%) and 88.7% (95%CI: 86.5-90.9%) by intention-to-treat and per protocol analysis, respectively. Re-treatment eradicated infection in 91.4% (95%CI: 86-96.8%) of 105 nonresponders. Adequate compliance was achieved in 798 (90.1 %) of 886 subjects receiving the initial treatment and in all 105 re-treated subjects. Mild side-effects occurred in 24% of subjects. Overall intention-to-treat and per protocol eradication rates were 97.7% (95%CI: 96.7-98.7%) and 98.8% (95%CI: 98.5-99.3%), respectively, which were only affected by poor compliance (odds ratio, 3.3; 95%CI, 1.99-5.48; p

A 60-year-old man with a history of atrial fibrillation had an acute onset of ballistic movements of the left limbs with sensory extinction (video on the Neurology® Web site at www.neurology.org). The patient was treated with risperidone and anticoagulant; symptoms subsided 3 days later. Brain MRI showed acute infarction of the right posterior parietal lobe (figure 1) and SPECT revealed hypoperfusion in the right frontoparietal areas (figure 2).

While the technology node continually and aggressively scales, the resolution of FIB techniques does not scale as fast. Thus, the percentage of nets which can be observed or repaired through FIB probing or circuit editing is significantly decreased for advanced process technologies, which limits the candidates that can be physically examined through the FIB techniques during the debugging process. This paper introduces a design-for-debug framework which can adjust the layout to increase the FIB observable rate and the FIB repairable rate for its signals. The layout adjustment is made through pre-defined simple operations subject to the design rules and the timing constraints. Hence, the proposed framework does not require a complicated router as its core and can be applied in conjunction with any commercial APR tool. The experimental result based on an 90nm technology has demonstrated that the proposed DFD framework can effectively increase the FIB observable and repairable rates under different parameter settings while the overall area and circuit performance remain the same.

Non-Manhattan structures, such as the X and Y architectures, propose different flavors in reducing the use of physical resources, such as total wirelength and number of vias. However, in order to take full advantage of these structures, we need to develop new tools for these architectures, especially for early stages in physical design. In this paper, we propose the packing algorithm with isosceles right triangular and trapezoidal blocks using the B∗-tree representation. Our approach can be further applied to packing with any block which can be divided into rectangles and isosceles right triangles. Experimental results based on the modified MCNC benchmarks show that the average area usage is above 95% and the run time of our proposed algorithm is comparable when performing rectangular and non-rectangular block packing with original B∗-tree.

Using voltage island methodology to reduce power consumption for system-on-a-chip (SoC) designs has become more and more popular recently. Currently this approach has been considered either in system-level architecture or post-placement stage. Since hierarchical design and reusable intellectual property (IP) are widely used, it is necessary to optimize floorplanning/placement methodology considering voltage islands generation to solve power and critical path delay problems. In this paper, we propose a floorplanning methodology considering voltage islands generation and performance constraints. Our method is flexible and can be extended to hierarchical design. The experimental results on some MCNC benchmarks show that our method is effective in meeting performance constraints and simultaneously considers the tradeoff between power routing cost and the assignment of supply voltage in modules.

A 60-year-old man with a history of atrial fibrillation had an acute onset of ballistic movements of the left limbs with sensory extinction (video on the Neurology® Web site at [www.neurology.org][1]). The patient was treated with risperidone and anticoagulant; symptoms subsided 3 days later. Brain MRI showed acute infarction of the right posterior parietal lobe (figure 1) and SPECT revealed hypoperfusion in the right frontoparietal areas (figure 2). [1]: http://www.neurology.org/

AIM: To investigate the prevalence of advanced polyps in asymptomatic Chinese and to determine the risk of proximal advanced colonic polyps in subjects with and without polyps in the distal colon. METHODS: Data were collected prospectively during colonoscopic examinations performed in 5 973 subjects as part of health evaluation at our unit from December 1997 to December 2003. Polyps were considered advanced, if they were larger than 10 mm or were tubovillous, villous or malignant. Proximal colon was defined as the splenic flexure and more proximal portions of the colon. RESULTS: Colon polyps were detected in 971 (16.3%) subjects (613 males and 358 females) with their mean age being 56.6 ± 10.7 years. Advanced polyps were noted in 199 (3.3%) individuals. Subjects were sub-classified according to the location of polyps into three groups: distal (569, 58.6%), proximal (284, 29.2%), and combined proximal and distal (118, 12.2%) groups. Subjects with advanced polyps in these three groups were 95 (9.8%), 56 (5.8%), and 48 (4.9%) respectively. In the 48 subjects with advanced combined polyps, 13 advanced polyps were distributed at the distal colon, 17 at the proximal colon, and 18 at both. Eighteen colon cancers including 12 at sigmoid and 6 at ascending colon were confirmed by final pathology. The relative risk for advanced proximal polyp according to distal findings was 3.1 (95%CI: 1.3-7.4) for hyperplastic polyp, 2.7 (95%CI: 1.4-5.3) for tubular polyp and 13.5 (95%CI: 5.1-35.4) for advanced polyp as compared to that for no polyp. However, 56 (28.2%) of 199 subjects with advanced polyps had no index polyps at the distal colon and might go undetected under sigmoidoscopic screening. CONCLUSION: Although distal lesions can predict the risk of advanced proximal polyps, a substantial portion of Chinese with advanced proximal polyps is not associated with any distal sentinel lesions. These data have implications for screening policy of colon cancers in Taiwanese Chinese.