bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultra‐performance liquid chromatography tandem mass spectrometry method for the determination of AZ66, a sigma receptor ligand, in rat plasma and its application to in vivo pharmacokinetics
Authors: Jamalapuram Seshulatha , Vuppala Pradeep Kumar , Abdelazeem Ahmed H. , McCurdy Christopher R. , Avery Bonnie A.
Published: April 2013

Methamphetamine abuse continues as a major problem in the USA owing to its powerful psychological addictive properties. AZ66, 3‐[4‐(4‐cyclohexylpiperazine‐1‐yl)pentyl]‐6‐fluorobenzo[d]thiazole‐2(3H)‐one, an optimized sigma receptor ligand, is a promising therapeutic agent against methamphetamine. To study the in vivo pharmacokinetics of this novel sigma receptor ligand in rats, a sensitive ultra‐performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed in rat plasma and validated. The developed method requires a small volume of plasma (100 μL) and a simple liquid–liquid extraction. The chromatographic separations were achieved in 3.3 min using an Acquity UPLC BEH Shield RP18 column. The mass spectrophotometric detection was carried out using a Waters Micromass Quattro MicroTM triple‐quadrupole system. Multiple reaction monitoring was used for the quantitation with transitions m/z 406 → m/z 181 for AZ66 and m/z 448 → m/z 285 for aripiprazole. The method was validated over a concentration range of 1–3500 ng/mL and the lower limit of quantitation was determined to be 1 ng/mL. Validation of the assay demonstrated that the developed UPLC/MS/MS method was sensitive, accurate and selective for the determination of AZ66 in rat plasma. The present method has been successfully applied to an i.v. pharmacokinetic study in Sprague–Dawley rats. Copyright © 2013 John Wiley & Sons, Ltd.
Optimization of Ultrasonic Enhanced Salt‐Containing Hydrodistillation by Response Surface Methodology
Authors: Yu S. , Xie X. , Li S. , Li W.
Published: April 2013

An ultrasonic enhanced salt‐containing hydrodistillation (UESHD) method for separating essential oil from lavender (Lavandula angustifolia) flowers was investigated using response surface methodology (RSM). The experimental data obtained from a 27‐run experiment were fitted to a second‐order polynomial equation. The optimal conditions were determined by the 3D response surface and the contour plots derived from the models. The efficiency of UESHD and conventional hydrodistillation (HD) was compared. The extraction yield of UESHD was two‐fold higher than that of HD. In addition, GC‐MS results indicated some differences in composition and content between the two essential oils from UESHD and HD.
An Experimental Study on Binderless Briquetting of Low‐Rank Coals
Authors: Han Y. , Tahmasebi A. , Yu J. , Li X. , Meesri C.
Published: April 2013

The potential of binderless briquetting as a means of transforming low‐rank coals into low moisture high grade solid fuel products has been studied. Using two dried low‐rank coals, binderless briquettes with high mechanical strength have been successfully produced through mechanical compression. An increase in heating value was achieved as a result of moisture reduction in the briquettes compared to as‐received coals. The residue moisture content in the briquettes had a predominant effect on briquetting characteristics and there existed an optimum moisture content for the maximum briquettes strength. The chemical structure and wettability of binderless briquettes were analyzed using FTIR and contact angle measurement. The results showed that hydrophobicity and chemical structure significantly affected the briquette properties.
Induction of Motion in a Synthetic Molecular Machine: Effect of Tuning the Driving Force
Authors: Baggerman Jacob , Haraszkiewicz Natalia , Wiering Piet G. , Fioravanti Giulia , Marcaccio Massimo , Paolucci Francesco , Kay Euan R. , Leigh David A. , Brouwer Albert M.
Published: April 2013

Rotaxane molecular shuttles were studied in which a tetralactam macrocyclic ring moves between a succinamide station and a second station in which the structure is varied. Station 2 in all cases is an aromatic imide, which is a poor hydrogen‐bond acceptor in the neutral form, but a strong one when reduced with one or two electrons. When the charge density on the hydrogen‐bond‐accepting carbonyl groups in station 2 is reduced by changing a naphthalimide into a naphthalene diimide radical anion, the shuttling rate changes only slightly. When station 2 is a pyromellitimide radical anion, however, the shuttling rate is significantly reduced. This implies that the shuttling rate is not only determined by the initial unbinding of the ring from the first station, as previously supposed. An alternative reaction mechanism is proposed in which the ring binds to both stations in the transition state.
A Novel Approach for the Evaluation of Positive Cooperative Guest Binding: Kinetic Consequences of Structural Tightening
Authors: Carrillo Romen , Morales Ezequiel Q. , Martín Víctor S. , Martín Tomás
Published: April 2013

Cooperativity is one of the most relevant features displayed by biomolecules. Thus, one of the challenges in the field of supramolecular chemistry is to understand the mechanisms underlying cooperative binding effects. Traditionally, cooperativity has been related to multivalent receptors, but Williams et al. have proposed a different interpretation based on the strengthening of noncovalent interactions within receptors upon binding. According to such an interpretation, positive cooperative binding operates through structural tightening. Hence, a quite counterintuitive kinetic behavior for positively cooperative bound complexes may be postulated: the more stable the complex, the slower it is formed. Such a hypothesis was tested in a synthetic system in which positive cooperative binding was previously confirmed by calorimetric experiments. Indeed, a linear correlation between the thermodynamics (ΔG°) and the kinetics (ΔG≠) of guest binding confirmed the expected behavior. These distinctive kinetics provide solid evidence of positive cooperative guest binding, which is particularly useful bearing in mind that kinetic experiments are frequently and accurately carried out in both synthetic and biological systems.
Patient–physician communication about code status preferences
Authors: Rhondali Wadih , Perez‐Cruz Pedro , Hui David , Chisholm Gary B. , Dalal Shalini , Baile Walter , Chittenden Eva , Bruera Eduardo
Published: April 2013

BACKGROUND

Code status discussions are important in cancer care, but the best modality for such discussions has not been established. The objective of this study was to determine the impact of a physician ending a code status discussion with a question (autonomy approach) versus a recommendation (beneficence approach) on patients' do‐not‐resuscitate (DNR) preference.

METHODS

Patients in a supportive care clinic watched 2 videos showing a physician–patient discussion regarding code status. Both videos were identical except for the ending: one ended with the physician asking for the patient's code status preference and the other with the physician recommending DNR. Patients were randomly assigned to watch the videos in different sequences. The main outcome was the proportion of patients choosing DNR for the video patient.

RESULTS

A total of 78 patients completed the study, and 74% chose DNR after the question video, whereas 73% chose DNR after the recommendation video. Median physician compassion score was very high and not different for both videos. All 30 of 30 patients who had chosen DNR for themselves and 30 of 48 patients who had not chosen DNR for themselves chose DNR for the video patient (100% versus 62%). Age (odds ratio = 1.1/year) and white ethnicity (odds ratio = 9.43) predicted DNR choice for the video patient.

CONCLUSIONS

Ending DNR discussions with a question or a recommendation did not impact DNR choice or perception of physician compassion. Therefore, both approaches are clinically appropriate. All patients who chose DNR for themselves and most patients who did not choose DNR for themselves chose DNR for the video patient. Age and race predicted DNR choice. Cancer 2013;119:2067–2073. © 2013 American Cancer Society.
SIN1 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial‐mesenchymal transition
Authors: Xu Jiangfeng , Li Xuedong , Yang Hao , Chang RuiMin , Kong Chenchen , Yang Lianyue
Published: April 2013

BACKGROUND

Stress‐activated protein kinase (SAPK) interacting protein 1 (SIN1) is essential for early embryonic development and is the key regulator of Akt, which plays an important role in various pathological conditions such as cancer. However, the biological function and clinical significance of SIN1 in hepatocellular carcinoma (HCC) remains unknown.

METHODS

Real‐time quantitative reverse‐transcriptase polymerase chain reaction analysis, western blot analysis, and immunohistochemical staining were used to test the expression level of SIN1, and its correlation with clinicopathologic parameters as well as the prognosis for patients with HCC were analyzed. In addition, the biological function and molecular mechanisms of SIN1 in HCC were investigated.

RESULTS

SIN1 levels were elevated predominantly in HCC tissues, and its level in solitary large HCC was significantly lower than those in nodular HCC (P = .016), but showed no significant differences between solitary large HCC and small HCC (P > .05). Levels of SIN1 were up‐regulated in highly metastatic HCC cell lines (HCCLM3 and MHCC97‐H), whereas their invasion and migration significantly decreased after depletion of SIN1. High expression of SIN1 was associated with tumor number (P = .012), capsular formation (P = .037), and venous invasion (P = .023) and was an independent risk factor for overall survival (P = .046). Finally, SIN1 was capable of promoting invasion and metastasis of HCC by facilitating epithelial‐mesenchymal transition.

CONCLUSIONS

The current findings suggest that SIN1 plays an important role in HCC invasion and metastasis by facilitating epithelial‐mesenchymal transition. Cancer 2013;119:2247–2257. © 2013 American Cancer Society.
Chiral Induction and Amplification in Supramolecular Systems at the Liquid–Solid Interface
Authors: Xu Hong , Ghijsens Elke , George Subi J. , Wolffs Martin , Tomović Željko , Schenning Albertus P. H. J. , De Feyter Steven
Published: April 2013

Chiral induction and amplification in surface‐confined supramolecular monolayers are investigated at the liquid–solid interface. Scanning tunneling microscopy (STM) proves that achiral molecules can self‐assemble into globally chiral patterns through a variety of approaches, including induction by chiral solvents or by a novel chiral amplification method. Our study demonstrates the aptness of both approaches, which have already been applied to (supramolecular) polymers in solution, to create chiral supramolecular monolayers at the liquid–solid interface.
Naloxone Reverses the Antinociceptive Synergistic Interaction Between Acetaminophen and Lysine Clonixinate in the Formalin Test
Authors: Isiordia‐Espinoza Mario A. , Tiznado‐Orozco Gaby E. , Pozos‐Guillén Amaury de J.
Published: April 2013

Preclinical Research

The purpose of this study was to evaluate the antinociceptive interaction between acetaminophen and lysine clonixinate in the formalin test, and the possible role of opioidergic and nitric oxide pathways in the interaction. The effect of individual drugs and their combination was evaluated using the 3% formalin test in mice. Acetaminophen (31.6, 100, 178, and 316 mg/kg, i.p.) or lysine clonixinate (5.6, 10, 17.8, and 31.6 mg/kg, i.p.) were administered 10 min before formalin injection. To assess the possible mechanism(s) of action for the combination, naloxone (1 mg/kg) and N (G)‐nitro‐L‐arginine methyl ester (L‐NAME) (3 mg/kg) were used. Isobolographic analysis and the interaction index showed a synergistic effect. The experimental ED30 was lower when compared with theoretical ED30. Naloxone, but not L‐NAME, reduced the antinociceptive effect of the combination. Administration of antagonists alone did not modify formalin‐induced nociception. These data suggest that the acetaminophen–lysine clonixinate combination produces a synergistic effect involving opioid receptors.
Functionalized Carbon Nanotubes with Self‐Templating Assembly Behavior
Authors: Lei Youan , Du Lingzhi
Published: April 2013

We report the design, synthesis, and assembly of functionalized carbon nanotubes (f‐CNTs) in the absence of other templates by using a polysiloxane quaternary ammonium salt. Specifically, the perpendicular organic coating has a depth of ca. 3.2 nm and its hydrophobic nature provides the hydrophobic interactions (driving force) between near‐neighbor CNTs. Once a complete coverage (ca. 100 %) of CNTs is achieved, the upper‐layer nanotubes can spontaneously and readily interact with the sublayer tubes to assemble into oriented nanostructures with a tube distance of 26 nm along the tube axis. Therefore, the spontaneous assembly of f‐CNTs in aqueous solution becomes possible without the help of other templates. Additionally, further investigations suggest that it is easier to obtain arrayed nanostructures with straight f‐CNTs with 100 % coverage than with curved ones. Our strategy seems very attractive because the aligned CNT array can be achieved through simple control of the chemical functionalization of the nanotubes. This offers us a valuable insight into the bottom‐up design of f‐CNTs, one‐dimensional nanostructures, and building blocks for supramolecular chemistry and nanotechnology.
Molecular Tweezers with Freely Rotating Linker and Porphyrin Moieties
Authors: Murphy Rhys B. , Pham Duc‐Truc , Lincoln Stephen F. , Johnston Martin R.
Published: April 2013

Molecular tweezers were synthesised by using a microwave accelerated alkene plus cyclobutane epoxide reaction between norbornyl appended porphyrin moieties and a diepoxide functionalised phenyl diimide spacer. The tweezers contain several rotational degrees of freedom; about the porphyrin with respect to the norbornyl linker, and between the two norbornyl backbone sections. The ability of ZnII metallated tweezer 1 to complex 1,4‐diazabicyclo[2.2.2]octane (DABCO) was studied by UV/Vis and 1H NMR spectroscopy and multivariate global spectral analysis. The system was found to form a strong 1:1 intramolecular complex (1:DABCO) with an association constant of K11 = 8.1 × 107 M–1, transforming to a 1:2 open complex [1:(DABCO)2] with K12 = 2.7 × 109 M–2 at high concentrations of DABCO.
Approximating peak responses in seismically isolated buildings using generalized modal analysis
Authors: Becker Tracy C. , Mahin Stephen A.
Published: April 2013

Although the ability to simulate accurately the detailed behavior of nonlinear isolation bearings and the effects of this nonlinearity on dynamic response of the isolated building is desirable, such detailed analyses are not feasible during initial design stages when bearing properties are being selected. However, it would be very beneficial to be able to estimate accurately key engineering demand parameters at the early stages of design to understand the dynamic response characteristics of the isolated structure and to balance and optimize the bearing and structural characteristics to achieve the performance goals set for the building. Unfortunately, classical modal response spectrum analysis methods do not provide accurate results for problems with large, nonclassical damping, as is characteristic of isolated buildings. To find a method capable of predicting peak building responses even with large nonclassical damping, generalized modal response spectrum analysis is implemented. The responses of several buildings having different heights and isolated by linear viscous as well as triple friction pendulum and single friction pendulum isolation systems are investigated. Generalized modal response spectrum analysis methods were found to give significantly better predictions for all systems compared with classical methods. The behavior of buildings isolated with single friction pendulum systems exhibiting sudden changes in stiffness could not be well predicted by either general or classical modal response spectrum analysis when effective damping was increased. Copyright © 2013 John Wiley & Sons, Ltd.
A Dynamic Factor Approach to Mortality Modeling
Authors: French Declan , O'Hare Colin
Published: April 2013

Longevity risk has become one of the major risks facing the insurance and pensions markets globally. The trade in longevity risk is underpinned by accurate forecasting of mortality rates. Using techniques from macroeconomic forecasting we propose a dynamic factor model of mortality that fits and forecasts age‐specific mortality rates parsimoniously. We compare the forecasting quality of this model against the Lee–Carter model and its variants. Our results show the dynamic factor model generally provides superior forecasts when applied to international mortality data. We also show that existing multifactorial models have superior fit but their forecasting performance worsens as more factors are added. The dynamic factor approach used here can potentially be further improved upon by applying an appropriate stopping rule for the number of static and dynamic factors. Copyright © 2013 John Wiley & Sons, Ltd.
Paleoenvironment and Human Occupation in the Maya Lowlands of the Usumacinta River, Southern Mexico
Authors: Solís‐Castillo Berenice , Solleiro‐Rebolledo Elizabeth , Sedov Sergey , Liendo Rodrigo , Ortiz‐Pérez Mario , López‐Rivera Sara
Published: April 2013

Paleosol sequences along the lowest terraces of the Usumacinta River in southern Mexico were used to reconstruct Holocene environmental changes and examine human–environmental interactions. Study sections were correlated through paleosol morphology, radiocarbon dating, and artifact seriation of Formative, Classic, and Postclassic ceramics. The oldest paleosols have gleyic features. Although they contain hard carbonate concretions dating to 5450–5380 cal. yr B.P., these Gleysols formed in the Late Pleistocene to Early Holocene. Carbonates were deposited later. The uppermost paleosols lack gleyic features, the oldest of which contains vertic features, dating to 2000–2700 cal. yr B.P., and contains abundant Formative period ceramics. The upper two paleosols are morphologically less developed and are strongly affected by human activities; radiocarbon ages and ceramic assemblages indicate that they belong to the Maya Classic and Postclassic periods. Stable carbon isotope values from the decalcified organic matter vary among paleosols of different ages and sites. δ13C values are highest (−16 to −20‰) in the Formative period paleosol. Although it is possible that maize cultivation could contribute to the isotopic signatures, we believe that the δ13C values indicate the dominance of drought‐resistant C4 and CAM vegetation due to their association with vertic soils. The Classic period paleosol has a slightly lower isotopic value (−20 to −22‰), while the Postclassic paleosol shows the lowest values (−22 to −23‰), suggesting reforestation of the floodplain. These results indicate that the Early Holocene paleosols formed in a humid climate similar to that of today, which transitions toward dryer conditions around 5500 cal. yr B.P. In the Late Holocene (approximately 3000 B.P.) an increase in seasonality occurs. This condition favored the formation of Vertisols, suitable for agriculture.
The effect of P2X7 receptor activation on nuclear factor‐kappa B phosphorylation induced by status epilepticus in the rat hippocampus
Authors: Kim Ji‐Eun , Kim Duk‐Soo , Jin Ryu Hea , Il Kim Won , Kim Min‐Ju , Won Kim Dae , Young Choi Soo , Kang Tea‐Cheon
Published: April 2013

Nuclear factor‐kappa B (NFκB) signal is essential for neuronal survival and its activation may protect neuron against various stimuli. Since purinergic signals activate NFκB through the P2X7 receptor, we investigated the distinct pattern of NF‐κB phosphorylation in neurons by P2X7 receptor activation following status epilepticus (SE) in an effort to understand the role of P2X7 receptor in epileptogenic insult. In non‐SE animals, 2′(3′)‐O‐(4‐benzoyl)benzoyl adenosine 5′‐triphosphate (BzATP, a P2X7R agonist) treatment increased only p52‐Ser869 NF‐κB phosphorylation in neuron. Following SE, p52‐Ser865, p52‐Ser869, p65‐Ser276, p65‐Ser311, p65‐Ser468, and p65‐Ser529 NF‐κB phosphorylation was significantly decreased in CA1 and CA3 neurons. However, BzATP treatment prevented reductions in p65‐Ser276, p65‐Ser311, p65‐Ser529, and p52‐Ser869 NF‐κB phosphorylations in CA1 and/or CA3 neurons induced by SE. Furthermore, BzATP treatment reduced SE‐induced p65‐Ser311, p65‐Ser468, p65‐Ser536, and p52‐Ser869 NF‐κB phosphorylations in astrocytes. These findings indicate that P2X7 functions may be involved in the regulation of SE‐induced reactive astrocytes and neuronal degeneration via NF‐κB phosphorylations in response to pilocarpine‐induced SE in the rat hippocampus. © 2013 Wiley Periodicals, Inc.
Association of the dopamine β‐hydroxylase 19 bp insertion/deletion polymorphism with positive symptoms but not tardive dyskinesia in schizophrenia
Authors: Zhou Na , Yu Qiong , Li Xiaokun , Yu Yaqin , Kou Changgui , Li Wenjun , Xu Hongqin , Luo Xingguang , Zuo Lingjun , Kosten Thomas R. , Zhang Xiang Yang
Published: April 2013

Objective

Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Dopamine beta‐hydroxylase (DBH) is a key enzyme in the conversion of dopamine to norepinephrine, and plasma DBH activity is altered in TD patients. This study examined whether the functional DBH 5'‐Ins/Del polymorphism was associated with TD severity in Chinese patients with schizophrenia.

Methods

We compared the rate of this polymorphism in patients with (n = 312) and without TD (n = 435), and healthy controls (n = 625). The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) and psychopathology using the Positive and Negative Syndrome Scale (PANSS).

Results

There were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls, or between the patients with and without TD. Also, there was no significant difference in the AIMS total score between the three genotype groups. However, the PANSS positive symptom subscore was significantly higher in patients with Del/Del genotype (13.2 ± 5.2) than those with Ins/Del (11.2 ± 4.9) and Ins/Ins (11.1 ± 3.1) genotypes (both p < 0.05).

Conclusion

These results suggest that although the DBH 5'‐Ins/Del polymorphism was not associated with susceptibility to TD in patients with schizophrenia, it might be related to positive symptoms of schizophrenia. Copyright © 2013 John Wiley & Sons, Ltd.
Identification of endogenous reference genes for RT‐qPCR analysis of plasma microRNAs levels in rats with acetaminophen‐induced hepatotoxicity
Authors: Wang Yan , Tang Naping , Hui Taotao , Wang Shuyan , Zeng Xiancheng , Li Hua , Ma Jing
Published: April 2013

Circulating microRNA (miRNA) expression profiles have been reported to be promising biomarkers for drug‐induced liver injury in preclinical and clinical practice. Proper normalization is critical for accurate miRNAs expression analysis. Herein, using SYBR green quantitative real‐time PCR (RT‐qPCR), we evaluated the expression stability of six candidate reference genes including two commonly used small RNAs (U6, 5S) and four miRNAs (let‐7a, miR‐92a, miR‐103 and miR‐16) in plasma of rats with acetaminophen‐induced hepatotoxicity. Data were analysed using geNorm, Normfinder, BestKeeper and comparative delta‐Ct statistical models, and the results consistently show that miR‐103 is the most stably expressed reference gene. Whereas the commonly used housekeeping genes 5S or U6 are all not suitable normalizers, because 5S exhibits extensive variability in expression and U6 has a low expression level across the plasma samples. Then the effect of reference genes on normalization of plasma miR‐122 was assessed; when normalized to the most stable reference gene there were significant differences between the acetaminophen‐treated group and the vehicle group. However, when the data were normalized to a less stably expressed gene, miR‐16, a biased result was obtained. Therefore, we recommend that miR‐103 as suitable reference gene for plasma miRNAs analysis for acetaminophen‐induced liver injury. Data presented in this paper are crucial to successful biomarker discovery and validation for the diagnosis of the early stage of acetaminophen hepatotoxicity. Copyright © 2013 John Wiley & Sons, Ltd.
Genomic biomarkers for cardiotoxicity in rats as a sensitive tool in preclinical studies
Authors: Nishimura Yoko , Morikawa Yuji , Kondo Chiaki , Tonomura Yutaka , Fukushima Ryou , Torii Mikinori , Uehara Takeki
Published: April 2013

The development of safer drugs is a high priority for pharmaceutical companies. Among the various toxicities caused by drugs, cardiotoxicity is an important issue because of its lethality. In addition, cardiovascular toxicity leads to the attrition of many drug candidates in both preclinical and clinical phases. Although histopathological and blood chemistry examinations are the current gold standards for detecting cardiotoxicity in preclinical studies, the large number of withdrawals from clinical studies owing to safety problems indicate that a more sensitive tool is required. We recently identified 32 genes that were candidate genomic biomarkers for cardiotoxicity in rats. Based on their functions, the present study focused on 8 of these 32 genes (Spp1, Fhl1, Timp1, Serpine1, Bcat1, Lmcd1, Rnd1 and Tgfb2). Diagnostic accuracy for the genes was determined by a receiver‐operating characteristic (ROC) analysis using more cardiotoxic and non‐cardiotoxic compounds. In addition, an optimized support vector machine (SVM) model that was composed of Spp1 and Timp1 was newly constructed. This new multi‐gene model exhibited a much higher diagnostic accuracy than that observed for plasma cardiac troponin I (cTnI), which is one of the most useful plasma biomarkers for cardiotoxicity detection. Furthermore, we determined that this multi‐gene model could predict potential cardiotoxicity in rats in the absence of any cardiac histopathological lesions or elevations of plasma cTnI. Overall, this multi‐gene model exhibited advantages over classic tools commonly used for cardiotoxicity evaluations in rats. Our current results suggest that application of the model could potentially lead to the production of safer drugs. Copyright © 2013 John Wiley & Sons, Ltd.
Student award winner in the Ph.D. category for the 2013 society for biomaterials annual meeting and exposition, april 10–13, 2013, Boston, Massachusetts
Authors: Tzeng Stephany Y. , Higgins Luke J. , Pomper Martin G. , Green Jordan J.
Published: April 2013

Liver cancer is a leading cause of cancer death. Most patients are treated by arterial injection of chemoembolizing agents, providing a convenient avenue for local treatment by novel therapies, including gene therapy. Poly(beta‐amino ester)s (PBAEs) were synthesized and used to form nanoparticles for non‐viral transfection of buffalo rat hepatoma (MCA‐RH7777) and hepatocyte (BRL‐3A) lines with eGFP and luciferase DNA. Hepatoma cells were transfected with up to (98 ± 0.4)% efficacy with no measurable cytotoxicity. Hepatocytes were transfected with as high as (73 ± 0.4)% efficacy with (10 ± 4)% non‐specific cytotoxicity. In contrast, positive controls (branched polyethylenimine, Lipofectamine™ 2000, and X‐tremeGENE® DNA HP) caused 30–90% toxicity in BRL‐3A cells at doses required for >50% transfection. Of the 21 optimized PBAE‐DNA formulations tested, 12 showed significant specificity for hepatoma cells over hepatocytes in monoculture (p < 0.05 for both percentage transfected and eGFP expression intensity). Top polymers from eGFP studies also delivered luciferase DNA with 220 ± 30‐fold and 470 ± 30‐fold greater specificity for hepatoma cells than hepatocytes. Transfections of co‐cultures of hepatoma and hepatocytes with eGFP DNA also showed high specificity (1.9 ± 0.1‐ to 5.8± 1.4‐fold more transfected hepatoma cells than hepatocytes, measured by percentage transfected and flow cytometry). By eGFP intensity, up to 530 ±60‐fold higher average expression per cell was measured in hepatoma cells. One top formulation caused (95 ± 0.2)% transfection in hepatoma cells and (27 ± 0.2)% in hepatocytes [(96 ± 9)% relative hepatocyte viability]. PBAE‐based nanoparticles are a viable strategy for liver cancer treatment, delivering genes to nearly 100% of cancer cells while maintaining high biomaterial‐mediated specificity to prevent toxic side‐effects on healthy hepatocytes. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
Complex Trauma in Children and Adolescents: Evidence‐Based Practice in Clinical Settings
Authors: Lawson David M. , Quinn Jamie
Published: April 2013

Complex trauma (CT) results from exposure to severe stressors that occur within the caregiver system or with another presumably responsible adult, are repetitive, and begin in childhood or adolescence. As a result, many of these children and adolescents experience lifelong difficulties related to self‐regulation, relationships, psychological symptoms, alterations in attention and consciousness, self‐injury, identity, and cognitive distortions. The aims of this article include the following: (a) to examine several representative approaches identified as treatments for children and adolescents exposed to CT with respect to similarities and differences; (b) to examine representative evidence of model effectiveness; (c) to discuss how these approaches are and/or could be implemented in clinical practice; and (d) to suggest research designs that would facilitate greater translation of effective treatment into clinical settings.
Weighted registration of 123I‐FP‐CIT SPECT images improves accuracy of binding potential estimates in pathologically low striatal uptake
Authors: Ciarmiello Andrea , Giovacchini Giampiero , Guidotti Claudio , Meniconi Martina , Lazzeri Patrizia , Carabelli Elena , Mansi Luigi , Mariani Giuliano , Volterrani Duccio , Del Sette Massimo
Published: April 2013

To test whether the use of a striatum weighted image may improve registration accuracy and diagnostic outcome in patients with parkinsonian syndromes (PS), weighted images were generated by increasing signal intensity of striatal voxels and used as intermediate dataset for co‐registering the brain image onto template. Experimental validation was performed using an anthropomorphic striatal phantom. 123I‐FP‐CIT SPECT binding ratios were manually determined in 67 PS subjects and compared to those obtained using unsupervised standard (UWR) and weighted registered (WR) approach. Normalized cost function was used to evaluate the accuracy of phantom and subjects registered images to the template. Reproducibility between unsupervised and manual ratios was assessed by using intra‐class correlation coefficient (ICC) and Bland and Altman analysis. Correlation coefficient was used to assess the dependence of semi‐quantitative ratios on clinical findings. Weighted method improves accuracy of brain registration onto template as determined by cost function in phantom (0.86 ± 0.06 vs. 0.98 ± 0.02; Student's t‐test, P = 0.04) and in subject scans (0.69 ± 0.06 vs. 0.53 ± 0.06; Student's t‐test, P < 0.0001). Agreement between manual and unsupervised derived binding ratios as measured by ICC was significantly higher on WR as compared to UWR images (0.91 vs. 0.76). Motor UPDRS score was significantly correlated with manual and unsupervised derived binding potential. In phantom, as well as in subjects studies, correlations were more significant using the WR method (BPm: R2 = 0.36, P = 0.0001; BPwr: R2 = 0.368, P = 0.0001; BPuwr: R2 = 0.300, P = 0.0008). Weighted registration improves accuracy of binding potential estimates and may be a promising approach to enhance the diagnostic outcome of SPECT imaging, correlation with disease severity, and for monitoring disease progression in Parkinsonian syndromes. J. Cell. Physiol. 228: 2086–2094, 2013. © 2013 Wiley Periodicals, Inc.
Effect of different parameters used for in vitro gene electrotransfer on gene expression efficiency, cell viability and visualization of plasmid DNA at the membrane level
Authors: Haberl Saša , Kandušer Maša , Flisar Karel , Hodžić Duša , Bregar Vladimir Boštjan , Miklavčič Damijan , Escoffre Jean‐Michel , Rols Marie‐Pierre , Pavlin Mojca
Published: April 2013

Background

Gene electrotransfer is a nonviral method used for DNA delivery into cells. Several steps are involved. One of them is the interaction of DNA with the cell membrane, which is crucial before DNA can enter the cell. We analysed the level of DNA–membrane interaction in relation to electrotransfer efficiency and the importance of the electrophoretic accumulation of DNA at the cell membrane. Systematic comparison of long‐duration, short‐duration and combinations of electropermeabilizing short (high‐voltage; HV) and electrophoretic long (low‐voltage; LV) pulses were performed. The effect of Mg2+ ion concentrations on electrotransfer and their effect on DNase activity were explored.

Methods

To visualize the DNA–membrane interaction, TOTO‐1 labeled DNA was used. Transfection efficiency was assessed with plasmid DNA coding for green fluorescent protein.

Results

Higher relative electrotransfer efficiency was obtained by using longer pulses, whereas shorter pulses preserved cell viability. Short‐duration pulses enabled higher (24%) overall transfection yield compared to long‐duration pulses (12%), although a higher DNA–membrane interaction was observed. No significant difference in transfection was obtained between different HV‐LV pulsing protocols, although the highest DNA–membrane interaction was observed with HV + LV pulses. The formation of the DNA–membrane complex depended on the Mg2+ concentration, whereas DNase inhibitor did not affect gene expression.

Conclusions

Gene electrotransfer is a complex phenomenon, where many factors mutually affect the process and the DNA–membrane interaction only comprises the first step. We showed that longer electric pulses are optimal for higher transfection efficiency but reduce viability, whereas shorter pulses enable moderate transfection efficiency and preserve viability. Thus, each application needs a careful choice of pulsing protocol. Copyright © 2013 John Wiley & Sons, Ltd.
Development of a handoff evaluation tool for shift‐to‐shift physician handoffs: The handoff CEX
Authors: Horwitz Leora I. , Rand David , Staisiunas Paul , Van Ness Peter H. , Araujo Katy L. B. , Banerjee Stacy S. , Farnan Jeanne M. , Arora Vineet M.
Published: April 2013

BACKGROUND

Increasing frequency of shift‐to‐shift handoffs coupled with regulatory requirements to evaluate handoff quality make a handoff evaluation tool necessary.

OBJECTIVE

To develop a handoff evaluation tool.

DESIGN

Tool development.

SETTING

Two academic medical centers.

SUBJECTS

Nurse practitioners, medicine housestaff, and hospitalist attendings.

INTERVENTION

Concurrent peer and external evaluations of shift‐to‐shift handoffs.

MEASUREMENTS

The Handoff CEX (clinical evaluation exercise) consists of 6 subdomains and 1 overall assessment, each scored from 1 to 9, where 1 to 3 is unsatisfactory and 7 to 9 is superior. We assessed range of scores, performance among subgroups, internal consistency, and agreement among types of raters.

RESULTS

We conducted 675 evaluations of 97 unique individuals during 149 handoff sessions. Scores ranged from unsatisfactory to superior in each domain. The highest rated domain for handoff providers was professionalism (median: 8; interquartile range [IQR]: 7–9); the lowest was content (median: 7; IQR: 6–8). Scores at the 2 institutions were similar, and scores did not differ significantly by training level. Spearman correlation coefficients among the CEX subdomains for provider scores ranged from 0.71 to 0.86, except for setting (0.39–0.40). Third‐party external evaluators consistently gave lower marks for the same handoff than peer evaluators did. Weighted kappa scores for provider evaluations comparing external evaluators to peers ranged from 0.28 (95% confidence interval [CI]: 0.01, 0.56) for setting to 0.59 (95% CI: 0.38, 0.80) for organization.

CONCLUSIONS

This handoff evaluation tool was easily used by trainees and attendings, had high internal consistency, and performed similarly across institutions. Because peers consistently provided higher scores than external evaluators, this tool may be most appropriate for external evaluation. Journal of Hospital Medicine 2013;8:191–200. © 2013 Society of Hospital Medicine
Brain iron MRI: A biomarker for amyotrophic lateral sclerosis
Authors: Ignjatović Aleksandar , Stević Zorica , Lavrnić Slobodan , Daković Marko , Bačić Goran
Published: April 2013

Purpose

To evaluate the usefulness of MRI detection of hypointensity areas (iron deposits) in the brain using a dedicated MRI technique in patients with ALS in establishing this sign as a potential surrogate biomarker that correlates with the severity of disease.

Materials and Methods

Forty‐six ALS patients and 26 age‐matched controls were examined by MRI. The ALS Functional Rating Scale (ALSFRS) score was determined before the first MRI examination. The sub‐set of 25 ALS patients was re‐examined around 6 months after the first MRI examination. The MRI examination consisted of routine T1W, T2W, and FLAIR sequences with the addition of a thin slice heavily T2* weighted sequence to accentuate magnetic susceptibility artifacts.

Results

T2*W sequence is superior to any other MRI sequence in detecting hypointensities in the brain of ALS patients. Hypointensities were found only in the precentral gyruses gray matter (PGGM) and were detected in 42 patients. The extent of hypointensities was measured and scored (0–3) and correlated with ALSFRS (r = −0.545). Twenty‐five patients were re‐examined 6 months later, and the majority of them showed the shift toward higher MRI scores. No control subjects had hypointensities in PGGM.

Conclusion

The detection of hypointensities in PGGM appears to be a very promising surrogate MRI biomarker for ALS due to its simplicity, high sensitivity and specificity, suitability for longitudinal studies, and relationship with the pathogenesis of the disease. J. Magn. Reson. Imaging 2013;38:1472–1479. © 2013 Wiley Periodicals, Inc.
Cardiac diffusion‐weighted MR imaging in recent, subacute, and chronic myocardial infarction: A pilot study
Authors: Laissy Jean‐Pierre , Gaxotte Virginia , Ironde‐Laissy Elisabeth , Klein Isabelle , Ribet Aurélie , Bendriss Ahmed , Chillon Sylvie , Schouman‐Claeys Elisabeth , Steg P. Gabriel , Serfaty Jean‐Michel
Published: April 2013

Purpose

To investigate the clinical feasibility of diffusion‐weighted imaging (DWI) to detect recent myocardial infarction (MI) and to differentiate it from subacute and chronic MI, with late‐gadolinium enhancement (LGE) sequence as reference. Furthermore, to measure variation of the myocardial apparent diffusion coefficient (ADC) according to the age of MI.

Materials and Methods

Seventy‐four MI patients were separated in 3 groups. Group A included 34 recent (< 8 days) MI patients; group B, 22 subacute (9–90 days) MI patients; group C, 18 chronic (> 90 days) MI patients; a fourth group (group D) included 24 controls. DWI and LGE images were acquired on a 1.5T system. DWI and LGE matched images were assessed visually by two blinded observers for hyperintense areas in corresponding segments.

Results

Qualitative assessment of DWI compared with LGE images yielded a sensitivity of 97% and a specificity of 61%/14% to differentiate recent from chronic/subacute MI, respectively. The absolute ADCs (recent 0.00632 ± 0.00037 mm2/s, subacute 0.00639 ± 0.00035 mm2/s, chronic 0.00743 ± 0.00056 mm2/s, remote or normal 0.00895 ± 0.00019 mm2/s) and relative ADCs were significantly different between groups (P < 0.001) except between recent and subacute MIs.

Conclusion

DWI is a sensitive technique to diagnose recent MI. DWI MR sequences could help differentiate recent from chronic MI. From these preliminary results, one should expect DWI to be used in the triage of emergency patients with atypical chest pain, to clarify if an MI is present or not in just a few minutes. J. Magn. Reson. Imaging 2013;38:1377–1387. © 2013 Wiley Periodicals, Inc.
Wie das Krokodil zu Zähnen kam
Authors: Groß Michael
Published: April 2013

Da Zähne vielfältige, genetisch determinierte Formen bilden und sich post mortem gut erhalten, eignen sie sich ideal, um Entwicklung und Evolution zu untersuchen. Diese Forschung ist noch lange nicht abgeschlossen und könnte eines Tages die Zahnmedizin revolutionieren.
Pseudo‐static analysis of tunnel face stability using the generalized Hoek–Brown strength criterion
Authors: Saada Z. , Maghous S. , Garnier D.
Published: April 2013

The stability of a tunnel face driven by a pressurized shield is investigated in the light of a limit analysis kinematic approach formulated in the context of the modified Hoek–Brown strength criterion. The analysis focuses on evaluating the destabilizing effects induced by seismic loading. The pseudo‐static approach is adopted to account for the effects of inertial forces developed in the rock mass by the passage of seismic waves. Taking advantage of the ability to compute analytically, the expressions of the support functions for the modified Hoek–Brown strength criterion, rigorous limit analysis solutions can be derived semi‐analytically for the tunnel face stability. Particular emphasis is given to the description of the Horn failure mechanism and associated lower bound estimates of the limit face supporting pressure. The approach is then applied to investigate the influence of some relevant strength and loading parameters in the tunnel face stability.Copyright © 2013 John Wiley & Sons, Ltd.
Amide proton transfer imaging of the human breast at 7T: development and reproducibility
Authors: Klomp Dennis W. J. , Dula Adrienne N. , Arlinghaus Lori R. , Italiaander Michel , Dortch Richard D. , Zu Zhongliang , Williams Jason M. , Gochberg Daniel F. , Luijten Peter R. , Gore John C. , Yankeelov Thomas E. , Smith Seth A.
Published: April 2013

Chemical exchange saturation transfer (CEST) can offer information about protons associated with mobile proteins through the amide proton transfer (APT) effect, which has been shown to discriminate tumor from healthy tissue and, more recently, has been suggested as a prognosticator of response to therapy. Despite this promise, APT effects are small (only a few percent of the total signal), and APT imaging is often prone to artifacts resulting from system instability. Here we present a procedure that enables the detection of APT effects in the human breast at 7T while mitigating these issues. Adequate signal‐to‐noise ratio (SNR) was achieved via an optimized quadrature RF breast coil and 3D acquisitions. To reduce the influence of fat, effective fat suppression schemes were developed that did not degrade SNR. To reduce the levels of ghosting artifacts, dummy scans have been integrated into the scanning protocol. Compared with results obtained at 3T, the standard deviation of the measured APT effect was reduced by a factor of four at 7T, allowing for the detection of APT effects with a standard deviation of 1% in the human breast at 7T. Together, these results demonstrate that the APT effect can be reliably detected in the healthy human breast with a high level of precision at 7T. Copyright © 2013 John Wiley & Sons, Ltd.
A posteriori analysis and adaptive error control for operator decomposition solution of coupled semilinear elliptic systems
Authors: Carey V. , Estep D. , Tavener S.
Published: April 2013

In this paper, we develop an a posteriori error analysis for operator decomposition iteration methods applied to systems of coupled semilinear elliptic problems. The goal is to compute accurate error estimates that account for the combined effects arising from numerical approximation (discretization) and operator decomposition iteration. In an earlier paper, we considered ‘triangular’ systems that can be solved without iteration. In contrast, operator decomposition iterative methods for fully coupled systems involve an iterative solution technique. We construct an error estimate for the numerical approximation error that specifically addresses the propagation of error between iterates and provide a computable estimate for the iteration error arising because of the decomposition of the operator. Finally, we develop an adaptive discretization strategy to systematically reduce the discretization error.Copyright © 2013 John Wiley & Sons, Ltd.
The fiber‐free approach in the evaluation of the tangent stiffness matrix for elastoplastic uniaxial constitutive laws
Authors: Marmo Francesco , Rosati Luciano
Published: April 2013

It has been shown in a previous paper that the normal stress resultants for an arbitrary polygonal section endowed with a uniaxial elastoplastic law can be computed exactly by means of a general approach; it has been denominated fiber free as no fiber discretization of the section is required. The aim of this paper was to extend the fiber‐free approach to the evaluation of the tangent stiffness matrix to allow for the analytical integration of all the basic quantities required by the section state determination occurring in nonlinear frame analysis. The numerical examples showed that the general properties of the fiber‐free approach, already discussed with reference to the stress resultants, carry over to the tangent stiffness matrix as well. Namely, independent from the complexity of the constitutive law, the accuracy in the evaluation of the tangent stiffness matrix allowed by the number of fibers adopted in commercial software for nonlinear frame analysis is even worse than that associated with the computation of the stress resultants. Copyright © 2013 John Wiley & Sons, Ltd.
Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease
Authors: Osborne C. Michael , Hardisty Emily , Devers Patricia , Kaiser‐Rogers Kathleen , Hayden Melissa A. , Goodnight William , Vora Neeta L.
Published: April 2013

What's already known about this topic?

Noninvasive prenatal testing for detection of trisomies 21, 18, and 13 is clinically available and is reported to have a false positive rate of 1% or less

This technology utilizes massively parallel shotgun sequencing of cell‐free DNA, of maternal and placental origin, present in maternal plasma

What does this study add?

Unexplained abnormal noninvasive prenatal testing results should prompt consideration of a maternal source of the abnormal cell‐free DNA, such as malignancy