Accuracy of thoracic pedicle screw placement in adolescent patients with severe spinal deformities: a retrospective study comparing drill guide template with free-hand technique.

PURPOSE: Patients with severe spinal deformities often have small pedicle diameters, and pedicle dimensions vary between segments and individuals. Free-hand pedicle screw placement can be inaccurate. Individualized drill guide templates may be used, but the accuracy of pedicle screw placement in severe scoliosis remains unknown. The accuracy of drill guide templates and free-hand technique for the treatment of adolescent patients with severe idiopathic scoliosis are compared in this study. METHODS: This study included 37 adolescent patients (mean age 16.4 ± 1.3 years) with severe idiopathic scoliosis treated surgically at a single spine center between January 2014 and June 2017. Spinal deformities were corrected using posterior pedicle screw fixation. Patients in group I were treated with rapid prototype drill guide template technique (20 patients; 396 screws) and patients in group II were treated with free-hand technique (17 patients; 312 screws). Outcomes that included operative time, correction rate, and the incidence and distribution of screw misplacement were evaluated. RESULTS: Operative time in group I was 283 ± 22.7 min compared to 285 ± 25.8 min in group II (p = 0.89). The scoliosis correction rate was 55.0% in group I and 52.9% in group II (p = 0.33). Based on both axial and sagittal reconstruction images, the accuracy rate of pedicle screw placement was 96.7% in group I and 86.9% in group II (p = 0.000). CONCLUSION: The drill guide template technique has potential to offer more accurate and thus safer placement of pedicle screws than free-hand technique in the treatment of severe scoliosis in adolescents.

[Determination of biomarkers in exhaled breath condensation of acute exacerbation of chronic obstructive pulmonary disease and its clinical implications].

Objective: To analyse the changes and clinical implication of biomarkers in exhaled breath condensates (EBC) of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) before and after treatment. Methods: 20 patients with AECOPD were enrolled, including 15 males and 5 females. The average age was 71±10, ranging from 50-85. The concentrations of Leukotriene B4 (LTB4) and Interleukin 6 (IL-6) from EBC were assayed by ELISA kit before and after treatment. Serum inflammatory indexes, pulmonary function test and quality of life (CAT) were observed at the same time, the relationship between EBC biomarkers and clinical markers were investigated. Results: The concentration of LTB4 and IL-6 of AECOPD patients with treated [(20.79±2.27)ng/L, (0.39±0.18)ng/L, respectively], were significantly lower compared with that before treatment [(22.64±3.01)ng/L, (0.60±0.36)ng/L, P<0.05, respectively]. The percentage of neutrophils, CRP were decreased after treatment. But no correlation was found between LTB4, IL-6 and serum inflammatory indexes, pulmonary function or CAT(P>0.05). Conclusion: The concentration of biomarkers (LTB4, IL-6) in EBC of AECOPD patients can dynamically monitor the inflammation in respiratory tract and evaluate the therapeutic effect.

[Effect of asymmetrical dimethylarginine for predicting pro-thrombotic risk in atrial fibrillation].

OBJECTIVE: Atrial fibrillation (AF) is responsible for some thromboembolic events. Asymmetrical dimethylarginine(ADMA) increases in atrial fibrillation(AF) animals with dysfunction of endothelium, but its role in pro-thrombotic state of AF was unknown. The aim of our study was to explore the role of ADMA in predicting the pro-thrombotic state in AF and to reveal its mechanism. METHODS: One hundred and thirty-eight patients in the First Affiliated Hospital, Sun Yat-sen University, from 2010 to 2012, were enrolled (persistent atrial fibrillation group, PAF, n=80; paroxysmal atrial fibrillation group, Paf, n=30; sinus rhythm, SR, n=28). Plasma ADMA levels were detected by ELISA-kits. CHADS2 and CHA2DS2-VASc scores were estimated for each patient.14 Beagles (pacing group, n=8; sham group, n=6) were subjected to rapid atrial pacing (RAP). ADMA level was detected after 4 weeks of RAP. RESULTS: ADMA level was elevated significantly in patients with atrial fibrillation especially in patients with persistent atrial fibrillation, and showed a significant linear correlation to CHADS2 and CHA2DS2-VASc score. With ADMA, ROC area under the curve was 0.865 in CHADS2 score ≥2 and was 0.959 in CHA2DS2-VASc score ≥2 (P<0.001 respectively). After 4 weeks of RAP, ADMA level was elevated compared to sham group and before operation. ADMA showed a linear correlation with atrial fibrillation susceptibility(r=0.686, P=0.007). CONCLUSIONS: ADMA levels are elevated both in AF patients and RAP beagles. ADMA correlates with stroke risk concerning with CHADS2/CHA2DS2-VASc score. ADMA may become a new biomarker for predicting pro-thrombotic risk in AF.

Biomarker responses in fish exposed to sediments from northern Taihu Lake.

Our study investigated multiple biomarker responses of goldfish exposed to sediments collected from northern Taihu Lake. The activities of acetylcholinesterase, 7-ethoxyresorufin-O-deethylase, glutathione-S-transferase and superoxide dismutase did not differ significantly from controls following exposure to sediment from the center of the lake. However, sediment collected from the northern bays did significantly alter enzymatic activities. An integrated biomarker response (IBR) was calculated and used to evaluate the impact of pollutants from different stations. The results indicated that Mashan in Meiliang Bay and Xiaogongshan in Gong Bay were the most stressful places for fish. Sediment polychlorinated biphenyl and polybrominated diphenyl ether concentrations were associated with IBR variation.

Mechanisms for <100> interstitial dislocation loops to diffuse in BCC iron.

The mobility of dislocation loops in materials is a principle factor in understanding the mechanical strength, and the evolution of microstructures due to deformation and radiation. In body-centered cubic (BCC) iron, the common belief is that <100> interstitial dislocation loops are immobile once formed. However, using self-adaptive accelerated molecular dynamics (SSAMD), a new diffusion mechanism has been discovered for <100> interstitial dislocation loops. The key aspect of the mechanism is the changing of the habit planes between the {100} plane and the {110} plane, which provides a path for the <100> loops to diffuse one-dimensionally. The migration behavior modeled with SSAMD is further confirmed by in-situ transmission electron microscopy (TEM) measurements, and represents a significant step for understanding the formation of <100> loop walls and the mechanical behavior of BCC Fe under irradiation.

A synonymous mutation in IGF-1 impacts the transcription and translation process of gene expression.

Insulin-like growth factor 1 (IGF-1) is considered to be a crucial gene in the animal development of bone and body size. In this study, a unique synonymous mutation (c.258 A > G) of the IGF-1 gene was modified with an adenine base editor to observe the growth and developmental situation of mutant mice. Significant expression differences and molecular mechanisms among vectors with different alanine synonymous codons were explored. Although modification of a single synonymous codon rarely interferes with animal phenotypes, we observed that the expression and secretion of IGF-1 were different between 8-week-old homozygous (Ho) and wild-type (WT) mice. In addition, the IGF-1 with optimal codon combinations showed a higher expression content than other codon combination modes at both transcription and translation levels and performed proliferation promotion. The gene stability and translation initiation efficiency also changed significantly. Our findings illustrated that the synonymous mutation altered the IGF-1 gene expression in individual mice and suggested that the synonymous mutation affected the IGF-1 expression and biological function through the transcription and translation processes.

Integrated biomarker response index for the assessment of environmental stress of the Yangtze River (Nanjing section).

In the present study, multibiomarker effects of the river water of three representative sections in Nanjing section of the Yangtze River were investigated in goldfish (Carassius auratus). The organic toxicants were extracted from the water samples using solid phase extraction. Acetylcholinesterase (AChE), glutathione-S-transferase (GST), 7-ethoxyresorufin-O-deethylase (EROD), glutathione peroxidase (GPx) and Na+/K+-ATPase activities were determined after exposure of the extracted components. The fractions of water samples from three sections (Daqiao, Sanchahe and Jiangxinzhou) altered these enzymatic activities. With the change of the extracts polarity, the levels of AChE, GST, EROD, Na+/K+-ATPase activities were different. The responses of enzymatic activities were mostly significant for those exposures of intermediate polar components (50-80% methanol extracts) and weakly polar components (ether and ether/hexane extracts). It has been shown that toxicants were mainly concentrated in these fractions in the Yangtze River (Nanjing section). With regard to response for different sections, EROD and GST activities seem to be more sensitive biomarkers. Integrated biomarker response index (IBR) were calculated and used to evaluate an integrated impact of pollutants from different sampling sections. The order of negative biological effects of the three sections was Jiangxinzhou>Sanchahe>Daqiao. The wild fish living in Nanjing section of the Yangtze River were at potential ecological risk.

Study on environmental estrogen pollution in Yangtze River (Nanjing section) by an in vivo bioassay.

Estrogenic activities and main causative fractions in three representative sections of Yangtze River (Nanjing section) were determined. The results showed that significant vitellogenin (VTG) and 17beta-estradiol (E(2)) induction and gonad atrophy were observed. Estradiol equivalents of actual water samples from Jiangxinzhou section, Sanchahe section and Daqiao section were 0.3651, 0.1301 and 0.5060 ng L(-1), respectively. Polar contaminants were responsible for the estrogenic activities in Jiangxinzhou section and Daqiao section while mid-polar and nonpolar contaminants resulted in majority of the estrogenic activity in Sanchahe section. To Jiangxinzhou section, Sanchahe section and Daqiao section, good positive correlations between VTG and E(2) (the correlation coefficients were 0.737, 0.690 and 0.817, respectively) and good inverse correlations between VTG and gonado-somatic index (GSI; the correlation coefficients were -0.838, -0.540 and -0.794, respectively) were obtained, whereas the correlations between E(2) and GSI were relatively poor (the correlation coefficients were only -0.557, -0.620 and -0.509, respectively).

[Clinical characteristics and survival analysis of 15 cases of HIV-negative plasmablastic lymphoma].

Objective: To evaluate the clinicopathologic characteristics and outcomes of HIV-negative plasmablastic lymphoma (PBL) . Methods: Medical records of 15 patients diagnosed with HIV-negative PBL in Changhai Hospital between January 2013 and August 2019 were reviewed, and clinicopathologic characteristics and outcomes were analyzed. Results: Median age was 59 years (range: 17-69) . All patients had extranodal involvement. According to the Cotswolds-modified Ann Arbor staging system, 1 (6.7%) , 2 (13.3%) , 3 (20.0%) , and 9 (60.0%) patients were classified as at Ⅰ,Ⅱ,Ⅲ and Ⅳ, respectively. Plasmablast and immunoblast proliferations were typical manifestations of PBL. Immunohistochemical staining showed tumor cells were diffusely positive for plasma cell markers CD38, CD138, and Mum-1, while negative for B cell markers CD20, CD10, PAX-5, and BCL-6. Median Ki-67 index was 80% (70%-90%) . Epstein-Barr virus-encoded RNA (EBER) expression was detected in 3 patients, and 1 of them was positive. All patients received chemotherapy, 80% combined with bortezomib as the first line, and responses were observed in 8 patients (6 complete and 2 partial responses) . Median progression-free survival (PFS) and overall survival (OS) were 6.8 (95% CI 2.5-11.1) months and 17.9 (95% CI 5.6-30.2) months, the 3-year PFS and OS rates were 21.2% (95% CI 1.4%-56.8%) and 38.5% (95% CI 12.0%-65.0%) , respectively. Conclusion: HIV-negative PBL with high invasiveness is extremely prone to extranodal involvement and most patients were at the advanced stage. Patients receiving an intensive therapy combined with bortezomib and bridged autologous stem cell transplantation may improve long-time survival.

The dose-response relationships for EROD and GST induced by polyaromatic hydrocarbons in Carassius auratus.

Freshwater fish Carassius auratus were chosen as experimental animals, the hepatic biochemical responses to medium-term exposure of five PAHs were measured as ethoxyresorufin O-deethylase (EROD) activity (phase I) and glutathione S-transferase (GST) activity (phase II) to assess sub-lethal effects. The fold increases of EROD and GST activity were calculated and both increased in the order Fluoranthene < Fluorene < Benzo(b)fluoranthene < Benzo(g,h,i)perylene < Indeno(1,2,3-cd)-pyrene. The clear dose-response relationships were found for liver EROD and GST activity induced by PAHs. The enzyme EROD and GST in Carassius auratus were confirmed as useful biomarkers of exposure to both PAH and PAH-like compounds.

Joint toxicity evaluation and QSAR modeling of aromatic amines and phenols to bacteria.

Acute toxicity of aromatic amines and phenols and their mixtures to bacteria in natural waters was determined and the median inhibition concentration IC(50) values for single compounds and IC(50mix) values for binary and multiple mixtures were obtained. Based on the quantitative structure-activity relationship model for single chemical toxicity, a two-descriptor model accounting for n-octanol/water partition coefficient (log P(mix)) and the energy of the lowest unoccupied molecular orbital (E(LUMOmix)) was developed for the toxicity of a mixture: log(1/IC(50mix) = 0.326 log P(mix) - 0.660E(LUMOmix) + 3.323 (n = 32, R(2) = 0.834). This model can be used successfully to predict the toxicity of a mixture, whether binary mixtures or multiple mixtures of three or four chemicals are used as predictors.

Involvement of LeMRP, an ATP-binding cassette transporter, in shikonin transport and biosynthesis in Lithospermum erythrorhizon.

Shikonin and its derivatives are important medicinal secondary metabolites accumulating in roots of Lithospermum erythrorhizon. Although some membrane proteins have been identified as transporters of secondary metabolites, the mechanisms underlying shikonin transport and accumulation in L. erythrorhizon cells still remain largely unknown. In this study, we isolated a cDNA encoding LeMRP, an ATP-binding cassette transporter from L. erythrorhizon, and further investigated its functions in the transport and biosynthesis of shikonin using the yeast transformation and transgenic hairy root methods, respectively. Real-time PCR was applied for expression analyses of LeMRP and shikonin biosynthetic enzyme genes. Functional analysis of LeMRP using the heterologous yeast cell expression system showed that LeMRP could be involved in shikonin transport. Transgenic hairy roots of L. erythrorhizon demonstrated that LeMRP overexpressing hairy roots produced more shikonin than the empty vector (EV) control. Real-time PCR results revealed that the enhanced shikonin biosynthesis in the overexpression lines was mainly caused by highly up-regulated expression of genes coding key enzymes (LePAL, HMGR, Le4CL and LePGT) involved in shikonin biosynthesis. Conversely, LeMRP RNAi decreased the accumulation of shikonin and effectively down-regulated expression level of the above genes. Typical inhibitors of ABC proteins, such as azide and buthionine sulphoximine, dramatically inhibited accumulation of shikonin in hairy roots. Our findings provide evidence for the important direct or indirect role of LeMRP in transmembrane transport and biosynthesis of shikonin.

Qualitative and quantitative analyses of nucleosides and nucleobases in Ganoderma spp. by HPLC-DAD-MS.

A high-performance liquid chromatography-diode array detector-mass spectrometry (HPLC-DAD-MS) analytical method was developed for detection of the nucleosides and nucleobases in two species of Lingzhi, the dried sporophore of Ganoderma lucidum and G. sinense. The method, combining advantages of both DAD and MS, was successfully used to qualitatively identify for six nucleosides namely, adenosine, cytidine, guanosine, inosine, thymidine, uridine and five nucleobases namely, adenine, guanine, hypoxanthine, thymine and uracil in Lingzhi samples. Quantitative analyses showed that uridine was the most abundant nucleoside in these Lingzhi samples and the contents of nine target analytes were found to be different in pileus and stipes of the fruiting bodies and among the different species of G. spp. The established method might apply as an alternative approach for the quality assessment of Lingzhi.

Perfluoroalkyl substances in waters along the Grand Canal, China.

The Grand Canal, also known as the Beijing-Hangzhou Grand Canal, is a UNESCO World Heritage Site and the longest canal in the world. It is an important trunk line of the South-to-North Water Diversion Project in China. The contamination status and spatial distributions of perfluoroalky substances (PFASs) in waters of the Grand Canal were investigated. The total concentrations of PFASs (∑PFASs) range from 7.8 ng/L to 218.0 ng/L, with high ∑PFASs occurring in the southern part of the Grand Canal which is located in a highly urbanized and economically developed region. The dominance of PFOA showed a decreasing trend toward north while shorter chain homologue proportions increased in the northern part of the Canal which mainly traverses underdeveloped and rural areas in Eastern China. Positive correlations were observed between ∑PFASs and the population density as well as GDP per capita. Intersection with large rivers may affect the contamination levels and composition of PFASs in the water of the Grand Canal near the intersection sites.

Nonpeptide angiotensin II receptor antagonists. 1. Synthesis and in vitro structure-activity relationships of 4-[[[(1H-pyrrol-1-ylacetyl)amino]phenyl]methyl]imidazole derivatives as angiotensin II receptor antagonists.

A novel series of non-biphenylyltetrazole angiotensin II receptor antagonists which contain a 1H-pyrrol-1-ylacetyl residue in place of the benzoyl residue in EXP 6803 have been developed. The receptor binding activity of several members of this new series was in the 10(-8) M range, which was better than that of EXP 6803. Introduction of a carboxylic acid moiety at the 2-position of the pyrrole ring enhanced the in vitro binding affinity at the receptor by 10-fold. Compounds containing an acetic acid (18) or a propionic acid residue (20) at the 5-position of the imidazole were more potent than the carboxylic acid analogue (24). The binding IC50 of the most potent compound 20 was 22 nM. Compounds 18, 20, and 24 in their best fit conformations were manually overlayed on that of the template conformation of EXP 6803 and EXP 8623, respectively. The synthesis and structure-activity relationship data are described.

Design of peptidomimetics that inhibit the association of phosphatidylinositol 3-kinase with platelet-derived growth factor-beta receptor and possess cellular activity.

Phosphorylated tyrosine residues of growth factor receptors that associate with intracellular proteins containing src-homology 2 (SH2) domains are integral components in several signal transduction pathways related to proliferative diseases such as cancer, atherosclerosis, and restenosis. In particular, a phosphorylated pentapeptide [pTyr751-Val-Pro-Met754-Leu (pTyr = phosphotyrosine)] derived from the primary sequence of platelet-derived growth factor-beta (PDGF-beta) receptor blocks the association of the C-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) to PDGF-beta receptor with an IC50 of 0.445 +/- 0.047 microM. Further evaluation of the structure-activity relationships for pTyr751-Val-Pro-Met-Leu resulted in the design of smaller peptidomimetics with enhanced affinity including Ac-pTyr-Val-Ala-N(C6H13)2 (IC50 = 0.076 +/- 0.010 microM). In addition, the phosphotyrosine residue was replaced with a difluorophosphonate derivative [4-phosphono(difluoromethyl)phenylalanine (CF2Pmp)] which has been shown to be stable to cellular phosphatases. The extracellular administration of either CF2Pmp-Val-Pro-Met-Leu or Ac-CF2Pmp-Val-Pro-Met-NH2 in a whole cell assay resulted in specific inhibition of the PDGF-stimulated association from the C-terminal SH2 domain of the p85 subunit of PI 3-kinase to the PDGF-beta receptor in a dose-dependent manner. These compounds were also effective in inhibiting GLUT4 translocation, c-fos expression, and cell membrane ruffling in single-cell microinjection assay.

Multiple binding modes for the receptor-bound conformations of cyclic AII agonists.

Angiotensin II, Asp-Arg-Val-Tyr-His-Pro-Phe, binds its receptor with a postulated turn centered at residue four. Analogs of angiotensin II which contain a disulfide bridge between the side chains of residues 3 and 5 retain significant activity consistent with this hypothesis. Incorporation of 4-mercaptoproline residues, a hybrid, or chimeric amino acid which combines the properties of proline and homocysteine, into either of these positions with analogous disulfide bridges allows retention of high affinity for the receptor. These more highly constrained bicyclic systems give new insight into the details of molecular recognition of residues 3-5 of angiotensin by the receptor. Retention of activity by the antiparallel dimer of [Sar1,Cys3,5]-AII in which the peptide backbone is held in an extended conformation was unexpected. Analysis of the conformational constraints imposed in these active analogs suggests that AII agonists bind to their receptor with different backbone conformations in the region of the central tyrosine residue.

Synthesis and structure-activity relationships of 7-substituted 3-(2, 6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones as selective inhibitors of pp60(c-src).

7-substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones are potent inhibitors of protein tyrosine kinases, with some selectivity for c-Src. The compounds were prepared by condensing 4, 6-diaminonicotinaldehyde with 2,6-dichlorophenylacetonitrile and selectively converting the 2- and 7-amino groups of the product to hydroxy and fluoro groups, respectively, by prolonged diazotization in 50% aqueous fluoboric acid. N-Methylation, followed by treatment with aliphatic diamines, aromatic amines, or their derived lithium anions, gave the desired compounds. Selected isomeric 1, 8-naphthyridin-2(1H)-ones were also prepared in order to evaluate the relative contributions of both ring A aza atoms of the related pyrido[2,3-d]pyrimidin-7(8H)-ones to the inhibitory activity. The compounds were evaluated for their ability to prevent phosphorylation of a model substrate by c-Src, FGF-1 receptor, and PDGF-beta receptor enzymes. Overall, there was a high degree of correlation of the activities against the different kinases, with c-Src being generally the most sensitive to structural changes. 1, 6-Naphthyridin-2(1H)-one analogues bearing basic aliphatic side chains [7-NH(CH(2))(n)()NRR, 7-NHPhO(CH(2))(n)()NRR, or 7-NHPhN(CH(2))(4)NMe] were the most potent against c-Src (IC(50)s of 10-80 nM), showing good selectivity with respect to PDGFR (10-300-fold) but less with respect to FGFR. The 1, 6-naphthyridin-2(1H)-ones showed broadly similar activity to the analogous pyrido[2,3-d]pyrimidin-7(8H)-ones, whereas the 1, 8-naphthyridin-2(1H)-ones were at least 10(3)-fold less potent. These results, indicating that the 3-aza atom in the pyrido[2, 3-d]pyrimidin-7(8H)-ones is mandatory, whereas the 1-aza atom is not, support the published binding model for these compounds to c-Src (J. Med. Chem. 1998, 41, 1752), where the 3-aza and 2-NH atoms form a bidentate H-bond donor-acceptor motif that interacts with Met341 and the 1-aza atom is not involved in specific binding interactions.

Structure-activity relationships for 5-substituted 1-phenylbenzimidazoles as selective inhibitors of the platelet-derived growth factor receptor.

Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR), further structure-activity relationships for analogues (particularly 5-substituted derivatives) are reported. The data are consistent with a binding model (constructed from the homology-modeled structure of the catalytic subunit of the PDGFR using protein kinase A as the template) in which the ligand binds in the relatively narrow ATP site, with the phenyl ring pointing toward the interior of the pocket and the 5-position of the benzimidazole ring toward the mouth of the pocket. The narrow binding pocket allows a maximum torsion angle between the phenyl and benzimidazole rings of about 40 degrees, consistent with that calculated (43.6 degrees) for the minimum-energy conformation of the unsubstituted free ligand. The inactivity of 7- or 2'-substituted analogues is consistent with the greater torsion angle (and thus larger ligand cross-section) of such substituted analogues. There is substantial bulk tolerance for 5-substituents, which protrude out of the mouth of the hydrophobic pocket, with the most effective analogues being those bearing weak bases. On the basis of this model, 5-OR derivatives bearing cationic side chains were prepared as soluble analogues, and these showed sub-micromolar potencies against the isolated PDGFR enzyme. They were also moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic vascular smooth muscle cells, with IC50s in the range 0.1-1 microM.