bluuebunny/crossref_metadata_2025 huggingface dataset:
Lithotrophic Bacterial Leaching of Heavy Metals from Sediments Dredged from the Deûle Canal, France
Authors: Y. Sabra N. , C. Dubourguier H. , Benmimouna A. , N. Duval M. , Camuzeaux S. , Hamieh T.
Published: December 2011

Lithotrophic bacterial leaching of heavy metals from dredged sediments was studied in semi-pilot scale air-lift
bioreactors. Prior to the bioleaching experiments, a physico-chemical characterization of the sediments comprising a
sequential extraction study was conducted. The sediments turned out to be highly loaded with heavy metals, and with the
exception of managanese, mainly associated to the oxidizable fraction of the sediments and thus strongly linked to the
latter. The heavy metals could be classified by decreasing order of mobility as follows: Mn>Zn>Cu>Cd>Pb.

The bacterial leaching was found to be strongly dependent on the nature of the mineral substrate. Sulfur gave the best
solubilization results in comparison with reduced iron or with a combination of reduced iron and sulfur. In the presence of
oxygen, lithotrophic bacteria oxidized sulfur into sulfates and induced an acidification of the sediments. These conditions
led to the release of the metals that were tightly linked to the sediments, that is those associated with the sulfides and/or
with the organic matter. With sulfur as a substrate, the solubilization percentages varied within 30 days between 72 and
93% of the total sediment content (wt/wt) for cadmium, copper, manganese and zinc. Much lower biosolubilization
percentages were obtained in the case of lead because of the poor solubility of lead sulfate.
Peripheral Synergistic Interaction Between Lidocaine and Lumiracoxib on the 1% Formalin Test in Rats
Authors: I. Ortiz Mario , Castaneda-Hernandez Gilberto , A. Izquierdo-Vega Jeannett , A. Ponce-Monter Hector
Published: December 2011

It has been shown that the association of non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic agents can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the aim of the present study was to examine the possible pharmacological interaction between lumiracoxib and lidocaine at the local peripheral level in the rat using the 1% formalin test and isobolographic analysis. Lumiracoxib, lidocaine or fixed-dose ratio (1:1) lumiracoxib-lidocaine combinations were administered locally in the formalin-injured paw and the antinociceptive effect was evaluated. All treatments produced a dose-dependent antinociceptive effect. ED40 values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED40 for the lumiracoxiblidocaine combination was 599.3 ± 58.8 μg/paw, being significantly higher than the actually observed experimental ED40 value, 393.6 ± 39.7 μg/paw. This result correspond to a synergistic interaction between lumiracoxib and lidocaine at the
local peripheral level, potency being about one and half times higher with regard to that expected from the addition of the effects of the individual drugs. Data suggest that low doses of the lumiracoxib-lidocaine combination can interact synergistically at the peripheral level and therefore this drug association may represent a therapeutic advantage for the clinical treatment of procedural or inflammatory pain.
Infectious Complications in Kidney-Transplant Recipients Desensitized with Rituximab and Intravenous Immunoglobulin
Authors: Kahwaji Joseph , Sinha Aditi , Toyoda Mieko , Ge Shili , Reinsmoen Nancy , Cao Kai , Lai Chih-Hung , Villicana Rafael , Peng Alice , Jordan Stanley , Vo Ashley
Published: December 2011

Background and objectives

Rituximab and intravenous Ig (IVIG) are commonly used for desensitization of HLA and blood group–incompatible (ABOi) transplants. However, serious infections have been noted in association with rituximab administration. In this study, we retrospectively compared infectious outcomes in those who received rituximab plus IVIG for HLA or ABOi transplants (RIT group) with a group of nonsensitized, ABO-compatible transplant recipients (non-RIT group).

Design, setting, participants, & measurements

Patients undergoing kidney transplantation at Cedars-Sinai Medical Center were included in the analysis. A total of 361 patients were identified. All received antimicrobial prophylaxis and viral surveillance. The primary outcome was infection.

Results

Overall patient survival was 97 and 96%, and graft survival was 91 and 89% in the RIT and non-RIT groups, respectively, after an average follow-up of 18 months. There were equal rates of bacterial (34.7% versus 39.1%), viral (21.8% versus 25.1%), fungal (5.9% versus 5.2%), and serious infections (22.9% versus 25.5%) in the RIT and non-RIT groups respectively. Urinary tract infection was the most common infection, accounting for 50% of all bacterial infections. Cytomegalovirus viremia was nonsignificantly more common in the nonrituximab-treated group (15.2% versus 10%), whereas BK viremia was marginally more frequent in the rituximab-treated group (10.6% versus 5.8%). There were no graft losses caused by BK-associated nephropathy. There were two deaths in each group related to infection (1%).

Conclusion

Rituximab does not increase infection risk when used with intravenous Ig for desensitization.
Chronic Kidney Disease and Coronary Artery Vulnerable Plaques
Authors: Wada Mitsuru , Ueda Yasunori , Higo Tomoaki , Matsuo Koshi , Nishio Mayu , Hirata Akio , Asai Mitsutoshi , Nemoto Takayoshi , Kashiyama Toshikazu , Murakami Ayaka , Kashiwase Kazunori , Kodama Kazuhisa
Published: December 2011

Background and objectives

Chronic kidney disease (CKD) is a risk factor of cardiovascular disease. The number of yellow plaques is a predictor of future cardiovascular events. We assumed that CKD might raise the risk of cardiovascular events by increasing the number of yellow plaques. Therefore, we compared the number of yellow plaques between patients with and without CKD.

Design, setting, participants, & measurements

Consecutive 136 patients with acute myocardial infarction who received percutaneous coronary intervention (PCI) and angioscopic examination were analyzed. The infarct-related artery was angioscopically examined. The number of yellow plaques, maximum yellow color grade of detected yellow plaques, and prevalence of disrupted yellow plaques in nonculprit segments were compared between patients with and without CKD.

Results

The number of yellow plaques was significantly larger in CKD than in non-CKD patients (median [interquartile range]: 4.0 [2.0 to 6.0] versus 2.0 [1.0 to 4.0], P = 0.001). Maximum yellow color grade and prevalence of disrupted plaques in the nonculprit segments were not different between patients with and without CKD. Multivariate logistic regression analysis revealed CKD as an independent risk of multiple yellow plaques per vessel (odds ratio 3.49, 95% confidence interval 1.10 to 11.10, P = 0.03).

Conclusion

CKD was an independent risk factor of multiple coronary yellow plaques, suggesting that patients with CKD would have a higher risk of coronary events because they had more yellow plaques than patients without CKD.
Computer use and musculoskeletal complaints in the Lithuanian adolescent population
Authors: Skemiene Lina , Ustinaviciene Ruta , Luksiene Dalia , Radisauskas Ricardas , Kaliniene Gintare
Published: December 2011

The purpose of this study was to evaluate self-rated musculoskeletal complaints and their association with computer use time in the adolescent population in Lithuania. The cross-sectional study done in 2008–2009 in Lithuania. 1806 students aged 13–18 years from randomly selected schools were questioned (response rate 95.8%). Logistic regression analysis results show that musculoskeletal complaints in adolescence are associated with duration of computer use as related to age and gender. Compared with adolescents using computer <2 hours daily, a statistically significant probability of experiencing back pain was determined for younger boys and girls groups (13–15 years) who reported working on a computer >4 hours (OR=2.36 and OR=2.50, respectively) in older age groups (16–18 years); in girls only the ORs of back pain significantly increased with increased time of computer use. the probability of experiencing the neck-shoulder pain was determined only in girls aged 16–18 years who reported working on a computer 2–4 hours (OR=1.62, p=0.020). Musculoskeletal complaints in adolescence are related to duration of computer use. Increasing the time spent at the computer increased complaints of musculoskeletal pain among Lithuanian adolescents. The main guidelines for prevention point to restriction of time of computer use.
Stem Cells: A Personal Perspective
Authors: Wong S
Published: December 2011

Stem Cells: A Personal Perspective
Modified concept of permanent magnet excited synchronous machines with improved high-speed features
Authors: May H. , Palka R. , Paplicki P. , Szkolny S. , Canders W.-R.
Published: December 2011

Modified concept of permanent magnet excited synchronous machines with improved high-speed features

Permanent magnet (PM) excited synchronous machines used in modern drives for electro-mobiles suffer in high speed regions from the limited battery-voltage. The field weakening requires designing machines with reduced power conversion properties or increasing the size of the power converter. A new concept of such a machine features PM excitation, single-tooth winding and an additional circumferential excitation coil fixed on the stator in the axial center of the machine. By the appropriate feeding of this coil, the amplitude of the voltage effective excitation field can be varied from zero to values above those of the conventional PM-machines. The capability of reducing the excitation field to zero is an important safety aspect in case of failing of the feeding convertor.
Professor Janush Bronislavovich Danilevich (1931 - 2011)
Authors: Sobczyk Tadeusz
Published: December 2011

Professor Janush Bronislavovich Danilevich (1931 - 2011)
Structural, optical and luminescence studies of ZnSe nanowires
Authors: Venugopal R. , Vijayalakshmi R. P. , Murali G. , Reddy D. Amaranatha , Chen Yit-Tsong
Published: December 2011

ZnSe nanowires have been successfully synthesized through chemical vapor deposition assisted by laser ablation in a tube furnace on a silicon substrate coated with a gold film of 2 nm thickness. X-ray powder diffraction measurements reveal that the synthesized products had pure hexagonal wurtzite structure. The microstructures and chemical composition of the as-grown nanowires have been investigated by means of electron microscopy, energy dispersive spectroscopy, photoluminescence and Raman spectroscopy. The results reveal that the as-grown material consists of ZnSe nanowires with diameters ranging from 60 – 100 nm and with lengths up to several tens of micrometers. High resolution transmission electron microscopy and selected area electron diffraction indicated that as-synthesized nanowires were single crystalline in nature. Micro-photoluminescence studies on ZnSe nanowire reveal strong emission at 460 nm. The Raman peak at 251 cm−1 is attributed to the longitudinal optic phonon mode of ZnSe.
Recovery and recrystallisation processes in plastically deformed WE43 alloy
Authors: Lambri Osvaldo Agustin , Riehemann Werner
Published: December 2011

Mechanical spectroscopy, differential scanning calorimetry measurements and light microscopy studies were performed on homogenised and plastically deformed samples of commercial WE43 magnesium alloy. Plastic deformation was performed both at 300 K and 643 K, and at 1 % and 10 % of uniform plastic deformation. Samples 1 % deformed at 300 K did not show recrystallisation, but recovery at about 633 K was detected. Samples 1 % deformed at 643 K recovered dynamically, during hot working. Samples 10 % deformed at 300 K began to recrystallise at about 730 K, meanwhile samples 10 % deformed at 643 K dynamically recrystallised during hot working.
Semisolid microstructure of AM60B magnesium alloy refined by SiC particles
Authors: Chen T. J. , Lü W. B. , Ma Y. , Huang H. J. , Hao Y.
Published: December 2011

Microstructural evolution during partial remelting of AM60B alloy refined by 0.2 wt.% SiC particles at 615 °C has been investigated. The effect of as-cast microstructure on the resulting semisolid microstructure has also been discussed. The results indicate that the evolution process includes five stages, initial rapid coarsening, structure separation, spheroidization and coarsening, partial melting and final coarsening. The finer the as-cast microstructure is, the smaller and more spheroidal the primary particles of the resulting semisolid microstructure are. There is a threshold for the grain size of the as-cast microstructure. When the grain size is about 100 μm, one dendrite frequently evolves into one primary particle after being partially remelted. But when the grain size is larger than 100 μm, one dendrite often separates into several particles, and when it is smaller than 100 μm, one primary particle always originates from several dendrites.
An investigation into the microstructure and weldability of a tantalum-containing cast cobalt-based superalloy
Authors: Montazeri Mojtaba , Ghaini Farshid Malek , Farnia Amirreza
Published: December 2011

The weld metal microstructures and the weldability of a tantalum-containing cast cobalt-based superalloy were investigated using gas tungsten arc welding. It was found that the tantalum carbides in the base metal have remained stable up to the fusion line. The results showed that the formation of Ta-rich carbides (TaC) is very sensitive to time and temperature; so the as-weld microstructure is unstable from a metallurgical aspect. The formation of fine precipitates due to the high cooling rate of the welding process resulted in a weld metal with an undesirable hardness and microstructure after autogenous welding, especially after post weld heat treatment. Further results revealed that using a filler metal containing significantly less carbon and tantalum has solved the mentioned problems and made acceptable welds after post weld heat treatment.
Accelerated axon outgrowth, guidance, and target reinnervation across nerve transection gaps following a brief electrical stimulation paradigm
Authors: Singh Bhagat , Xu Qing-Gui , Franz Colin K. , Zhang Rumi , Dalton Colin , Gordon Tessa , Verge Valerie M. K. , Midha Rajiv , Zochodne Douglas W.
Published: December 2011

Object

Regeneration of peripheral nerves is remarkably restrained across transection injuries, limiting recovery of function. Strategies to reverse this common and unfortunate outcome are limited. Remarkably, however, new evidence suggests that a brief extracellular electrical stimulation (ES), delivered at the time of injury, improves the regrowth of motor and sensory axons.

Methods

In this work, the authors explored and tested this ES paradigm, which was applied proximal to transected sciatic nerves in mice, and identified several novel and compelling impacts of the approach. Using thy-1 yellow fluorescent protein mice with fluorescent axons that allow serial in vivo tracking of regeneration, the morphological, electrophysiological, and behavioral indices of nerve regrowth were measured.

Results

The authors show that ES is associated with a 30%–50% improvement in several indices of regeneration: regrowth of axons and their partnered Schwann cells across transection sites, maturation of regenerated fibers in gaps spanning transection zones, and entry of axons into their muscle and cutaneous target zones. In parallel studies, the authors analyzed adult sensory neurons and their response to extracellular ES while plated on a novel microelectrode array construct designed to deliver the identical ES paradigm used in vivo. The ES accelerated neurite outgrowth, supporting the concept of a neuron-autonomous mechanism of action.

Conclusions

Taken together, these results support a robust role for brief ES following peripheral nerve injuries in promoting regeneration. Electrical stimulation has a wider repertoire of impact than previously recognized, and its impact in vitro supports the hypothesis that a neuron-specific reprogrammed injury response is recruited by the ES protocol.
The efficacy of superficial temporal artery–middle cerebral artery anastomosis in patients with moyamoya disease complaining of severe headache
Authors: Okada Yoshikazu , Kawamata Takakazu , Kawashima Akitsugu , Yamaguchi Kohji , Ono Yuko , Hori Tomokatsu
Published: December 2011

Object

Some patients with moyamoya disease complain of severe headache, which may be closely related to cerebral ischemia. The efficacy of superficial temporal artery–middle cerebral artery (STA-MCA) anastomosis in these patients was evaluated by clinicoradiological studies.

Methods

Of 117 consecutive patients with ischemic moyamoya disease, 25 complained mainly of severe headache (headache group) and 92 had no significant headache (nonheadache group). Intensity of headache was evaluated pre- and postoperatively. Furthermore, regional cerebral blood flow (rCBF) and cerebrovascular reactivity (CVR) were assessed pre- and postoperatively.

Results

The headache group was significantly younger than the nonheadache group. In a group corrected for the age distribution, preoperative rCBF and CVR were similar in headache and nonheadache groups. After STA-MCA anastomosis, 16 patients with headache experienced complete relief from headache, 7 patients showed remarkable improvements and discontinued medications for headache, and the remaining 2 patients had some alleviation of headache but sometimes required medication. In the headache group, the postoperative rCBF was significantly greater than the preoperative value. The postoperative rCBF in this group was also significantly greater than the postoperative rCBF in the nonheadache group.

Conclusions

These data suggest that severe headache is one of the main symptoms in young patients with moyamoya disease probably related to cerebral circulatory disturbances. An STA-MCA anastomosis is effective in relieving headache in patients with ischemic moyamoya disease manifesting severe headache, probably by improving perfusion pressure and cerebral circulation.
Unilateral cervical facet dislocation: a biomechanical study of several constructs including unilateral lateral mass fixation supplemented by an interspinous cable
Authors: Riesenburger Ron I. , Potluri Tejaswy , Kulkarni Nikhil , Lavelle William , Roguski Marie , Goel Vijay K. , Benzel Edward C.
Published: December 2011

Object

Both ventral and dorsal operative approaches have been used to treat unilateral cervical facet injuries. The gold standard ventral approach is anterior cervical discectomy and fusion. There is, however, no clear gold standard dorsal operation. In this study, the authors tested the stability of multiple posterior constructs, including unilateral lateral mass fixation supplemented by an interspinous cable.

Methods

Six fresh human cervical spine specimens (C3–T1) were tested by applying pure moments to the C-3 vertebral body in increments of 0.5 Nm from 0 Nm to 2.0 Nm. Each specimen was tested in the following 8 conditions (in the order shown): 1) intact; 2) after destabilization via injury to the C5–6 facet; 3) with bilateral C5–6 lateral mass screws and rods; 4) after further destabilization by creating a right unilateral lateral mass fracture of C-5 (which rendered secure screw placement into the right C-5 lateral mass impossible); 5) with unilateral left C5–6 lateral mass screws and rod; 6) with unilateral C5–6 lateral mass screws and rod supplemented with an interspinous cable; 7) with a bilateral multilevel dorsal construct C4–6; and 8) after a C5–6 anterior cervical discectomy and fusion (ACDF) procedure with a polyetheretherketone graft and plate.

Results

The bilateral C5–6 lateral mass construct reduced the range of C5–6 motion to 33.6% of normal. The unilateral C5–6 lateral mass construct resulted in an increased range of motion to 110.1% of normal. The unilateral lateral mass construct supplemented by an interspinous cable reduced the C5–6 range of motion to 89.4% of normal. The bilateral C4–6 lateral mass construct reduced the C5–6 range of motion to 44.2% of normal. The C5–6 ACDF construct reduced the C5–6 range of motion to 62.6% of normal.

Conclusions

The unilateral lateral mass construct supplemented by an interspinous cable does reduce range of motion compared with an intact specimen, but is significantly inferior to a C4–6 bilateral lateral mass construct. When using a dorsal approach, the unilateral construct with a cable should only be considered in selected instances.
Zinc and prostate cancer: a short review
Authors: Rahman Md Tahminur , Mumu Mahbuba Ashrafi , Kabir Yearul
Published: December 2011

Keywords: zinc; association; prostatic cancerDOI: http://dx.doi.org/10.3329/bjpath.v26i1.9148 BJPATH 2011; 26(1): 26-31
Differential Motor Neuron Impairment and Axonal Regeneration in Sporadic and Familiar Amyotrophic Lateral Sclerosis with SOD-1 Mutations: Lessons from Neurophysiology
Authors: Bocci Tommaso , Pecori Chiara , Giorli Elisa , Briscese Lucia , Tognazzi Silvia , Caleo Matteo , Sartucci Ferdinando
Published: December 2011

Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder of the motor system. About 10% of cases are familial and 20% of these families have point mutations in the Cu/Zn superoxide dismutase 1 (SOD-1) gene. SOD-1 catalyses the superoxide radical (O−2) into hydrogen peroxide and molecular oxygen. The clinical neurophysiology in ALS plays a fundamental role in differential diagnosis between the familial and sporadic forms and in the assessment of its severity and progression. Sixty ALS patients (34 males; 26 females) were enrolled in the study and examined basally (T0) and every 4 months (T1, T2, and T3). Fifteen of these patients are SOD-1 symptomatic mutation carriers (nine males, six females). We used Macro-EMG and Motor Unit Number Estimation (MUNE) in order to evaluate the neuronal loss and the re-innervation process at the onset of disease and during follow-up period. Results and Discussion: SOD-1 mutation carriers have a higher number of motor units at the moment of diagnosis when compared with the sporadic form, despite a more dramatic drop in later stages. Moreover, in familiar SOD-1 ALS there is not a specific time interval in which the axonal regeneration can balance the neuronal damage. Taken together, these results strengthen the idea of a different pathogenetic mechanism at the base of sALS and fALS.
The Effect of the Acetone Extract of Arctotis arctotoides (Asteraceae) on the Growth and Ultrastructure of Some Opportunistic Fungi Associated with HIV/AIDS
Authors: Otang Wilfred M. , Grierson Donald S. , Ndip Roland N.
Published: December 2011

In this study, the effect of the acetone extract of Arctotis arctotoides (L.f.) O. Hoffm. (Asteraceae) on the growth and ultrastructure of some opportunistic fungi associated with HIV/AIDS was analyzed by means of scanning electron microscope (SEM). Remarkable morphological alterations in the fungal mycelia which were attributed to the loss of cell wall strength ranged from loss of turgidity and uniformity, collapse of entire hyphae to evident destruction of the hyphae. The elements responsible for giving the fungi their characteristic virulence were detected and quantified by energy dispersive X-ray microanalysis techniques. X-ray microanalysis showed the specific spectra of sodium, potassium and sulfur as the principal intersection of the four pathogenic fungi studied. Since these ions have the potential of fostering fungal invasion by altering the permeability of hosts’ membranes, their presence was considered inherent to the pathogenicity of the opportunistic fungi. Hence, these findings indicate the potential of the crude extract of A. arctotoides in preventing fungal invasion and subsequent infection of host’s membranes.
Low Power Testing—What Can Commercial Design-for-Test Tools Provide?
Authors: Lin Xijiang
Published: December 2011

Minimizing power consumption during functional operation and during manufacturing tests has become one of the dominant requirements for the semiconductor designs in the past decade. From commercial design-for-test (DFT) tools’ point of view, this paper describes how DFT tools can help to achieve comprehensive testing of low power designs and reduce test power consumption during test application.
Preparation, Spectrochemical, and Computational Analysis of L-Carnosine (2-[(3-Aminopropanoyl)amino]-3-(1H-imidazol-5-yl)propanoic Acid) and Its Ruthenium (II) Coordination Complexes in Aqueous Solution
Authors: Branham Michael Lee , Singh Parvesh , Bisetty Krishna , Sabela Myalo , Govender Thirumala
Published: December 2011

This study reports the synthesis and characterization of novel ruthenium (II) complexes with the polydentate dipeptide, L-carnosine (2-[(3-aminopropanoyl)amino]-3-(1H-imidazol-5-yl)propanoic acid). Mixed-ligand complexes with the general composition [MLp(Cl)q(H2O)r]·xH2O (M = Ru(II); L = L-carnosine; p = 3 − q; r = 0–1; and x = 1–3) were prepared by refluxing aqueous solutions of the ligand with equimolar amounts of ruthenium chloride (black-alpha form) at 60 °C for 36 h. Physical properties of the complexes were characterized by elemental analysis, DSC/TGA, and cyclic voltammetry. The molecular structures of the complexes were elucidated using UV-Vis, ATR-IR, and heteronuclear NMR spectroscopy, then confirmed by density function theory (DFT) calculations at the B3LYP/LANL2DZ level. Two-dimensional NMR experiments (1H COSY, 13C gHMBC, and 15N gHMBC) were also conducted for the assignment of chemical shifts and calculation of relative coordination-induced shifts (RCIS) by the complex formed. According to our results, the most probable coordination geometries of ruthenium in these compounds involve nitrogen (N1) from the imidazole ring and an oxygen atom from the carboxylic acid group of the ligand as donor atoms. Additional thermogravimetric and electrochemical data suggest that while the tetrahedral-monomer or octahedral-dimer are both possible structures of the formed complexes, the metal in either structure occurs in the (2+) oxidation state. Resulting RCIS values indicate that the amide-carbonyl, and the amino-terminus of the dipeptide are not involved in chelation and these observations correlate well with theoretical shift predictions by DFT.
Ionic Channels as Targets for Drug Design: A Review on Computational Methods
Authors: Fernández-Ballester Gregorio , Fernández-Carvajal Asia , González-Ros José Manuel , Ferrer-Montiel Antonio
Published: December 2011

Ion channels are involved in a broad range of physiological and pathological processes. The implications of ion channels in a variety of diseases, including diabetes, epilepsy, hypertension, cancer and even chronic pain, have signaled them as pivotal drug targets. Thus far, drugs targeting ion channels were developed without detailed knowledge of the molecular interactions between the lead compounds and the target channels. In recent years, however, the emergence of high-resolution structures for a plethora of ion channels paves the way for computer-assisted drug design. Currently, available functional and structural data provide an attractive platform to generate models that combine substrate-based and protein-based approaches. In silico approaches include homology modeling, quantitative structure-activity relationships, virtual ligand screening, similarity and pharmacophore searching, data mining, and data analysis tools. These strategies have been frequently used in the discovery and optimization of novel molecules with enhanced affinity and specificity for the selected therapeutic targets. In this review we summarize recent applications of in silico methods that are being used for the development of ion channel drugs.
Autologous Lung-Derived Mesenchymal Stem Cell Transplantation in Experimental Emphysema
Authors: Ingenito Edward P. , Tsai Larry , Murthy Shankar , Tyagi Shivraj , Mazan Melissa , Hoffman Andrew
Published: December 2011

Autologous lung-derived mesenchymal stem cells (LMSCs) were transplanted endoscopically into sheep with experimental emphysema to assess their capacity to regenerate functional tissue. LMSC lines were derived from transbronchial biopsies, cloned at passage 2, expanded in culture, and labeled. A delivery scaffold containing 1% fibrinogen, 20 μg/ml of fibronectin, and 20 μg/ml of poly-L-lysine was used to promote cell attachment and spreading. Treatment animals received scaffold containing 5–10 × 106cells/site; control animals received scaffold alone. Phenotypic markers, differentiation capacity, extracellular matrix protein expression, and paracrine function of LMSCs were characterized in vitro. Responses to LMSC transplantation in vivo were assessed in terms of clinical toxicity, lung physiology, change in tissue mass (measured by CT scanning) and perfusion (measured by scintigraphy scanning), and tissue histology. At 4-week follow-up, transplants were well tolerated and associated with increased tissue mass and lung perfusion compared to control treatment. Histology confirmed cell retention, increased cellularity, and increased extracellular matrix content following LMSC treatment. Labeled cells were distributed in the alveolar septum and peribronchiolar interstitium. Some label was also present within phagocytes, indicating that a fraction of autologous LMSCs do not survive transplantation. These results suggest that endobronchial delivery of autologous LMSCs has potential therapeutic utility for regenerating functional lung in emphysema.
Improving Efficacy of Clinical Islet Transplantation with Iodixanol-Based Islet Purification, Thymoglobulin Induction, and Blockage of IL-1β and TNF-α
Authors: Matsumoto Shinichi , Takita Morihito , Chaussabel Damien , Noguchi Hirofumi , Shimoda Masayuki , Sugimoto Koji , Itoh Takeshi , Chujo Daisuke , Sorelle Jeff , Onaca Nicholas , Naziruddin Bashoo , Levy Marlon F.
Published: December 2011

Poor efficacy is one of the issues for clinical islet transplantation. Recently, we demonstrated that pancreatic ductal preservation significantly improved the success rate of islet isolation; however, two transplants were necessary to achieve insulin independence. In this study, we introduced iodixanol-based purification, thymoglobulin induction, and double blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression to improve the efficacy of clinical islet transplantation. Nine clinical-grade human pancreata were procured. Pancreatic ductal preservation was performed using ET-Kyoto solution in all cases. When the isolated islets met the clinical criteria, they were transplanted. We utilized two methods of immunosuppression and anti-inflammation. The first protocol prescribed daclizumab for induction, then sirolimus and tacrolimus to maintain immunosuppression. The second protocol used thymoglobulin for induction and tacrolimus and mycophenolate mofetil to maintain immunosuppression. Eternacept and anakinra were administered as anti-inflammatory drugs. The total amount of insulin required, HbA1c, and the SUITO index were determined to analyze and compare the results of transplantation. All isolated islet preparations (9/9) met the criteria for clinical transplantation, and they were transplanted into six type 1 diabetic patients. All patients achieved insulin independence with normal HbA1c levels; however, the first protocol required two islet infusions ( N = 3) and the second protocol only required a single infusion ( N = 3). The average SUITO index, at 1 month after a single-donor islet transplantation, was significantly higher in the second protocol (49.6 ± 8.3 vs. 19.3 ± 6.3, p < 0.05). Pancreatic ductal preservation, iodixanol-based purification combined with thymoglobulin induction, and blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression dramatically improved the efficacy of clinical islet transplantations. This protocol enabled us to perform successful single-donor islet transplantations. Further large-scale studies are necessary to confirm these results and clarify the mechanism of each component.
Hypoxic Conditions during Expansion Culture Prime Human Mesenchymal Stromal Precursor Cells for Chondrogenic Differentiation in Three-Dimensional Cultures
Authors: Müller Jana , Benz Karin , Ahlers Michael , Gaissmaier Christoph , Mollenhauer Jürgen
Published: December 2011

Cell-based approaches using mesenchymal stromal precursor cells (MSCs) for the regeneration of intervertebral discs are attracting increased interest, even though the intervertebral disc is a very demanding environment. Implanted cells eventually face acidic pH, hypoxia, and a lack of nutrients. While the regenerative potential of MSCs for skeletal tissues has been well described, it is still questionable whether human MSCs can be prepared for prolonged survival and proper functioning and whether they can differentiate under the adverse conditions encountered in the disc. Here we examined the influence of hypoxia during expansion and differentiation on the chondrogenesis of MSCs. Chondrogenic differentiation was performed in in situ solidifying gelatin hydrogels, which represent a suitable matrix for delivering and anchoring cells within the disc tissue. To consider limitations in nutrition in the intervertebral disc, differentiation was performed at low cell concentrations in the gelatin hydrogels. Standard high-density micromass cultures served as reference controls. To determine the quality of chondrogenesis we analyzed typical marker molecules such as collagen types I, II, X, Sox-9, MIA, and aggrecan mRNA using RT-qPCR and determined protein deposition by histological stainings and biochemical methods. We could demonstrate that in gelatin-based hydrogels chondrogenic differentiation of human MSCs is possible at low cell concentrations. The quality of chondrogenic differentiation could be improved by hypoxia. Best results were obtained when the entire in vitro process, including MSC expansion and subsequent differentiation, was done under hypoxic conditions. MSCs that were expanded under reduced oxygen tension were primed for a chondrogenic differentiation.
Transplantation of Encapsulated Hepatocytes during Acute Liver Failure Improves Survival without Stimulating Native Liver Regeneration
Authors: Sgroi Antonino , Mai Gang , Morel Philippe , Baertschiger Reto M. , Gonelle-Gispert Carmen , Serre-Beinier Véronique , Buhler Leo H.
Published: December 2011

The aim of this study was to evaluate the effects of intraperitoneal transplantation of encapsulated human hepatocytes on liver metabolism and regeneration of mice with acute liver failure. Primary human hepatocytes were immortalized using lentiviral vectors coding for antiapoptotic genes and microencapsulated using alginate-polylysine polymers. In vitro, immortalized human hepatocytes showed low, but stable, synthetic and catabolitic functions over time, when compared to primary hepatocytes. In vivo, mice with acute liver failure and transplanted with encapsulated immortalized human hepatocytes had a significantly improved survival and biochemical profile, compared to mice transplanted with empty capsules. Serum levels of cytokines implicated in liver regeneration were lower in mice transplanted with hepatocytes compared to mice receiving empty capsules. This decrease was significant for IL-6 and HGF at 3 h. Measurement of liver regeneration showed no significant difference between mice transplanted with hepatocytes compared to control groups. Intraperitoneal transplantation of encapsulated immortalized hepatocytes significantly improved survival of mice with acute liver failure by providing metabolic support and without modifying liver regeneration. The lower levels of cytokines implicated in liver regeneration suggest that the metabolic support provided by the encapsulated hepatocytes reduced the inflammatory stress on the liver and herein decreased the regenerative trigger on residual hepatocytes. These data emphasize that metabolic function and regeneration of hepatocytes are two distinct aspects that need to be studied and approached separately during acute liver failure.
Endothelial Colony-Forming Cell Coating of Pig Islets Prevents Xenogeneic Instant Blood-Mediated Inflammatory Reaction
Authors: Kim Jae Hyeon , Oh Bae Jun , Lee Han Na , Park Ho Sun , Park Sang Gyu , Park Kyong Soo
Published: December 2011

Instant blood-mediated inflammatory reaction (IBMIR) causes rapid islet loss in islet transplantation. Endothelial colony-forming cells (ECFCs) display unique abilities to promote angiogenesis and repair vascular injury compared to those of endothelial cells (ECs), which inhibits the allogeneic and xenogeneic IBMIR. We investigated the coating of pig islets with ex vivo-expanded ECFCs as a strategy to overcome xenogeneic IBMIR. Porcine islets were cocultured with human ECFCs in a specially modified culture medium for 2 days to obtain 70–90% coverage. The coating of pig islets with human ECFCs did not affect the glucose-stimulated insulin secretion capacity or diabetes reversal rate after the transplantation of a marginal islet mass under the kidney capsules of diabetic nude mice compared to that of untreated islets. Uncoated islets, PBS control without islets, and the ECFC-coated islets were examined with an in vitro tubing loop assay using human blood. After 60 min of incubation in human blood, the ECFC-coated islets showed platelet consumption inhibition and low C3a and TAT assay results compared to those of the uncoated islets. Furthermore, there was very little macroscopic or microscopic clotting in the human ECFC-coated pig islets. The protective effect was more prominent compared to that of human EC coating of pig islets in our previous study. We investigated the changes in human-specific MCP-1, IL-8, and tissue factor (TF) levels after the coating of pig islets with human ECFCs or human ECs. The IL-8 levels after coating pig islets with ECFCs were significantly lower than those after coating pig islets with ECs, but there were no significant differences in the MCP-1 or TF levels between the ECFCs and ECs. In conclusion, the coating of pig islets with ECFCs completely prevented all components of xenogeneic IBMIR. ECFCs may be a better source of protection against xenogeneic IBMIR than are mature ECs.
Comparison of Canine Umbilical Cord Blood-Derived Mesenchymal Stem Cell Transplantation Times: Involvement of Astrogliosis, Inflammation, Intracellular Actin Cytoskeleton Pathways, and Neurotrophin-3
Authors: Park Sung-Su , Byeon Ye-Eun , Ryu Hak-Hyun , Kang Byung-Jae , Kim Yongsun , Kim Wan-Hee , Kang Kyung-Sun , Han Ho-Jae , Kweon Oh-Kyeong
Published: December 2011

Canine mesenchymal stem cells (cMSCs) derived from umbilical cord blood represent a potentially useful source of stem cells for therapy. The aim of this study was to compare the effects of different transplantation times of cMSCs after spinal cord injury (SCI). A total of 21 dogs were subjected to SCI by balloon-induced compression of the first lumbar vertebrae for 12 h. Of the 21 dogs, 12 were divided into four groups of three according to the time of stem cell (1 × 106) transplantation at the injury site: control no treatment, 12 h, 1 week, and 2 weeks. The remaining 9 animals were negative harvest (HA) time controls for each treatment group ( n = 3). Olby and Tarlov scores were used to evaluate functional recovery of the hindlimbs. Markers for neuronal regeneration (Tuj-1, nestin, MAP2, and NF-M), astrogliosis (GALC, GFAP, and pSTAT3), signal molecules for actin cytoskeleton (RhoA, Cdc42, and Rac1), inflammation (COX-2), and neurotrophins (NT-3) were evaluated by Western blot analysis. Scores of the 1-week transplantation group showed significant improvement compared to controls. Hematoxylin and eosin (H&E) staining revealed less fibrosis at the injury site in the 1-week transplantation group compared to other groups and immunohistochemistry showed increased expression of neuronal markers. Furthermore, in both 1-week and 2-week transplantation groups, Tuj-1, nestin, MAP2, NF-M, NT-3, and GFAP increased, but pSTAT3, GALC, and COX2 decreased. RhoA decreased and Rac1 and Cdc42 increased in the 1-week transplantation group. In conclusion, transplantation of cMSCs 1 week after SCI was more effective in improving clinical signs and neuronal regeneration and reducing fibrosis formation compared to the other transplantation times evaluated. Subsequently, these data may contribute to the optimization of timing for MSC transplantation used as a therapeutic modality.
Functional Evaluation of Primary Renal Cell/Biomaterial Neo-Kidney Augment Prototypes for Renal Tissue Engineering
Authors: Basu Joydeep , Genheimer Christopher W. , Rivera Elias A. , Payne Richard , Mihalko Kim , Guthrie Kelly , Bruce Andrew T. , Robbins Neil , McCoy Darell , Sangha Namrata , Ilagan Roger , Knight Toyin , Spencer Thomas , Wagner Belinda J. , Jayo Manuel J. , Jain Deepak , Ludlow John W. , Halberstadt Craig
Published: December 2011

Development of a tissue-engineered neo-kidney augment (NKA) requires evaluation of defined, therapeutically relevant cell and cell/biomaterial composites (NKA constructs) for regenerative potential in mammalian kidney. Previous work identified primary renal cell populations that extended survival and improved renal function in a rodent model of chronic kidney disease (CKD). This study extends that work toward the goal of developing NKA by (i) screening in vivo inflammatory and fibrotic responses to acellular biomaterials delivered to healthy rodent renal parenchyma, (ii) evaluating the functionality of renal cell/biomaterial combinations in vitro, (iii) generating NKA constructs by combining therapeutically relevant cell populations with biocompatible biomaterial, and (iv) evaluating in vivo neokidney tissue development in response to NKA constructs delivered to healthy rodent renal parenchyma. Gelatin and hyaluronic acid (HA)-based hydrogels elicited the least inflammatory and fibrotic responses in renal parenchyma relative to polycaprolactone (PCL) and poly(lactic- co-glycolic acid) (PLGA) beads or particles and were associated with neovascularization and cellular infiltration by 4 weeks postimplantation. Renal cell populations seeded onto gelatin or HA-based hydrogels were viable and maintained a tubular epithelial functional phenotype during an in vitro maturation of 3 days as measured by transcriptomic, proteomic, secretomic, and confocal immunofluorescence assays. In vivo delivery of cell-seeded NKA constructs (bioactive renal cells + gelatin hydrogels) to healthy rodent renal parenchyma elicited neokidney tissue formation at 1 week postimplantation. To investigate a potential mechanism by which NKA constructs could impact a disease state, the effect of conditioned media on TGF-β signaling pathways related to tubulo-interstitial fibrosis associated with CKD progression was evaluated. Conditioned medium was observed to attenuate TGF-β-induced epithelial–mesenchymal transition (EMT) in vitro in a human proximal tubular cell line (HK2).
Bone Marrow Mesenchymal Stem Cells in a Three-Dimensional Gelatin Sponge Scaffold Attenuate Inflammation, Promote Angiogenesis, and Reduce Cavity Formation in Experimental Spinal Cord Injury
Authors: Zeng Xiang , Zeng Yuan-Shan , Ma Yuan-Huan , Lu Li-Ya , Du Bao-Ling , Zhang Wei , Li Yan , Chan Wood Yee
Published: December 2011

Three-dimensional (3D) gelatin sponge (GS) scaffolds were constructed by ensheathing GS with a thin film of poly-(lactide- co-glycolide) (PLGA). Rat bone marrow-derived mesenchymal stem cells (MSCs) were isolated, cultured, and then seeded to the scaffolds. Distribution of cells and cell growth, survival, and proliferation within the scaffolds were then determined. Immunofluorescence and Western blot analysis were employed to detect the deposition of fibronectin to the scaffolds on day 3 and day 7 of culture. Scaffolds with or without MSCs were then transplanted into the transected rat spinal cord. One or 8 weeks following transplantation, cavity areas, activated macrophages/microglia, expression of TNF-α and IL-1β, and neovascularization within the grafts were examined and quantified. Deposition of fibronectin (FN) and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) as potential inducing factors for angiogenesis were also examined. Results showed that 3D GS scaffolds allowed MSCs to adhere, survive, and proliferate and also FN to deposit. In vivo transplantation experiments demonstrated that these scaffolds were biocompatible, and MSCs seeded to the scaffolds played an important role in attenuating inflammation, promoting angiogenesis, and reducing cavity formation. Therefore, the GS scaffolds with MSCs may serve as promising supporting transplants for repairing spinal cord injury.
Injection Parameters Affect Cell Viability and Implant Volumes in Automated Cell Delivery for the Brain
Authors: Kondziolka Douglas , Gobbel Glenn T. , Fellows-Mayle Wendy , Chang Yue-Fang , Uram Martin
Published: December 2011

The technique of central nervous system cell implantation can affect the outcome of preclinical or clinical studies. Our goal was to evaluate the impact of various injection parameters that may be of consequence during the delivery of solute-suspended cells. These parameters included ( 1 ) the type and concentration of cells used for implantation, ( 2 ) the rate at which cells are injected (flow rate), ( 3 ) the acceleration of the delivery device, ( 4 ) the period of time between cell loading and injection into the CNS (delay), and ( 5 ) the length and gauge of the needle used to deliver the cells. Neural progenitor cells (NPCs) and bone marrow stromal cells (BMSCs) were injected an automated device. These parameters were assessed in relation to their effect on the volume of cells injected and cell viability. Longer and thinner cannulae and higher cell concentrations were detrimental for cell delivery. Devices and techniques that optimize these parameters should be of benefit.