TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.protein aggregation | neuronal apoptosis T DP-43 is a 43-kDa, ubiquitously expressed protein, well conserved among eukaryotes (1). This DNA/RNA-binding factor is predominantly located in the nucleus as a dimer (2), and it has been implicated in multiple cellular functions, e.g., transcriptional repression, splicing, and translation (3-6). TDP-43 has also been identified as the pathological signature protein of a range of neurodegenerative diseases (7). The pathological samples of these diseases, which have been termed TDP-43 proteinopathies, are characterized by cytoplasmic and, to a much lesser extent, nuclear TDP-43-positive (+) and ubiquitinated inclusions (UBIs) containing full-length TDP-43, polyubiquinated TDP-43, phosphorylated TDP-43, as well as 35-and 25-kDa carboxy1 fragments of TDP-43 (for reviews, see refs. 7-11). Of the two major categories of TDP-43 proteinopathies are frontotemporal lobar degeneration with ubiquitin (+) inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). It has been estimated that ∼50% of FTLD-U and 80-90% of ALS, which has an incidence rate between 1.5 and 2.5 per 100,000 (12), are signified...

This study aimed to establish the psychometric properties of parent ratings on the Chinese version of the Swanson, Nolan, and Pelham IV scale (SNAP-IV) in a school-based sample of 3534 students in grades 1 to 8 from two cities and two suburbs in Taiwan and 189 children diagnosed with attention deficit/hyperactivity disorder (ADHD) (aged 6 to 15) consecutively recruited from a medical center in Taipei. Parents completed the Chinese versions of the SNAP-IV, Strengths and Difficulties Questionnaire, and Child Behavior Checklist. The Chinese SNAP-IV demonstrated similar three factor structure (Inattention, Hyperactivity/Impulsivity, and Oppositional) as its English version, and satisfactory test-retest reliability (intraclass correlation = 0.59 approximately 0.72), internal consistency (alpha = 0.88 approximately 0.90), concurrent validity (Pearson correlations = 0.56 approximately 0.72), and discriminant validity. Boys scored higher than girls across the eight school grade levels. The SNAP-IV clearly distinguished children with ADHD from school-based participants. Comorbidity with oppositional defiant disorder/conduct disorder predicted higher SNAP-IV scores among children with ADHD. Our findings suggest that the Chinese SNAP-IV is a reliable and valid instrument for rating ADHD-related symptoms in both clinical and community settings in Taiwan.

Paraquat (PQ) is a widely used bipyridyl contact herbicide with a good safety record when used properly. Most cases of PQ poisoning result from PQ suicidal ingestion. There are three degrees of severity in PQ poisoning (1, 2). Mild poisoning can cause oral irritation and gastric upset, and brings complete recovery. Moderate to severe poisoning produces acute renal failure, and in severe cases, hepatitis followed by pulmonary fibrosis, leading to death after 2 to 3 wk. Acute fulminant poisoning results in death within 1 wk from multiple organ failure and cardiovascular collapse. Retrospective studies (3)(4)(5)(6) show that good predictors of outcome may be plasma and urine concentrations within the first 24 h of intoxication. The urine PQ tests taken on admission are reasonable guides to predict the severity of poisoning and have the advantage that a qualitative or semiquantitative result may be easily and rapidly obtained in an emergency situation (5-7).The results of treatments for PQ poisoning, including absorbents, pharmacological approaches (8), radiotherapy (9), hemodialysis, and hemoperfusion (10), were disappointing. Although the high-dose cyclophosphamide (CP) and dexamethasone (DX) treatments, including intravenous CP 5 mg/kg/d and DX 24 mg/d for 14 d, had a 75% survival rate after PQ poisoning (11), a subsequent study (12) did not demonstrate the efficacy of this approach. Therefore, the efficiency of highdose CP and DX in PQ poisoning remains controversial. Recently, pulse therapy with CP and methylprednisolone (MP), including intravenous CP or MP 1 g/d for 2 to 3 d, has been used to treat effectively many patients with severe lung damage from systemic lupus erythematosus (SLE) and Wegener's granulomatosis (13,14), with greater efficacy and less side effects than those of high doses of CP therapy. In addition, our preliminary report (15) demonstrated that pulse therapy might be effective in treating patients with moderate to severe PQ poisoning. Because the previous study was not prospective and only included a small number of patients, we designed the prospective study to evaluate its efficacy in treating a large group of PQ-poisoned patients. METHODSThis study was approved by the clinical research committee of Chang Gung Memorial Hospital and had the informed consent of all patients. This prospective study lasted from January 1992 to December 1997. During this period, 142 patients with PQ poisoning were admitted to our hospital within 24 h after ingestion. In urine samples taken on arrival at our emergency department, PQ was immediately detected by the sodium dithionite reaction. The sodium dithionite test is based on the reduction of PQ by sodium thionite under alkaline condition to form its stable blue radical ion. A strong "navy blue" (NB) or "dark blue" (DB) generally indicates significant PQ ingestion and subsequent poor prognosis (5-7). Patients were classified as having:( 1 ) fulminant poisoning if their urinary dithionite reaction yielded a NB or DB and if they died from multiple organ failur...

No abstract

IL-6 and IL-10 were the key cytokines in the pathogenesis of severe sepsis. IL-6 was comparatively more associated with septic shock and IL-10 was comparatively more associated with mortality.