The role of mitochondrial reactive oxygen species (mitoROS) in cellular function remains obscure. By synthesizing recent data, we propose here that local dynamic mitoROS in the form of "superoxide flashes" serve as "signaling ROS" rather than "homeostatic ROS", distinguishable from basal mitoROS due to constitutive leakage of the electron transfer chain (ETC). Individual superoxide flashes are 10-s mitoROS bursts that are compartmentalized to a single mitochondrion or local mitochondrial networks. As a highly-conserved universal mitochondrial activity, it occurs in intact cells, in ex vivo beating hearts, and even in living animals. Unlike basal mitoROS, superoxide flashes are ignited by transient openings of a type of mitochondrial permeability transition pore (mPTP), and their incidence is richly regulated by an array of factors that converge on either the mPTP or ETC. Emerging evidence has shown that superoxide flashes decode dietary and metabolic status or exercise, gauge oxidative stress (e.g., during reoxygenation after hypoxia or anoxia), and constitute early mitochondrial signals that initiate oxidative stress-related apoptosis in a context-dependent manner. That they make only a miniscule contribution to global ROS attests to the high efficiency of local ROS signaling. However, the exact mechanisms underlying superoxide flash formation, regulation and function remain uncertain. Future investigation is warranted to uncover the cellular logic and molecular pathways of local dynamic mitoROS signaling in heart muscle cells and many other cell types.

Thrombotic thrombocytopenic purpura (TTP) is primarily caused by immunoglobulin G (IgG) autoantibodies against A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, 13 (ADAMTS13). Nearly all adult idiopathic TTP patients harbor IgGs, which bind the spacer domain of ADAMTS13, a region critical for recognition and proteolysis of von Willebrand factor (VWF). We hypothesize that a modification of an exosite in the spacer domain may generate ADAMTS13 variants with reduced autoantibody binding while preserving or enhancing specific activity. Site-directed mutagenesis was used to generate a series of ADAMTS13 variants, and their functional properties were assessed. Of 24 novel ADAMTS13 variants, 2 (ie, M4, R660K/F592Y/R568K/Y661F and M5, R660K/F592Y/R568K/Y661F/Y665F) exhibited increased specific activity approximately 4- to 5-fold and approximately 10- to 12-fold cleaving a peptide VWF73 substrate and multimeric VWF, respectively. More interestingly, the gain-of-function ADAMTS13 variants were more resistant to inhibition by anti-ADAMTS13 autoantibodies from patients with acquired idiopathic TTP because of reduced binding by anti-ADAMTS13 IgGs. These results shed more light on the critical role of the exosite in the spacer domain in substrate recognition. Our findings also help understand the pathogenesis of acquired autoimmune TTP. The autoantibody-resistant ADAMTS13 variants may be further developed as a novel therapeutic for acquired TTP with inhibitors.

ABSTRACT: Study Design. Case report and literature reviewObjective. This paper reports two cases in which the patients accepted revision surgery following CTDA due to iatrogenic neurological injury.Summary of Background Data. Cervical total disc arthroplasty (CTDA) has been increasingly investigated to treat cervical degenerative disc disease. However, there are limited reports focused on its complications, especially the neurological complications following the procedure.Method. A 52-year-old male underwent total disc arthroplasty for C5-C6, but immediately after surgery, he was suffering from paralysis of his upper and lower limbs. Radiographic images indicated residual compression to the spinal cord in the level of C5-C6. Another patient, a 60-year-old male, underwent total disc arthroplasty for C4-C5. Afterwards, he suffered severe neck pain, and paralysis of upper and lower limbs. He was unresponsive to conservative treatments, thus, a laminectomy was performed 3 months later. However, little improvement was observed. Radiographic images indicated kyphosis and spinal cord compression at the level of C4-C5. Furthermore, both cases showed a high signal in the spinal cord by T2-weighted MR image, suggestive of spinal cord injuries.Results. Revision surgeries were performed in both cases. Cervical implants were first removed by the anterior approach, and fusion was then performed after a complete decompression. Motor exam of patient in case one showed Grade 3 strength in both his hands and feet 6 months after revision surgery. In case two, the patient's severe neck pain was resolved at the early postoperative stage. Motor exam showed Grade 1 strength in both his both hands and feet 3 months after revision surgery.Conclusion. Based on presented cases and other reports, the surgical goals in these patients were prioritized as follows: 1) safe and adequate neurologic decompression, 2) establishment and maintenance of cervical sagittal balance. Moreover, a criterion for selecting patients undergoing CTDA needs to be established in order to reduce the occurrence of neurologic complications associated with the procedure.

Age-related macular degeneration (AMD) is the predominant cause of irreversible blindness in the elderly population. Despite intensive basic and clinical research, its pathogenesis remains unclear. However, evidence suggests that immunological and inflammatory factors contribute to the pathogenesis of AMD. A newly identified cytokine, IL-33, appears to be an important pro-inflammatory cytokine promoting tissue inflammation. In this study, IL-33 was increased through amyloid-beta(1-40)(Aβ(1-40)) stimulation and regulated inflammatory cytokines including IL-6, IL-8, IL-1β, and TNF-α secretion using different signaling pathways in retinal pigment epithelium (RPE) cells. Furthermore, ST2L, the important component of the IL-33 receptor, was significantly increased following recombinant human IL-33 stimulation in RPE cells. These findings suggest that IL-33-mediated inflammatory responses in RPE cells are involved in the pathogenesis of AMD. Greater understanding of the inflammatory effect of IL-33 and its role in RPE cells should aid the development of future clinical therapeutics and enable novel pharmacological approaches towards the prevention of AMD.

Cervical kyphosis may be congenital, or occur as a result of laminectomy, post-traumatic deformity, infection, neuromuscular disorders such as muscular dystrophies, motor neuron disorders such as amyotrophic lateral sclerosis, tumor, and inflammation such as ankylosing spondylitis. Furthermore, adolescent idiopathic cervical kyphosis was defined as cervical kyphotic deformity of adolescent patient without any cause such as those previously described. As no standard values for "cervical kyphosis" could be found in the literature, many reported studies only report a subjective classification,"kyphotic, straight or lordotic". But this method had proven to be unreliable. Grob et al. defined "straight" for the global curvature as +4° to -4°, and lordotic and kyphotic as <-4° and >+4°, respectively. The etiology and pathogenesis of adolescent idiopathic cervical kyphosis remain little understood. Weakness of the neck extensors can result in "dropped head syndrome", a rare disorder characterized by weakness of neck extensor muscles causing an inability to extend the neck and resulting in a chin-on-chest deformity. The purpose of this paper is to propose a possible mechanical cause leading to the kyphotic deformity. We hypothesize that weakness of the neck extensors could be the initiating factor for adolescent idiopathic cervical kyphosis.

To explore how cytohesin-1 (CYTH-1) small interfering RNA (siRNA) influences the insulin-like growth factor receptor (IGFR)-associated signal transduction in prostate cancer, we transfected human prostate cancer PC-3 cell lines with liposome-encapsulatedCYTH-1 siRNA in serum-free medium and exposed the cells to 100 nM IGF-1. The mRNA and protein levels of the signal molecules involved in the IGFR signaling pathways were determined by real-time PCR and detected by Western blotting. The relative mRNA levels of CYTH-1, c-Myc, cyclinD1 and IGF-1R (CYTH-1 siRNA group vs scrambled siRNA group) were 0.26 vs 0.97, 0.34 vs 1.06, 0.10 vs 0.95, and 0.27 vs 0.41 (P < 0.05 for all), respectively. The relative protein levels of CYTH-1, pIGF-1R, pIRS1, pAkt1, pErk1, c-Myc, and cyclinD1 (CYTH-1 siRNA group vsscrambled siRNA group) were 0.10 vs 1.00 (30 min), 0.10 vs 0.98 (30 min), 0.04 vs 0.50 (30 min), 0.10 vs 1.00 (30 min), 0.10 vs 1.00 (30 min), 0.13 vs 0.85 (5 h), and 0.08 vs 0.80 (7 h), respectively. The tyrosine kinase activity of IGF-1R was associated with CYTH-1. The proliferative activity of PC-3 cells transfected with CYTH-1 siRNA was significantly lower than that of cells transfected with scrambled siRNA at 48 h (40.5 vs87.6%, P < 0.05) and at 72 h (34.5 vs 93.5%, P < 0.05). In conclusion, the interference of siRNA with cytohesin-1 leads to reduced IGFR signaling in prostate cancer; therefore, CYTH-1 might serve as a new molecular target for the treatment of prostate cancer.

Chinese sacbrood virus (CSBV) was purified from diseased insects, and its genome was cloned and sequenced. The genomic RNA of CSBV is 8863 nucleotides in length and contains a single large open reading frame encoding a 319.614 kDa polyprotein. The coding sequence is flanked by a 178-nucleotide 5' nontranslated leader sequence and a 142-nucleotide 3' nontranslated region, followed a poly(A) tail. Four major structural proteins, VP1,VP2, VP3 and VP4, were predicted in the N-teminal of the polyprotein. The C-terminal part of the polyprotein contains sequence motifs which is a typical and well-characterized picornavirus nonstructural proteins: an RNA helicase, a chymotrypsin-like 3C protease, and an RNA-dependent RNA polymerase. Genetic analysis shows that the CSBV-LN had a 13-amino-acid deletion at amino acid positions 710-719 and 727-729 in comparison with CSBV-GZ and SBV-UK, and the SBV-UK had a 7-amino-acid deletion at amino acid positions 2124-2132 in comparison with CSBV-GZ and CSBV-LN, and the CSBV-GZ and CSBV-LN had a 6-amino-acid deletion at amino acid positions 2143-2150 in comparison with SBV-UK. Phylogenetic analysis using RdRp of selected picorna-like viruses shows that CSBV/SBV and Deformed Wing Virus (DWV) tend to group together, which possesses an RNA of similar size and gene order.

An extremely useful evolution equation that allows systematically calculating the two-time correlation functions (CF's) of system operators for non-Markovian open (dissipative) quantum systems is derived. The derivation is based on perturbative quantum master equation approach, so non-Markovian open quantum system models that are not exactly solvable can use our derived evolution equation to easily obtain their two-time CF's of system operators, valid to second order in the system-environment interaction. Since the form and nature of the Hamiltonian are not specified in our derived evolution equation, our evolution equation is applicable for bosonic and/or fermionic environments and can be applied to a wide range of system-environment models with any factorized (separable) system-environment initial states (pure or mixed). When applied to a general model of a system coupled to a finite-temperature bosonic environment with a system coupling operator L in the system-environment interaction Hamiltonian, the resultant evolution equation is valid for both L = L(†) and L ≠ L(†) cases, in contrast to those evolution equations valid only for L = L(†) case in the literature. The derived equation that generalizes the quantum regression theorem (QRT) to the non-Markovian case will have broad applications in many different branches of physics. We then give conditions on which the QRT holds in the weak system-environment coupling case and apply the derived evolution equation to a problem of a two-level system (atom) coupled to the finite-temperature bosonic environment (electromagnetic fields) with L ≠ L(†).

To investigate the etiology and clinical features of fever of unknown origin (FUO). The clinical data including etiology, diagnostic approaches, and clinical features were retrospectively analyzed in 816 patients with FUO who were presented in our department from January 2000 to January 2009. Of these 816 FUO cases, 766 (93.9%) were confirmed to be with infective diseases(40.4%, n=330), connective tissue diseases (34.4%, n=281), malignant tumors (10.9%, n=89), other known diseases (8.1%, n=66), and unknown diseases (6.1%, n=50). The most common infective disease was tuberculosis (49.7%, 164/330), the most common connective tissue disease was adult-onset Stills disease (AOSD)(55.2%, 155/281), the most common malignant tumor was lymphoma(56.2%, 50/89), and the most common "other known disease" was Crohns disease(22.7%, 15/66). All lung cancer cases had obstructive pneumonia. Significantly more elderly patients suffered from infective diseases (49.4% vs.32.0%) and malignant tumor (15.6% vs. 6.4%) compared with the non-elderly (both P=0.0000), while the proportion of connective tissue diseases was significantly less than that of the non-elderly (17.9% vs. 50.1%, P=0.0000). Most FUO can be confirmed after careful examinations and analysis. The main cause of FUO is infective diseases, especially tuberculosis in the elderly. The connective tissue diseases and malignant tumors are also important causes.

OBJECTIVE Adjunctive therapies that reduce the cerebral edema in bacterial meningitis include osmotic agents. There is a lack of information comparing mannitol vs. hypertonic saline as an osmotic agent for adjunctive therapy of bacterial meningitis. We attempted to elucidate the impact of hypertonic saline in cerebral edema in the setting of bacterial meningitis as well as to explore potential mechanisms of action. DESIGN Randomized controlled in vivo study. SETTING University research laboratory. SUBJECTS Rabbits. INTERVENTIONS A rabbit model of bacterial meningitis was used comparing 3% hypertonic saline with 20% mannitol as adjunctive therapy. MEASUREMENTS AND MAIN RESULTS Adjunctive 3% hypertonic saline treatment persistently elevated mean arterial pressure as compared with the model or ampicillin group (p <.01). Although both 20% mannitol and 3% hypertonic saline efficiently elevated serum osmolality for almost 5 hrs (p <.01), 20% mannitol lowered intracranial pressure for only a short time (<2 hrs) and did not elevate cerebral perfusion pressure. Three percent hypertonic saline treatment efficiently lowered intracranial pressure and elevated cerebral perfusion pressure for almost 5 hrs (p <.01). Furthermore, 3% hypertonic saline treatment efficiently elevated serum Na+ concentration for >5 hrs (p <.01). Three percent hypertonic saline treatment was superior to 20% mannitol in lowering leukocyte number and protein content in cerebrospinal fluid (p <.01). Three percent hypertonic saline treatment reduced water content and Evans blue incorporation in the brain (p <.01). Three percent hypertonic saline treatment inhibited aquaporin 4 expression (p <.01) and attenuated pathologic brain damage more efficiently compared with adjuvant 20% mannitol treatment (p <.01). CONCLUSIONS Adjunctive 3% hypertonic saline treatment significantly elevated mean arterial pressure, reduced intracranial pressure, greatly improved cerebral perfusion pressure, inhibited brain aquaporin 4 expression, reduced cerebral edema, and attenuated brain damage with a superior effect over 20% mannitol in a rabbit bacterial meningitis model.