Sodium vanadate combined with l-ascorbic acid delays disease progression, enhances motor performance, and ameliorates muscle atrophy and weakness in mice with spinal muscular atrophy

BACKGROUND: Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. METHODS: Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. RESULTS: Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation in these organs. CONCLUSIONS: Combined treatment beginning at birth and continuing for 1 month conferred protection against neuromuscular damage in mice with milder types of SMA. Further, these mice exhibited enhanced motor performance in adulthood. Therefore, combined treatment could present a feasible treatment option for patients with late-onset SMA

The incidence of symptomatic venous thromboembolism following hip fractures with or without surgery in Taiwan

AbstractBackgroundInformation on the incidence of venous thromboembolism (VTE) following hip fractures in Asia is rare. This study will investigate the epidemiology of symptomatic VTE in Taiwanese patients experiencing hip fractures.Methods and resultsWe used Taiwan's National Health Insurance Research Database to retrospectively identify patients (≧45years) who experienced hip fractures from 1998 to 2007 and were followed up for 3months after the discharge. Logistic regression analysis determined the independent risk factors of symptomatic VTE after the fractures. We identified 134,034 patients (mean age: 76.2±9.7years; female: 57.8%) who experienced hip fractures, 83.2% of whom underwent hip surgery. The overall pharmacological thromboprophylaxis rate was 2.7%. The mean length of stay was 11.3±7.9days. The 3-month cumulative incidence of symptomatic VTE was 77 events per 10,000 persons. Multivariate analysis showed that previous DVT, previous PE, varicose veins, cancer, heart failure, renal insufficiency, and older age were independent risk factors of developing VTE.ConclusionsThe incidence of symptomatic VTE after hip fractures is low in Taiwan. Patients rarely received pharmacological thromboprophylaxis following hip fractures. Universal thromboprophylaxis for patients experiencing hip fractures was not necessary in Taiwan, but it should be considered in high-risk populations

A neural network model for constructing endophenotypes of common complex diseases: an application to male young-onset hypertension microarray data

Motivation: Identification of disease-related genes using high-throughput microarray data is more difficult for complex diseases as compared with monogenic ones. We hypothesized that an endophenotype derived from transcriptional data is associated with a set of genes corresponding to a pathway cluster. We assumed that a complex disease is associated with multiple endophenotypes and can be induced by their up/downregulated gene expression patterns. Thus, a neural network model was adopted to simulate the gene–endophenotype–disease relationship in which endophenotypes were represented by hidden nodes

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Currency Risk Facing Taiwan's Financial Institutions

[[abstract]]臺灣金融機構的短期外匯風險（通常為明顯且立即的）受到金融監理機構嚴格的規範，然而對於長期外匯風險（通常是潛在且間接的）則未在要求之列，這可能是因為傳統的資本市場法尚未檢測出長期外匯曝險之存在。本文採現金流量法來分析金融機構的長、短期外匯風險，結果發現金融機構對於貿易加權匯率指數之外匯曝險呈顯著者達61.54%，此比率超過傳統資本市場法平均不到四成的顯著比例。無論是由平均最適落後期數或長、短期顯著比例的比較，本文研究結果均指出長期外匯風險的確是存在著。此外，在外匯風險值影響方向性的結果上，本文實證顯示出美元（臺灣最大出口國貨幣）以及日圓（臺灣最大進口國貨幣）的兩組貨幣對立效果。為求結論的穩健性，本文進一步納入利率因素來衡量非預期的匯率變動，並再次評估其對金融業現金流量的衝擊，結果同樣證實長期外匯風險的存在性。這些結果意謂著不僅金融監理當局應將長期外匯曝險納入風險管理之規範，金融機構更應正視因匯率風險所延伸之訂價因子對銀行價值之衝擊。[[abstract]]Regulators only require banks to manage their short-term exchange rate risk. A possible reason is that the prevailing capital-market methodology fails to identify the long-term currency exposure. Using operating incomes generated by banks, this paper investigates the impact of fluctuating foreign exchange rates on the values of Taiwanese banking institutions, and decomposes the overall currency exposure into short-term and long-term components. We not only overcome the deficiency of prior studies that have limited success in detecting significant currency exposure, but also measure the magnitude of economic exposure that banks are faced with. In contrast to the capital market approach, the cash flow approach finds that 61.54% of the sample firms have a significant currency exposure, which is more than the percentage documented by prior research. Our results also show that the existence of significant long-term exchange rate risk is prevalent among banking institutions in Taiwan. Furthermore, the US dollar (the currency of a nation which is Taiwan's largest export market) has an opposite effect as opposed to the Japanese Yen (the currency of a nation which is Taiwan's largest source of imports). Our results have policy implications that banking institutions should manage long-term currency exposure