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1.  Reclaiming the Efficacy of β-Lactam–β-Lactamase Inhibitor Combinations: Avibactam Restores the Susceptibility of CMY-2-Producing Escherichia coli to Ceftazidime 
CMY-2 is a plasmid-encoded Ambler class C cephalosporinase that is widely disseminated in Enterobacteriaceae and is responsible for expanded-spectrum cephalosporin resistance. As a result of resistance to both ceftazidime and β-lactamase inhibitors in strains carrying blaCMY, novel β-lactam–β-lactamase inhibitor combinations are sought to combat this significant threat to β-lactam therapy. Avibactam is a bridged diazabicyclo [3.2.1]octanone non-β-lactam β-lactamase inhibitor in clinical development that reversibly inactivates serine β-lactamases. To define the spectrum of activity of ceftazidime-avibactam, we tested the susceptibilities of Escherichia coli clinical isolates that carry blaCMY-2 or blaCMY-69 and investigated the inactivation kinetics of CMY-2. Our analysis showed that CMY-2-containing clinical isolates of E. coli were highly susceptible to ceftazidime-avibactam (MIC90, ≤0.5 mg/liter); in comparison, ceftazidime had a MIC90 of >128 mg/liter. More importantly, avibactam was an extremely potent inhibitor of CMY-2 β-lactamase, as demonstrated by a second-order onset of acylation rate constant (k2/K) of (4.9 ± 0.5) × 104 M−1 s−1 and the off-rate constant (koff) of (3.7 ± 0.4) ×10−4 s−1. Analysis of the reaction of avibactam with CMY-2 using mass spectrometry to capture reaction intermediates revealed that the CMY-2–avibactam acyl-enzyme complex was stable for as long as 24 h. Molecular modeling studies raise the hypothesis that a series of successive hydrogen-bonding interactions occur as avibactam proceeds through the reaction coordinate with CMY-2 (e.g., T316, G317, S318, T319, S343, N346, and R349). Our findings support the microbiological and biochemical efficacy of ceftazidime-avibactam against E. coli containing plasmid-borne CMY-2 and CMY-69.
PMCID: PMC4136032  PMID: 24820081
2.  Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum 
Parkinson's Disease  2015;2015:253878.
L-DOPA-induced dyskinesias (LID) remain a major problem of long-term therapy of Parkinson's disease. Levetiracetam, a new antiepileptic drug, has been shown to reduce LID, but the mechanisms underlying its effects are unknown. In this study, we assessed the effect of levetiracetam on key mediators of LID in rats with 6-hydroxydopamine (6-OHDA) lesions. Following chronic administration of L-DOPA (12 mg/kg, twice daily for 14 days), rats developed abnormal involuntary movements (AIMs), but co-administration of levetiracetam (15, 30, and 60 mg/kg) with equivalent L-DOPA dosing significantly reduced AIMs scores in a dose dependent manner. The effects of levetiracetam were associated with changes in striatal expression of ΔFosB, phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2), and phosphorylated cAMP-regulated phosphoprotein of 32 kDa (p-DARPP-32). These data support that levetiracetam acts at multiple sites in the pathogenetic cascade of LID, and that further understanding of these actions of antiepileptics may contribute to developing new LID therapies.
PMCID: PMC4322303
3.  Exosomes: Novel Biomarkers for Clinical Diagnosis 
The Scientific World Journal  2015;2015:657086.
Exosomes are 30–120 nm endocytic membrane-derived vesicles that participate in cell-to-cell communication and protein and RNA delivery. Exosomes harbor a variety of proteins, nucleic acids, and lipids and are present in many and perhaps all bodily fluids. A significant body of literature has demonstrated that molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), hold great promise as novel biomarkers for clinical diagnosis. In this minireview, we summarize recent advances in the research of exosomal biomarkers and their potential application in clinical diagnostics. We also provide a brief overview of the formation, function, and isolation of exosomes.
PMCID: PMC4322857
4.  Centralized isolation of Helicobacter pylori from multiple centers and transport condition influences 
AIM: To evaluate the efficacy of centralized culture and possible influencing factors.
METHODS: From January 2010 to July 2012, 66452 patients with suspected Helicobacter pylori (H. pylori) infection from 26 hospitals in Zhejiang and Jiangsu Provinces in China underwent gastrointestinal endoscopy. Gastric mucosal biopsies were taken from the antrum for culture. These biopsies were transported under natural environmental temperature to the central laboratory in Hangzhou city and divided into three groups based on their transport time: 5, 24 and 48 h. The culture results were reported after 72 h and the positive culture rates were analyzed by a χ2 test. An additional 5736 biopsies from H. pylori-positive patients (5646 rapid urease test-positive and 90 14C-urease breath test-positive) were also cultured for quality control in the central laboratory setting.
RESULTS: The positive culture rate was 31.66% (21036/66452) for the patient samples and 71.72% (4114/5736) for the H. pylori-positive quality control specimens. In the 5 h transport group, the positive culture rate was 30.99% (3865/12471), and 32.84% (14960/45553) in the 24 h transport group. In contrast, the positive culture rate declined significantly in the 48 h transport group (26.25%; P < 0.001). During transportation, the average natural temperature increased from 4.67 to 29.14 °C, while the positive culture rate declined from 36.67% (1462/3987) to 24.12% (1799/7459). When the temperature exceeded 24 °C, the positive culture rate decreased significantly, especially in the 48 h transport group (23.17%).
CONCLUSION: Transportation of specimens within 24 h and below 24 °C is reasonable and acceptable for centralized culture of multicenter H. pylori samples.
PMCID: PMC4299348  PMID: 25624729
Centralized isolation; Helicobacter pylori; Influencing factor; Multiple centers; Personalized treatment
5.  Photoaffinity Labeling the Propofol Binding Site in GLIC† 
Biochemistry  2013;53(1):135-142.
Propofol, an intravenous general anesthetic, produces many of its anesthetic effects in vivo by potentiating the responses of GABA type A receptors (GABAAR), members of the superfamily of pentameric ligand-gated ion channels (pLGICs) that contain anion-selective channels. Propofol also inhibits pLGICs containing cation-selective channels, including nicotinic acetylcholine receptors and GLIC, a prokaryotic proton-gated homolog from Gloeobacter violaceus. In the structure of GLIC co-crystallized with propofol at pH 4 (presumed open/desensitized states), propofol was localized to an intrasubunit pocket at the extracellular end of the transmembrane domain within the bundle of transmembrane α-helices [Nury, H, et. al. (2011) Nature 469, 428–431]. To identify propofol binding sites in GLIC in solution, we used a recently developed photoreactive propofol analog (2-isopropyl-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenol or AziPm) which acts as an anesthetic in vivo and potentiates GABAAR in vitro. For GLIC expressed in Xenopus oocytes, propofol and AziPm inhibited current responses at pH 5.5 (EC20) with IC50s of 20 and 50 μM, respectively. When [3H]AziPm (7 μM) was used to photolabel detergent-solubilized, affinity-purified GLIC at pH 4.4, protein microsequencing identified propofol-inhibitable photolabeling of three residues in the GLIC transmembrane domain: Met-205, Tyr-254, and Asn-307 in the M1, M3, and M4 transmembrane helices, respectively. Thus, in GLIC in solution, propofol and AziPm bind competitively to a site in proximity to these residues, which in the GLIC crystal structure are in contact with the propofol bound in the intrasubunit pocket.
PMCID: PMC3935609  PMID: 24341978
6.  Prognostic role of apoptosis-related gene functional variants in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy 
OncoTargets and therapy  2015;8:147-155.
Single-nucleotide polymorphisms in apoptosis-related genes have been shown to play a role in the efficacy of platinum-based chemotherapy and may influence clinical outcomes. Our study aimed to evaluate the correlations of four functional single-nucleotide polymorphisms − FAS −670 A>G, FAS ligand −844 T>C, survivin −31 G>C, and survivin 9386 C>T – with drug response and clinical outcomes in advanced non-small-cell lung cancer patients who received platinum-based chemotherapy.
Materials and methods
Polymorphisms were evaluated using the polymerase chain reaction-based restriction fragment-length polymorphism technique.
Patients with the CC genotype of FAS −670 A>G had worse overall survival (OS) than those with the CT or TT genotype (P=0.044), with median OS values of 20.1 months, 22.8 months, and 26.0 months, respectively. Furthermore, progression-free survival was associated with the FAS −670 A>G polymorphism (P=0.032). In addition, patients with the TC and CC genotypes of survivin 9386 C>T experienced improved survival compared with patients with the TT genotype (median OS 31.4 months and 22.8 months, respectively).
The functional FAS −670 A>G and survivin 9386 C>T polymorphisms are potential independent prognostic factors in advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy.
PMCID: PMC4298310  PMID: 25609982
lung cancer; FAS −670 A>G; survivin 9386 C>T; polymorphism; chemotherapy response
7.  Starter Culture Selection for Making Chinese Sesame-Flavored Liquor Based on Microbial Metabolic Activity in Mixed-Culture Fermentation 
Applied and Environmental Microbiology  2014;80(14):4450-4459.
Selection of a starter culture with excellent viability and metabolic activity is important for inoculated fermentation of traditional food. To obtain a suitable starter culture for making Chinese sesame-flavored liquor, the yeast and bacterium community structures were investigated during spontaneous and solid-state fermentations of this type of liquor. Five dominant species in spontaneous fermentation were identified: Saccharomyces cerevisiae, Pichia membranaefaciens, Issatchenkia orientalis, Bacillus licheniformis, and Bacillus amyloliquefaciens. The metabolic activity of each species in mixed and inoculated fermentations of liquor was investigated in 14 different cocultures that used different combinations of these species. The relationships between the microbial species and volatile metabolites were analyzed by partial least-squares (PLS) regression analysis. We found that S. cerevisiae was positively correlated to nonanal, and B. licheniformis was positively associated with 2,3-butanediol, isobutyric acid, guaiacol, and 4-vinyl guaiacol, while I. orientalis was positively correlated to butyric acid, isovaleric acid, hexanoic acid, and 2,3-butanediol. These three species are excellent flavor producers for Chinese liquor. Although P. membranaefaciens and B. amyloliquefaciens were not efficient flavor producers, the addition of them alleviated competition among the other three species and altered their growth rates and flavor production. As a result, the coculture of all five dominant species produced the largest amount of flavor compounds. The result indicates that flavor producers and microbial interaction regulators are important for inoculated fermentation of Chinese sesame-flavored liquor.
PMCID: PMC4068675  PMID: 24814798
8.  Facilitation of Resident Scholarly Activity: Strategy and Outcome Analyses Using Historical Resident Cohorts and a Rank-to-Match Population 
Anesthesiology  2014;120(1):111-119.
Facilitation of residents’ scholarly activities is indispensable to the future of medical specialties. Research education initiatives and their outcomes, however, have rarely been reported.
Since Academic Year (AY) 2006, research education initiatives, including research lectures, research problem based learning discussions, and an elective research rotation under a new research director’s supervision, have been used. The effectiveness of the initiatives was evaluated by comparing the number of residents and faculty mentors involved in residents’ research activity (Pre-initiative [2003 to 2006] vs. Post-initiative [2007 to 2011]). The residents’ current post-graduation practices were also compared. To minimize potential historical confounding factors, peer reviewed publications based on work performed during residency written by residents who graduated from the program in AY2009 to AY2011 were further compared with those of rank-to-match residents, who were on the residency ranking list during the same AYs and could have been matched with our program had they ranked it high enough on their list.
The Post-initiative group showed greater resident research involvement compared to the Pre-initiative group (89.2% [58 in 65 residents] vs. 64.8% [35 in 54], p=0.0013) and greater faculty involvement (23.9% [161 in 673 faculty/year] vs. 9.2% [55 in 595], p<0.0001). Choice of academic practice did not increase (50.8% [Post] vs. 40.7% [Pre], p=0.36). Graduated residents (n=38) published more often than the rank-to-match residents (n=220) (55.3% [21 residents] vs. 13.2% [29], p<0.0001, odds ratio 8.1 with 95% confidence interval of 3.9 to 17.2).
Research education initiatives increased residents’ research involvement.
PMCID: PMC3905449  PMID: 24212198
9.  Targeted Antiangiogenesis Gene Therapy Using Targeted Cationic Microbubbles Conjugated with CD105 Antibody Compared with Untargeted Cationic and Neutral Microbubbles 
Theranostics  2015;5(4):399-417.
Objective This study aimed to develop targeted cationic microbubbles conjugated with a CD105 antibody (CMB105) for use in targeted vascular endothelial cell gene therapy and ultrasound imaging. We compared the results with untargeted cationic microbubbles (CMB) and neutral microbubbles (NMB).
Methods CMB105 were prepared and compared with untargeted CMB and NMB. First, the microbubbles were characterized in terms of size, zeta-potential, antibody binding ability and plasmid DNA loading capacity. A tumor model of subcutaneous breast cancer in nude mice was used for our experiments. The ability of different types of microbubbles to target HUVECs in vitro and tumor neovascularization in vivo was measured. The endostatin gene was selected for its outstanding antiangiogenesis effect. For in vitro experiments, the transfection efficiency and cell cycle were analyzed using flow cytometry, and the transcription and expression of endostatin were measured by qPCR and Western blotting, respectively. Vascular tube cavity formation and tumor cell invasion were used to evaluate the antiangiogenesis gene therapy efficiency in vitro. Tumors were exposed to ultrasound irradiation with different types of microbubbles, and the gene therapy effects were investigated by detecting apoptosis induction and changes in tumor volume.
Results CMB105 and CMB differed significantly from NMB in terms of zeta-potential, and the DNA loading capacities were 16.76±1.75 μg, 18.21±1.22 μg, and 0.48±0.04 μg per 5×108 microbubbles, respectively. The charge coupling of plasmid DNA to CMB105 was not affected by the presence of the CD105 antibody. Both CMB105 and CMB could target to HUVECs in vitro, whereas only CMB105 could target to tumor neovascularization in vivo. In in vitro experiments, the transfection efficiency of CMB105 was 24.7-fold higher than the transfection efficiency of NMB and 1.47-fold higher than the transfection efficiency of CMB (P<0.05). With ultrasound-targeted microbubble destruction (UTMD)-mediated gene therapy, the transcription and expression of endostatin were the highest in the CMB105 group (P<0.001); the antiangiogenesis effect and inhibition of tumor cells invasion was better with CMB105 than CMB or NMB in vitro (P<0.01). After gene therapy, the tumor volumes of CMB105 group were significantly smaller than that of CMB and NMB, and many tumor cells had begun apoptosis in the CMB105 group, which had the highest apoptosis index (P<0.001).
Conclusions As a contrast agent and plasmid carrier, CMB105 can be used not only for targeted ultrasound imaging but also for targeted gene therapy both in vitro and in vivo. The plasmid DNA binding ability of the CMB was not affected by conjugation of the CMB with the CD105 antibody, and because of its targeting ability, the gene transfection efficiency and therapeutic effect were better compared with the untargeted CMB and NMB. The advantages of targeted gene therapy with CMB105 in vivo were more prominent than with CMB or NMB because neither can target the endothelia in vivo.
PMCID: PMC4329503
Ultrasound-mediated gene delivery (UMGD); Antiangiogenesis; Target; Cationic microbubbles
10.  Knockout of vascular early response gene worsens chronic stroke outcomes in neonatal mice 
Brain research bulletin  2013;98:111-121.
Vascular early response gene (Verge) is a novel immediate early gene that is highly expressed during developmental angiogenesis and after ischemic insults in adult brain. However, the role of Verge after neonatal injury is not known. In the present study, we investigated the hypothesis that Verge contributes to vascular remodeling and tissue repair after neonatal ischemic injury. The Rice–Vanucci model (RVM) was employed to induce neonatal stroke in both Verge knockout (KO) and wild-type (WT) postnatal day 10 (P10) mice. Histological and behavioral outcomes at acute (24 h), subacute (7 days) and chronic (30 days) phases were evaluated. Angiogenesis, neurogenesis, and glial scar formation were also examined in the ischemic brain. No significant differences in outcomes were found between WT and Verge mice at 24 h or 7 days after stroke. However genetic deletion of Verge led to pronounced cystic cavitation, decreased angiogenensis and glial scar formation in the ischemic hemisphere compared to WT mice at 30 days. Verge KO mice also had significantly worse functional outcomes at 30 days which was accompanied by decreased neurogenesis and angiogenesis in the ischemic hemisphere. Our study suggests that Verge plays an important role in the induction of neurogenesis and angiogenesis after ischemia, contributes to improved tissue repair, and enhances chronic functional recovery.
PMCID: PMC4275796  PMID: 23973431
Angiogenesis; Ischemic stroke; Neonate; Neurogenesis; Vascular early response gene
11.  Effect of three common IL-17 single nucleotide polymorphisms on the risk of developing gastric cancer 
Oncology Letters  2014;9(3):1398-1402.
A 1:1 matched case-control study was conducted to analyze the association between three common interleukin (IL)-17A and IL-17F single nucleotide polymorphisms (SNPs) and the risk of developing gastric cancer. Genotyping of SNPs rs2275913, rs763780 and rs3748067 within the IL-17 gene were detected by performing polymerase chain reaction-restriction fragment length polymorphism analysis. Gastric cancer patients were more likely to be cigarette smokers, alcohol drinkers and have a family history of cancer in their first-degree relatives. Patients carrying the rs763780 polymorphism were correlated with a significant increased risk of gastric cancer in codominant, dominant and recessive models. Additionally, individuals with the rs763780 polymorphism were correlated with a markedly increased risk of gastric cancer among alcohol drinkers in codominant, dominant and recessive models. Furthermore, a significant correlation was identified between the rs763780 polymorphism and the consumption of alcohol. However, no association was identified between rs2275913 and rs3748067 polymorphisms and the risk of developing gastric cancer. Thus, the present study reported that the rs763780 polymorphism may be associated with risk of developing gastric cancer in the population studied, particularly in alcohol drinkers.
PMCID: PMC4314969  PMID: 25663919
IL-17; gastric cancer; polymorphism
12.  β-Lactamase Inhibition by 7-Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of an Unprecedented Stabilized Acyl-Enzyme 
Journal of the American Chemical Society  2013;135(49):18358-18369.
The inhibition of the class A SHV-1 β-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14Å X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A cephalosporin-derived enzyme complex of this type is unprecedented and the rearrangement leading to its formation may offer new possibilities for inhibitor design. The observed acyl-enzyme derives its stability from the resonance stabilization conveyed by the β-aminoacrylate (i.e. vinylogous urethane) functionality as there is relatively little interaction of the eight-membered ring with active site residues. Two mechanistic schemes are proposed, differing in whether, subsequent to acylation of the active site serine and opening of the β-lactam, the resultant dihydrothiazine fragments on its own, or is assisted by an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7 tert-butyloxycarbonyl group. This compound was also found to be a submicromolar inhibitor of the class C ADC-7 and PDC-3 β-lactamases.
PMCID: PMC4042847  PMID: 24219313
13.  Symptoms of depression and anxiety in patients with thalassemia: Prevalence and correlates in the thalassemia longitudinal cohort 
American journal of hematology  2010;85(10):802-805.
Thalassemia is an inherited blood disorder that requires lifelong adherence to a complicated and burdensome medical regimen which could potentially impact emotional functioning of patients. The importance of understanding and promoting healthy emotional functioning is crucial not only to psychological well-being, but also to physical health as it has been shown to impact adherence to medical regimens [1–4]. The current study aimed to [1] determine the prevalence of depressive and anxiety symptoms in adolescent and adult patients with thalassemia; and [2] explore possible demographic, medical, and psychosocial correlates of these symptoms in 276 patients (14–58 years old, M age = 27.83; 52% female). Overall, most patients did not report experiencing significant symptoms of anxiety and depression (33% of participants indicated experiencing symptoms of anxiety and 11% symptoms of depression). Females and older patients were more likely to experience these symptoms than males and younger patients. Symptoms of anxiety and depression were positively associated with self-report of difficulty with adherence and negatively associated with quality of life. Given these findings, regular screening for anxiety and depression symptoms could help to identify at-risk individuals to provide them with appropriate psychological support with the goal of improving both emotional and physical health.
PMCID: PMC4251654  PMID: 20806230
14.  In Situ Analysis of Metabolic Characteristics Reveals the Key Yeast in the Spontaneous and Solid-State Fermentation Process of Chinese Light-Style Liquor 
Applied and Environmental Microbiology  2014;80(12):3667-3676.
The in situ metabolic characteristics of the yeasts involved in spontaneous fermentation process of Chinese light-style liquor are poorly understood. The covariation between metabolic profiles and yeast communities in Chinese light-style liquor was modeled using the partial least square (PLS) regression method. The diversity of yeast species was evaluated by sequence analysis of the 26S ribosomal DNA (rDNA) D1/D2 domains of cultivable yeasts, and the volatile compounds in fermented grains were analyzed by gas chromatography (GC)-mass spectrometry (MS). Eight yeast species and 58 volatile compounds were identified, respectively. The modulation of 16 of these volatile compounds was associated with variations in the yeast population (goodness of prediction [Q2] > 20%). The results showed that Pichia anomala was responsible for the characteristic aroma of Chinese liquor, through the regulation of several important volatile compounds, such as ethyl lactate, octanoic acid, and ethyl tetradecanoate. Correspondingly, almost all of the compounds associated with P. anomala were detected in a pure culture of this yeast. In contrast to the PLS regression results, however, ethyl lactate and ethyl isobutyrate were not detected in the same pure culture, which indicated that some metabolites could be generated by P. anomala only when it existed in a community with other yeast species. Furthermore, different yeast communities provided different volatile patterns in the fermented grains, which resulted in distinct flavor profiles in the resulting liquors. This study could help identify the key yeast species involved in spontaneous fermentation and provide a deeper understanding of the role of individual yeast species in the community.
PMCID: PMC4054142  PMID: 24727269
15.  Feasibility and safety of sorafenib treatment in hepatocellular carcinoma patients with spontaneous rupture 
World Journal of Gastroenterology : WJG  2014;20(43):16275-16281.
AIM: To report the outcome of patients with ruptured hepatocellular carcinoma (HCC) treated at a single center during a 5-year period.
METHODS: We retrospectively analyzed 32 patients who presented with ruptured HCC at Shandong Provincial Hospital Affiliated to Shandong University between 2008 and 2013.
RESULTS: The mean age of the patients was 53 years (range 39-71 years). Of these patients, 22 received surgical management, 10 underwent transarterial embolization (TAE) or transarterial chemoembolization (TACE), and 12 received sorafenib after surgery, TAE or TACE. Cumulative survival rates at 4, 8 and 12 mo were 72.9%, 50.0% and 33.3%, respectively, in the surgery only group and were 90.0%, 80.6% and 64.1%, respectively, in the surgery plus sorafenib group. Cumulative survival rates at 4, 8 and 12 mo were 68.4%, 43.6% and 19.4%, respectively, in the surgery only or TAE/TACE only groups, and were 91.7%, 75.0% and 60.2%, respectively, in the sorafenib combination groups (P = 0.04). No unexpected side effects due to sorafenib were observed. The most common side effect was hand-foot skin reaction. To date, 5 patients have died. Median follow-up from the start of sorafenib therapy for the remaining 7 patients is 12.7 mo (range 5.8-32.2 mo).
CONCLUSION: Sorafenib can be used in patients with ruptured HCC as it has interesting activity and is well tolerated; dose adjustment is generally not required. However, a larger prospective study is necessary to determine the efficacy of sorafenib in this group of patients.
PMCID: PMC4239517  PMID: 25473183
Sorafenib; Hepatocellular carcinoma; Spontaneous rupture; Efficacy; Safety
16.  Spontaneous Aching Pain and Peculiar Involuntary Movements: A Case Report of Painful Legs and Moving Toes and Review of the Literature 
Case Reports in Medicine  2014;2014:581402.
Painful legs and moving toes (PLMT) is a rare syndrome characterized by spontaneous neuropathic pain and peculiar involuntary movements in the lower limbs, especially the toes and feet. As it is a relatively rare disorder worldwide, the exact pathophysiology still remains a mystery. Until recently, numerous methods of clinical treatments have been tried; however, the success rate of the therapies is still very low. Here, we report a case of PLMT and also summarize the recent clinical and research literatures regarding clinical presentation, electrophysiological features, etiology, treatment methods, and prognosis of this disorder. Doctors should be aware of this rare syndrome in a patient with painful and/or restless legs. On the other hand, multiple clinical treatments should be tried, even those which usually produce a poor outcome.
PMCID: PMC4235185  PMID: 25530763
17.  Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice 
Pulmonary surfactant protein-C (SP-C) gene–targeted mice (Sftpc−/−) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc+/+ and Sftpc−/− mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc−/− mice at 3 and 5 days after the final dose. Compared with Sftpc+/+mice, inflammatory injury persisted in the lungs of Sftpc−/− mice 30 days after the final LPS challenge. Sftpc−/− mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc−/− type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc+/+ cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C–containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.
PMCID: PMC3931093  PMID: 23795648
surfactant protein-C; LPS; lung inflammation; type II cells; Toll-like receptor 4
18.  Moderate/Severe Hyponatremia Increases the Risk of Death among Hospitalized Chinese Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Patients 
PLoS ONE  2014;9(10):e111077.
To evaluate whether the serum sodium concentration is associated with the progression and long-term prognosis of Chinese HIV/AIDS patients.
Three hundred and eighty seven hospitalized patients were recruited into this retrospective cohort study. The strata of serum sodium concentration were moderate/severe hyponatremia, mild hyponatremia and normonatremia. Disease progression was estimated using CD4 counts and the WHO clinical stage. Correlation analysis was used to evaluate the serum sodium concentration with disease progression. The Kaplan-Meier method and the Cox proportional hazards model were used to analyze the effect of different serum sodium levels on survival.
In this study 206 patients (53.2%) had hyponatremia, including 10.6% patients with moderate/severe hyponatremia and 42.6% with mild hyponatremia. The serum sodium concentration was significantly correlated with the HIV/AIDS progression (P<0.001). During the follow-up, 100 patients (25.6%) died. The cumulative survival rates of HIV/AIDS patients were 47.8%±8.5% in patients with moderate/severe hyponatremia, 59.8%±5.0% with mild hyponatremia and 79.9%±3.4% with normonatremia (log-rank P<0.001). After adjusting for sex, age, WHO stage, CD4 count, hemoglobin and albumin, the relative hazard was 3.5 (95% CI: 1.9–6.5) for patients with moderate/severe hyponatremia (P<0.001), and 1.5 (95% CI: 0.9–2.4) for those with mild hyponatremia (P = 0.161), compared with normonatremic patients.
The serum sodium level is closely correlated with the severity of patients. Only moderate/severe hyponatremia affects the prognosis of Chinese HIV/AIDS patients. Earlier intensive medical managements(including HAART)are necessary to increase the survival rates of Chinese HIV/AIDS patients with moderate/severe hyponatremia.
PMCID: PMC4215865  PMID: 25360785
19.  Anatomical Entity Recognition with a Hierarchical Framework Augmented by External Resources 
PLoS ONE  2014;9(10):e108396.
References to anatomical entities in medical records consist not only of explicit references to anatomical locations, but also other diverse types of expressions, such as specific diseases, clinical tests, clinical treatments, which constitute implicit references to anatomical entities. In order to identify these implicit anatomical entities, we propose a hierarchical framework, in which two layers of named entity recognizers (NERs) work in a cooperative manner. Each of the NERs is implemented using the Conditional Random Fields (CRF) model, which use a range of external resources to generate features. We constructed a dictionary of anatomical entity expressions by exploiting four existing resources, i.e., UMLS, MeSH, RadLex and BodyPart3D, and supplemented information from two external knowledge bases, i.e., Wikipedia and WordNet, to improve inference of anatomical entities from implicit expressions. Experiments conducted on 300 discharge summaries showed a micro-averaged performance of 0.8509 Precision, 0.7796 Recall and 0.8137 F1 for explicit anatomical entity recognition, and 0.8695 Precision, 0.6893 Recall and 0.7690 F1 for implicit anatomical entity recognition. The use of the hierarchical framework, which combines the recognition of named entities of various types (diseases, clinical tests, treatments) with information embedded in external knowledge bases, resulted in a 5.08% increment in F1. The resources constructed for this research will be made publicly available.
PMCID: PMC4208750  PMID: 25343498
20.  False esophageal hiatus hernia caused by a foreign body: A fatal event 
World Journal of Gastroenterology : WJG  2014;20(39):14510-14514.
Foreign body ingestion is a common complaint in gastrointestinal clinics. It is usually not difficult to diagnose because most of the patients report a definitive history of accidental foreign body ingestion. However, in rare cases, patients do not have a clear history. Thus, the actual condition of the patient is difficult to diagnosis or is misdiagnosed; consequently, treatment is delayed or the wrong treatment is administered, respectively. This report describes a fatal case of esophageal perforation caused by an unknowingly ingested fishbone, which resulted in lower esophageal necrosis, chest cavity infection, posterior mediastinum fester, and significant upper gastrointestinal accumulation of blood. However, his clinical symptoms and imaging data are very similar with esophageal hiatal hernia. Unfortunately, because the patient was too late in consulting a physician, he finally died of chest infection and hemorrhage caused by thoracic aortic rupture. First, this case report underlines the importance of immediate consultation with a physician as soon as symptoms are experienced so as not to delay diagnosis and treatment, and thus avoid a fatal outcome. Second, diagnostic imaging should be performed in the early stage, without interference by clinical judgment. Third, when computed tomography reveals esophageal hiatus hernia with stomach incarceration, posterior mediastinal hematoma, and pneumatosis caused by esophageal, a foreign body should be suspected. Finally, medical professionals are responsible for making people aware of the danger of foreign body ingestion, especially among children, those who abuse alcohol, and those who wear dentures, particularly among the elderly, whose discriminability of foreign bodies is decreased, to avoid dire consequences.
PMCID: PMC4202382  PMID: 25339840
Esophageal hiatus hernia; Foreign body; Esophageal perforation; Gastrointestinal accumulation
21.  Critical Role of Water in the Binding of Volatile Anesthetics to Proteins 
The journal of physical chemistry. B  2013;117(40):12007-12012.
Numerous small molecules exhibit drug-like properties by low-affinity binding to proteins. Such binding is known to be influenced by water, the detailed picture of which, however, remains unclear. One particular example is the controversial role of water in the binding of general anesthetics to proteins as an essential step in general anesthesia. Here we demonstrate that a critical amount of hydration water is a prerequisite for anesthetic-protein binding. Using nuclear magnetic resonance, the concurrent adsorption of hydration water and bound anesthetics on model proteins are simultaneously measured. Halothane binding on proteins can only take place after protein hydration reaches a threshold hydration level of ~0.31 gram of water per gram of proteins at the relative water vapor pressure of ~0.95. Similar dependence on hydration is also observed for several other proteins. The ratio of anesthetic partial pressures at which two different anesthetics reach the same fractional load is correlated with the anesthetic potency. The binding of nonimmobilizers, which are structurally similar to known anesthetics but unable to produce anesthesia, does not occur even after the proteins are fully hydrated. Our results provide the first unambiguous experimental evidence that water is absolutely required to enable anesthetic-protein interactions, shedding new light on the general mechanism of molecular recognition and binding.
PMCID: PMC3901425  PMID: 24050264
interfacial water; anesthetic-protein interaction; protein hydration
22.  Total Syntheses of Proposed (±)-Trichodermatides B and C 
Tetrahedron letters  2013;54(41):10.1016/j.tetlet.2013.07.137.
Total syntheses of putative (±)-trichodermatides B and C are described. These efficient syntheses feature the oxa-[3 + 3] annulation strategy, leading to B and C along with their respective C2-epimers. However, these synthetic samples are spectroscopically very different from the natural products. DFT calculations of C13 chemical shifts are conducted and the predicted values are in good agreement with those of synthetic samples, thereby questioning in the accuracy of structural assignments of trichodermatides B and C.
PMCID: PMC3818125  PMID: 24223440
Trichodermatides; oxa-[3 + 3] annulation; biosynthesis; Davis’ oxaziridine; electrocyclic ring-opening; DFT calculations
23.  Open-Channel Structures of the Human Glycine Receptor α1 Full-Length Transmembrane Domain 
Structure (London, England : 1993)  2013;21(10):10.1016/j.str.2013.07.014.
Glycine receptors play a major role in mediating fast inhibitory neurotransmission in the spinal cord and brain stem, yet their high-resolution structures remain unsolved. We determined open-channel structures of the full-length transmembrane domain (TMD) of the human glycine receptor α1-subunit (hGlyR-α1) using NMR and electron micrographs. The hGlyR-α1 TMD spontaneously forms pentameric Cl−-conducting channels, with structures sharing overall topology observed in crystal structures of homologous bacterial and nematode pentameric ligand-gated ion channels (pLGICs). However, the mammalian hGlyR-α1 structures present several unique features, including a shorter helix of the pore-lining TM2 with helical unwinding near the C-terminal end, a TM3 helical kink at A288 that partially overlaps with the homologous ivermectin-binding site in GluCl, and a highly dynamic segment between S267(15′) of TM2 and A288 that likely affects allosteric modulations of channel function. The NMR structures provide new templates for identifying potential drug targets in GlyRs and other mammalian pLGICs.
PMCID: PMC3864581  PMID: 23994010
24.  Biogenesis of C-Glycosyl Flavones and Profiling of Flavonoid Glycosides in Lotus (Nelumbo nucifera) 
PLoS ONE  2014;9(10):e108860.
Flavonoids in nine tissues of Nelumbo nucifera Gaertner were identified and quantified by high-performance liquid chromatography with diode array detector (HPLC-DAD) and HPLC-electrospray ionization-mass spectrometry (HPLC-ESI-MSn). Thirty-eight flavonoids were identified; eleven C-glycosides and five O-glycosides were discovered for the first time in N. nucifera. Most importantly, the C-glycosyl apigenin or luteolin detected in lotus plumules proved valuable for deep elucidation of flavonoid composition in lotus tissues and for further utilization as functional tea and medicine materials. Lotus leaves possessed the significantly highest amount of flavonoids (2.06E3±0.08 mg 100 g−1 FW) and separating and purifying the bioactive compound, quercetin 3-O-glucuronide, from leaves showed great potential. In contrast, flavonoids in flower stalks, seed coats and kernels were extremely low. Simultaneously, the optimal picking time was confirmed by comparing the compound contents in five developmental phases. Finally, we proposed the putative flavonoid biosynthesis pathway in N. nucifera.
PMCID: PMC4184820  PMID: 25279809
25.  Mitogenic and Oncogenic Stimulation of K433 Acetylation Promotes PKM2 Protein Kinase Activity and Nuclear Localization 
Molecular cell  2013;52(3):340-352.
Alternative splicing of the PKM2 gene produces two isoforms, M1 and M2, which are preferentially expressed in adult and embryonic tissues, respectively. The M2 isoform is reexpressed in human cancer and has nonmetabolic functions in the nucleus as a protein kinase. Here, we report that PKM2 is acetylated by p300 acetyltransferase at K433, which is unique to PKM2 and directly contacts its allosteric activator, fructose 1,6-bisphosphate (FBP). Acetylation prevents PKM2 activation by interfering with FBP binding and promotes the nuclear accumulation and protein kinase activity of PKM2. Acetylationmimetic PKM2(K433) mutant promotes cell proliferation and tumorigenesis. K433 acetylation is decreased by serum starvation and cell-cell contact, increased by cell cycle stimulation, epidermal growth factor (EGF), and oncoprotein E7, and enriched in breast cancers. Hence, K433 acetylation links cell proliferation and transformation to the switch of PKM2 from a cytoplasmic metabolite kinase to a nuclear protein kinase.
PMCID: PMC4183148  PMID: 24120661

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