bluuebunny/crossref_metadata_2025 huggingface dataset:
Endovascular management of intracranial blister aneurysms: spectrum and limitations of contemporary techniques
Authors: Ashour Ramsey , Dodson Stephen , Aziz-Sultan M Ali
Published: November 2014

Background

Intracranial blister aneurysms are rare lesions that are notoriously more difficult to treat than typical saccular aneurysms. High complication rates associated with surgery have sparked considerable interest in endovascular techniques, though not well-studied, to treat blister aneurysms.

Objective

To evaluate our experience using various endovascular approaches to treat blister aneurysms.

Methods

All consecutive blister aneurysms treated using an endovascular approach by the study authors over a 3-year period were retrospectively analyzed. A literature review was also performed.

Results

Nine patients with blister aneurysms underwent 11 endovascular interventions. In various combinations, stents were used in 8/11, coils in 5/11, and Onyx in 3/11 procedures. At mean angiographic follow-up of 200 days, 8/9 aneurysms were completely occluded by endovascular means alone requiring no further treatment and 1/9 aneurysms required surgical bypass/trapping after one failed surgical and two failed endovascular treatments. At mean clinical follow-up of 416 days, modified Rankin Scale scores were improved in six patients, stable in two, and worsened in one patient. One complication occurred in 11 procedures (9%), resulting in a permanent neurologic deficit. No unintended endovascular parent vessel sacrifice, intraprocedural aneurysmal ruptures, antiplatelet-related complications, post-treatment aneurysmal re-ruptures, or deaths occurred.

Conclusion

This series highlights both the spectrum and limitations of endovascular techniques currently used to treat blister aneurysms, including a novel application of stent-assisted Onyx embolization. Long-term follow-up and experience in larger studies are required to better define the role of endovascular therapy in the management of these difficult lesions.
Nitrogen-retention capacity in a fertilized forest after clear-cutting — the effect of forest-floor vegetation
Authors: Hedwall Per-Ola , Bergh Johan , Nordin Annika
Published: November 2014

Forest fertilization with nitrogen (N) has several benefits to society such as increased wood production and carbon sequestration. There are, however, concerns about N leakage, particularly following clear-cutting. The forest-floor vegetation may increase the N retention of forest ecosystems; however, very few studies have quantified the amount of vegetation required. We studied the relationship between vegetation cover and risk of N leakage, estimated by the amounts of ammonium-N and nitrate-N retained on ion-exchange capsules in the soil, during 4 years following the clear-cutting and harvesting of logging residues in a previously fertilized forest in southern Sweden. Previous fertilization increased the amount of nitrate-N captured on the capsules, whereas the amount of ammonium-N decreased. The vascular vegetation cover increased from almost zero to approximately 25% independent of fertilization. The amount of ammonium-N and nitrate-N retained on the capsules was already reduced by 50%–75% at 20% vegetation cover, and by 30%–40% cover, it approached zero, independent of the number of years since clear-cutting. The vegetation may impede tree-seedling establishment, implying a trade-off between seedling growth and N-retention capacity. However, our results indicate that maximum N retention may be achieved at a relatively low vegetation cover, which could be accomplished with less intrusive scarification methods than currently used.
Numerical simulation of a flat electroosmotic driven flow in the presence of a charged mid-plate
Authors: Mohammadipour Omid Reza , Niazmand Hamid
Published: November 2014

Motivated by the growing interest in electroosmotic flows (EOFs) as a reliable no moving parts strategy to control fluid motion in various micro fluidics, two-dimensional (2D) steady-state EOFs in the presence of a charged mid-plate have been numerically investigated. A variation of lattice Boltzmann models is used to recover all governing equations, where the Nernst–Planck equation is employed to model the internal electrical field. Results are validated by comparing the velocity profiles in the 2D uniform EOFs against their analytical solutions. The numerical results show that the velocity profile and volumetric flow rate are strongly influenced by the ratio of the electrical double layer (EDL) thickness to the channel height. In addition, the effects of positioning and thickness of the charged mid-plate on the electric field distribution, velocity profile and flow rate are examined in detail.
Yamabe flow on Berwald manifolds
Authors: Azami Shahroud , Razavi Asadollah
Published: November 2014

Studying the geometric flow plays a powerful role in mathematics and physics. We introduce the Yamabe flow on Finsler manifolds and we will prove the existence and uniqueness for solution of Yamabe flow on Berwald manifolds.
Synthesis and properties of palladium(II) complexes of aromatic hemiporphyrazines
Authors: Muranaka Atsuya , Kyotani Fumiko , Ouyang Xingmei , Hashizume Daisuke , Uchiyama Masanobu
Published: November 2014

Palladium(II) complexes of aromatic hemiporphyrazines were prepared by the reaction of bis(dibenzylideneacetone)palladium(0) with the corresponding metal-free macrocycles. Single crystal X-ray analysis revealed that a palladium(II) ion was coordinated inside the macrocyclic cavity to form two Pd – C bonds. Electronic properties of the metalloorganic compounds were characterized by NMR, UV-vis-NIR, and magnetic circular dichroism (MCD) spectroscopy.
Experimental study of surface-modified silica nanoparticles in enhancing oil recovery
Authors: Roustaei Abbas
Published: November 2014

One of the main objectives of nanotechnology in the oil industry is to identify applications that could bring significant benefits to enhanced oil recovery. Therefore, it has attracted the attention of many researchers over the last decade. This paper experimentally investigates the efficiency of surface-modified silica nanoparticles in enhanced oil recovery. These nanoparticles improve oil recovery through two main mechanisms: oil–water interfacial tension reduction; and wettability alteration. Various concentrations of nanofluid were made, and their effect on wettability and interfacial tension were investigated to determine the optimum concentration for injection into core samples. The results indicate that a concentration of 4 g l
−1
is the optimum concentration. Moreover, this paper reports the nanofluids’ potential in enhanced oil recovery of water-wet core plugs. The results of coreflood experiments reveal that oil recovery increases by 26.2% and total oil recovery considerably improves after the injection of nanofluid. In addition, filtration of the nanofluid before injection into the core was very effective in reducing the risk of possible permeability damage that occurred due to the deposition of large nanoparticle aggregates onto the rock surface.
Protein tyrosine phosphatase of liver regeneration-1 is required for normal timing of cell cycle progression during liver regeneration
Authors: Jiao Yang , Ye Diana Z. , Li Zhaoyu , Teta-Bissett Monica , Peng Yong , Taub Rebecca , Greenbaum Linda E. , Kaestner Klaus H.
Published: November 2014

Protein tyrosine phosphatase of liver regeneration-1 ( Prl-1) is an immediate-early gene that is significantly induced during liver regeneration. Several in vitro studies have suggested that Prl-1 is important for the regulation of cell cycle progression. To evaluate its function in liver regeneration, we ablated the Prl-1 gene specifically in mouse hepatocytes using the Cre-loxP system. Prl-1 mutant mice ( Prl-1loxP/loxP;AlfpCre) appeared normal and fertile. Liver size and metabolic function in Prl-1 mutants were comparable to controls, indicating that Prl-1 is dispensable for liver development, postnatal growth, and hepatocyte differentiation. Mutant mice demonstrated a delay in DNA synthesis after 70% partial hepatectomy, although ultimate liver mass restoration was not affected. At 40 h posthepatectomy, reduced protein levels of the cell cycle regulators cyclin E, cyclin A2, cyclin B1, and cyclin-dependent kinase 1 were observed in Prl-1 mutant liver. Investigation of the major signaling pathways involved in liver regeneration demonstrated that phosphorylation of protein kinase B (AKT) and signal transducer and activator of transcription (STAT) 3 were significantly reduced at 40 h posthepatectomy in Prl-1 mutants. Taken together, this study provides evidence that Prl-1 is required for proper timing of liver regeneration after partial hepatectomy. Prl-1 promotes G1/S progression via modulating expression of several cell cycle regulators through activation of the AKT and STAT3 signaling pathway.
Intestinal epithelial suppressor of cytokine signaling 3 enhances microbial-induced inflammatory tumor necrosis factor-α, contributing to epithelial barrier dysfunction
Authors: Thagia Imtiyaz , Shaw Elisabeth J. , Smith Emily , Else Kathryn J. , Rigby Rachael J.
Published: November 2014

A single layer of intestinal epithelial cells (IEC) lines the entire gastrointestinal tract and provides the first line of defense and barrier against an abundance of microbial stimuli. IEC homeostasis and repair are mediated through microbe-sensing Toll-like receptor (TLR)-induced inflammatory pathways. Increasing evidence supports a role of suppressor of cytokine signaling 3 (SOCS3) as a modulator of IEC turnover, balancing controlled repair and replenishment with excessive IEC proliferation predisposing to dysplasia and cancer. Our data indicate that SOCS3 can limit microbial-induced IEC repair, potentially through promoting tumor necrosis factor-α (TNF-α) and limiting TNFR2 expression. Activation of TLR5 signaling pathways, compared with other TLR, increases TNF-α mRNA in a dose-dependent manner and SOCS3 enhances TLR5-induced TNF-α. We also show that flagellin promotes transcription of TNFR2 and that SOCS3 limits this expression, presenting a mechanism of SOCS3 action. Our data also support the role of microbial ligands in epithelial wound healing and suggest that a functional consequence of increased TNF-α is reduced wound healing. These results provide further evidence to support the regulatory role of epithelial SOCS3 in intestinal health and suggest that the increased expression of SOCS3 observed in IBD may serve to perpetuate “inflammation” by promoting TNF-α production and limiting epithelial repair in response to commensal microflora.
Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis
Authors: Starr Marlene E. , Takahashi Hitoshi , Okamura Daiki , Zwischenberger Brittany A. , Mrazek Amy A. , Ueda Junji , Stromberg Arnold J. , Evers B. Mark , Esmon Charles T. , Saito Hiroshi
Published: November 2014

Sepsis is a life-threatening clinical condition that is particularly serious among the elderly who experience considerably higher mortality rates compared with younger patients. Using a sterile endotoxemia model, we previously reported age-dependent mortality in conjunction with enhanced coagulation and insufficient levels of anti-coagulant factor activated protein C (aPC). The purpose of the present study was to further investigate the mechanisms for age-dependent coagulation and aPC insufficiency during experimental sepsis. Intra-abdominal sepsis was induced by cecal ligation and puncture (CLP) using 21 or 16 gauge (G) needles (double-puncture) on young (4 to 6 mo old) and aged (20 to 25 mo old) male C57BL/6 mice. When compared with young mice, aged mice showed significantly increased mortality (92% vs. 28%), systemic inflammation, and coagulation in the lung and kidney after 21G CLP. Young mice with more severe CLP (16G) showed a mortality rate and inflammation equivalent to aged mice with 21G CLP; however, enhanced coagulation and kidney dysfunction were significant only in the aged. In young mice, increased levels of aPC after CLP were coupled with reduced levels of protein C (PC), suggesting the conversion of PC to aPC; however, PC and aPC levels remained unchanged in aged mice, indicating a lack of PC to aPC conversion. Activation of fibrinolysis, determined by plasma d-dimer levels, was similar regardless of age or CLP severity, and plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, showed severity-dependent induction independent of age. These results suggest that enhanced coagulation in aged mice during sepsis is due to dysfunction of the PC activation mechanism.
Angiotensin II-induced hypertension blunts thick ascending limb NO production by reducing NO synthase 3 expression and enhancing threonine 495 phosphorylation
Authors: Ramseyer Vanesa D. , Gonzalez-Vicente Agustin , Carretero Oscar A. , Garvin Jeffrey L.
Published: November 2014

Thick ascending limbs reabsorb 30% of the filtered NaCl load. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl transport by this segment. In contrast, chronic angiotensin II (ANG II) infusion increases net thick ascending limb transport. NOS3 activity is regulated by changes in expression and phosphorylation at threonine 495 (T495) and serine 1177 (S1177), inhibitory and stimulatory sites, respectively. We hypothesized that NO production by thick ascending limbs is impaired by chronic ANG II infusion, due to reduced NOS3 expression, increased phosphorylation of T495, and decreased phosphorylation of S1177. Rats were infused with 200 ng·kg−1·min−1ANG II or vehicle for 1 and 5 days. ANG II infusion for 5 days decreased NOS3 expression by 40 ± 12% ( P < 0.007; n = 6) and increased T495 phosphorylation by 147 ± 26% ( P < 0.008; n = 6). One-day ANG II infusion had no significant effect. NO production in response to endothelin-1 was blunted in thick ascending limbs from ANG II-infused animals [ANG II −0.01 ± 0.06 arbitrary fluorescence units (AFU)/min vs. 0.17 ± 0.02 AFU/min in controls; P < 0.01]. This was not due to reduced endothelin-1 receptor expression. Phosphatidylinositol 3,4,5-triphosphate (PIP3)-induced NO production was also reduced in ANG II-infused rats (ANG II −0.07 ± 0.06 vs. 0.13 ± 0.04 AFU/min in controls; P < 0.03), and this correlated with an impaired ability of PIP3 to increase S1177 phosphorylation. We conclude that in ANG II-induced hypertension NO production by thick ascending limbs is impaired due to decreased NOS3 expression and altered phosphorylation.
Renal NHE expression and activity in neonatal NHE3- and NHE8-null mice
Authors: Pirojsakul Kwanchai , Gattineni Jyothsna , Dwarakanath Vangipuram , Baum Michel
Published: November 2014

Na+/H+ exchanger (NHE)3 is the predominant NHE on the brush-border membrane of the proximal tubule in adult animals. NHE8 has been localized to the brush-border membrane of proximal tubules and is more highly expressed in neonates than in adult animals. However, the relative role of NHE8 in neonatal renal acidification is unclear. The present study examined if there was a compensatory increase in NHE3 in NHE8-null neonatal mice and whether there was a compensatory increase in NHE8 in NHE3-null neonatal mice. In addition, we examined whether wild-type, NHE3-null, and NHE8-null mice had an increase in NHE activity in response to metabolic acidosis. We found that at baseline, there was comparable renal NHE3 mRNA, total protein, and brush-border membrane protein abundance as in neonatal control and NHE8-null mice. There was comparable renal NHE8 mRNA, total protein, and brush-border membrane protein abundance in NHE3-null neonatal and control mice. Both NHE3- and NHE8-null mice had a comparable but lower rate of NHE activity than control mice. We next imposed metabolic acidosis in wild-type, NHE3-null, and NHE8-null mice. Acidemic NHE8-null mice had an increase in brush-border membrane vesicle NHE3 protein abundance and NHE activity compared with vehicle-treated mice. Likewise, NHE3-null mice had an increase in NHE8 brush-border membrane protein abundance and NHE activity in response to metabolic acidosis. In conclusion, both NHE3 and NHE8 likely play a role in neonatal acidification.
Initiation and modulation of locomotor circuitry output with multisite transcutaneous electrical stimulation of the spinal cord in noninjured humans
Authors: Gerasimenko Yury , Gorodnichev Ruslan , Puhov Aleksandr , Moshonkina Tatiana , Savochin Aleksandr , Selionov Victor , Roy Roland R. , Lu Daniel C. , Edgerton V. Reggie
Published: November 2014

The mammalian lumbar spinal cord has the capability to generate locomotor activity in the absence of input from the brain. Previously, we reported that transcutaneous electrical stimulation of the spinal cord at vertebral level T11 can activate the locomotor circuitry in noninjured subjects when their legs are placed in a gravity-neutral position (Gorodnichev RM, Pivovarova EA, Pukhov A, Moiseev SA, Savokhin AA, Moshonkina TR, Shcherbakova NA, Kilimnik VA, Selionov VA, Kozlovskaia IB, Edgerton VR, Gerasimenko IU. Fiziol Cheloveka 38: 46–56, 2012). In the present study we hypothesized that stimulating multiple spinal sites and therefore unique combinations of networks converging on postural and locomotor lumbosacral networks would be more effective in inducing more robust locomotor behavior and more selective control than stimulation of more restricted networks. We demonstrate that simultaneous stimulation at the cervical, thoracic, and lumbar levels induced coordinated stepping movements with a greater range of motion at multiple joints in five of six noninjured subjects. We show that the addition of stimulation at L1 and/or at C5 to stimulation at T11 immediately resulted in enhancing the kinematics and interlimb coordination as well as the EMG patterns in proximal and distal leg muscles. Sequential cessation of stimulation at C5 and then at L1 resulted in a progressive degradation of the stepping pattern. The synergistic and interactive effects of transcutaneous stimulation suggest a multisegmental convergence of descending and ascending, and most likely propriospinal, influences on the spinal neuronal circuitries associated with locomotor activity. The potential impact of using multisite spinal cord stimulation as a strategy to neuromodulate the spinal circuitry has significant implications in furthering our understanding of the mechanisms controlling posture and locomotion and for regaining significant sensorimotor function even after a severe spinal cord injury.
Intrinsic excitability varies by sex in prepubertal striatal medium spiny neurons
Authors: Dorris David M. , Cao Jinyan , Willett Jaime A. , Hauser Caitlin A. , Meitzen John
Published: November 2014

Sex differences in neuron electrophysiological properties were traditionally associated with brain regions directly involved in reproduction in adult, postpubertal animals. There is growing acknowledgement that sex differences can exist in other developmental periods and brain regions as well. This includes the dorsal striatum (caudate/putamen), which shows robust sex differences in gene expression, neuromodulator action (including dopamine and 17β-estradiol), and relevant sensorimotor behaviors and pathologies such as the responsiveness to drugs of abuse. Here we examine whether these sex differences extend to striatal neuron electrophysiology. We test the hypothesis that passive and active medium spiny neuron (MSN) electrophysiological properties in prepubertal rat dorsal striatum differ by sex. We made whole cell recordings from male and females MSNs from acute brain slices. The slope of the evoked firing rate to current injection curve was increased in MSNs recorded from females compared with males. The initial action potential firing rate was increased in MSNs recorded from females compared with males. Action potential after-hyperpolarization peak was decreased, and threshold was hyperpolarized in MSNs recorded from females compared with males. No sex differences in passive electrophysiological properties or miniature excitatory synaptic currents were detected. These findings indicate that MSN excitability is increased in prepubertal females compared with males, providing a new mechanism that potentially contributes to generating sex differences in striatal-mediated processes. Broadly, these findings demonstrate that sex differences in neuron electrophysiological properties can exist prepuberty in brain regions not directly related to reproduction.
Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy
Authors: Rosanò Laura , Cianfrocca Roberta , Tocci Piera , Spinella Francesca , Di Castro Valeriana , Caprara Valentina , Semprucci Elisa , Ferrandina Gabriella , Natali Pier Giorgio , Bagnato Anna
Published: November 2014

The high mortality of epithelial ovarian cancer (EOC) is mainly caused by resistance to the available therapies. In EOC, the endothelin-1 (ET-1, EDN1)–endothelin A receptor (ETAR, EDNRA) signaling axis regulates the epithelial–mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, we define a novel bypass mechanism through which ETAR/β-arrestin-1 (β-arr1, ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that ETAR/β-arr1 activity promoted nuclear complex with β-catenin and p300, resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as ET-1, enhancing the network that sustains chemoresistance. Silencing of β-arr1 or pharmacologic treatment with the dual ETAR/ETBR antagonist macitentan prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo macitentan treatment reduced tumor growth, vascularization, intravasation, and metastatic progression. The combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, indicating that macitentan can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant EOC tissues confirmed increased recruitment of β-arr1 and β-catenin to ET-1 gene promoter. In these tissues, high expression of ETAR significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which ETAR/β-arr1 signaling is integrated with the Wnt/β-catenin pathway to sustain chemoresistance in EOC, and they offer a solid rationale for clinical evaluation of macitentan in combination with chemotherapy to overcome chemoresistance in this setting. Cancer Res; 74(24); 7453–64. ©2014 AACR.
Personal Navigation Increases Colorectal Cancer Screening Uptake
Authors: Ritvo Paul G. , Myers Ronald E. , Paszat Lawrence F. , Tinmouth Jill M. , McColeman Joshua , Mitchell Brian , Serenity Mardie , Rabeneck Linda
Published: November 2014

Background: Prior randomized, controlled trials (RCTs) indicate that patient navigation can boost colorectal cancer screening rates in primary care. The sparse literature on pragmatic trials of interventions designed to increase colorectal cancer screening adherence motivated this trial on the impact of a patient navigation intervention that included support for performance of the participants' preferred screening test (colonoscopy or stool blood testing).

Materials and Methods: Primary care patients (n = 5,240), 50 to 74 years of age, with no prior diagnosis of bowel cancer and no record of a recent colorectal cancer screening test, were identified at the Group Health Centre in northern Ontario. These patients were randomly assigned to an intervention group (n = 2,629) or a usual care control group (n = 2,611). Intervention group participants were contacted by a trained nurse navigator by telephone to discuss colorectal cancer screening. Interested patients met with the navigator, who helped them identify and arrange for performance of the preferred screening test. Control group participants received usual care. Multivariate analyses were conducted using medical records data to assess intervention impact on screening adherence within 12 months after randomization.

Results: Mean patient age was 59 years, and 50% of participants were women. Colorectal cancer screening adherence was higher in the intervention group (35%) than in the control group (20%), a difference that was statistically significant (OR, 2.11; confidence interval, 1.87–2.39).

Conclusion: Preference-based patient navigation increased screening uptake in a pragmatic RCT.

Impact: Patient navigation increased colorectal cancer screening rates in a pragmatic RCT in proportions similar to those observed in explanatory RCTs. Cancer Epidemiol Biomarkers Prev; 24(3); 506–11. ©2014 AACR.
Reduction of Regulatory T Cells by Mogamulizumab, a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients with Aggressive/Refractory Mycosis Fungoides and Sézary Syndrome
Authors: Ni Xiao , Jorgensen Jeffrey L. , Goswami Meghali , Challagundla Pramoda , Decker William K. , Kim Youn H. , Duvic Madeleine A.
Published: November 2014

Purpose: The CC chemokine receptor 4 (CCR4) is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL) as well as on regulatory T cells (Treg). When mogamulizumab, a defucosylated monoclonal antibody, binds to CCR4, it induces antibody-dependent cellular cytotoxicity against CCR4+ malignant T cells. The goal of this study was to determine the effect of mogamulizumab on CCR4+ Tregs in patients with CTCL.

Experimental Design: Peripheral blood of 24 patients with CTCL participating in a phase I/II trial was analyzed for CCR4 expression on different T-cell subsets by flow cytometry, before and after one course of mogamulizumab. The number and function of natural killer (NK) cells were also analyzed. Lesional biopsies were examined for CCR4, Foxp3, and CD16 expression by immunohistochemistry.

Results: Malignant T cells in peripheral blood were 20.8%–100% positive for CCR4 at baseline. Fourteen patients who achieved a response in blood had high baseline CCR4 expression on malignant T cells. Tregs in blood were 58.6% to 100% positive for CCR4 at baseline and showed decreased numbers and CCR4 expression after treatment. CD8+ T cells in blood were 3.2% to 23.2% positive for CCR4 at baseline and showed limited reduction of CCR4 expression with increased percentages of CD8+ T cells after treatment. Of 14 patients tested for NK cells in blood, 10 showed increased percentages after treatment. Four of 6 patients tested showed increased NK cell cytotoxicity. Sixteen of 18 patients who had CCR4+ lymphocytes in baseline lesions showed decreased numbers after treatment.

Conclusions: Mogamulizumab reduces levels of CCR4+ malignant T cells and also CCR4+ Tregs in patients with CTCL, which may in turn improve immune profiles. Clin Cancer Res; 21(2); 274–85. ©2014 AACR.
Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human–Mouse Chimeric and Glycoengineered Antibody
Authors: Zhang Zheng , Zhang Yang , Sun Qian , Feng Fei , Huhe Muren , Mi Li , Chen Zhinan
Published: November 2014

Metuzumab is an affinity-optimized and nonfucosylated anti-CD147 human–mouse chimeric IgG1 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC). The purpose of this study was to characterize the pharmacokinetics, safety, and antitumor activities of metuzumab in mouse, rat, and monkey. The ADCC activity was assessed by a lactate dehydrogenase release assay. The pharmacokinetics of metuzumab were determined in Sprague–Dawley rats and in cynomolgus monkeys. Single- and repeat-dose toxicology studies of the i.v. administration of high-dose metuzumab were conducted in cynomolgus monkeys. Mice bearing human tumor xenografts were used to evaluate the antitumor efficacy of metuzumab. The ADCC potency of metuzumab was enhanced compared with the nonglycoengineered parental antibody. Metuzumab also effectively inhibited tumor growth in A549 and NCI-H520 xenograft models. In the monkey model, the total clearance of metuzumab decreased with increasing dose. The nonspecific clearance in monkeys was estimated to be 0.53 to 0.92 mL/h/kg. In single- and repeat-dose toxicology studies in cynomolgus monkeys, metuzumab did not induce any distinct or novel adverse findings and was well tolerated at all tested doses. These preclinical safety data facilitated the initiation of an ongoing clinical trial of metuzumab for the treatment of non–small cell lung cancer (NSCLC) in China. Mol Cancer Ther; 14(1); 162–73. ©2014 AACR.
Cathepsin D Repairing Role in Photodamaged Skin Barrier
Authors: Zheng Yue , Chen Haiyan , Lai Wei , Xu Qingfang , Liu Chen , Wu Lin , Maibach Howard I.
Published: November 2014

Backgrounds/Objectives: Cathepsin D plays an important part in maintaining a normal skin barrier. Our previous study found that cathepsin D decreased in chronic photodamaged skin. This study investigated the cathepsin D content change in the stratum corneum (SC) and the repairing role of cathepsin D in chronic photodamaged skin barrier via the application of cathepsin D gel. Methods: Cathepsin D gel (0.001%) was applied to chronic photodamaged (sun-exposed forearm) human skin on identical sites (1 cm²/area) twice daily for 2 weeks. At 30 min and at 1, 3, 7, and 14 days, skin hydration and transepidermal water loss (TEWL) average values were detected via noninvasive skin detection equipment. Cathepsin D and transglutaminase (TGase)-1 in the skin sublayers were separated and detected via tape stripping, ELISA and Western blot. Results: After 2 weeks of cathepsin D gel application, the skin moisture value increased from 86.8 ± 1.2 to 95.2 ± 2.7 (p < 0.05), while TEWL decreased from 17.88 ± 1.87 to 11.58 ± 2.14 (p < 0.05). Cathepsin D protein was detected in the upper epidermis (12.6 ± 2.6 ng/cm2), mid-epidermis (8.4 ± 0.8 ng/cm2) and deep epidermis (16.2 ± 2.6 ng/cm2) in the cathepsin D gel group compared to the control group (2.2 ± 0.7, 3.0 ± 1.1 and 3.85 ± 1.4 ng/cm2, respectively; p < 0.05). TGase-1 enzyme expression was upregulated 2.54 ± 0.19 times in the matrix gel-treated skin. Conclusions: These data suggest that cathepsin D gel could increase the SC cathepsin D content and repair the epidermal barrier in chronic photodamaged skin. The mechanism might be related to increasing TGase-1 expression and activity. © 2014 S. Karger AG, Basel
Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab
Authors: Bianco Assunta , Patanella Agata Katia , Nociti Viviana , Marti Alessandro , Frisullo Giovanni , Plantone Domenico , De Fino Chiara , Fetta Anna , Batocchi Anna Paola , Rossini Paolo Maria , Mirabella Massimiliano
Published: November 2014

Background: To evaluate efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis, particularly in patients previously exposed to natalizumab. Method: Prospective observational single-centre second-line cohort study. Results: Among 71 patients treated with fingolimod 0.5 mg/day for a mean duration of 21.75 w 12.60 months, the annualized relapse rate was 0.66 (C.I. 95% 0.27-1.05) with a significant difference between 26 patients with prior natalizumab exposure (1.15; C.I. 95% 0.12-2.17) and 45 not exposed (0.38; C.I. 95% 0.18-0.57; p = 0.002). In a multivariate negative regression model, only previous exposure to natalizumab (p = 0.049) and duration of fingolimod treatment (p < 0.001) significantly correlated with the annualized relapse rate. Previous exposure to natalizumab (p = 0.028) and duration of treatment with fingolimod (p < 0.001) were confirmed by restricting the analysis to the first 12 months of treatment with fingolimod, but were no longer statistically significant by analysing only patients (n = 51) with at least 12 months of treatment with fingolimod (0.32; C.I. 95% 0.08-0.55 vs. 0.22; C.I. 95% 0.11-0.32; p = NS). No differences were observed in neuroradiological outcomes and disability progression in patients exposed to natalizumab and not exposed. The rate of discontinuation due to adverse events was 11.3%, with no differences between the two groups. Conclusions: Our study confirms efficacy and side effects of fingolimod in a second-line clinical practice cohort. Prior natalizumab exposure and duration of treatment with fingolimod are independent predictors of annualized relapse rate during the first 12 months of treatment with fingolimod, but not in the long-term, and may be influenced by the 3 months washout period between the two drugs. i 2014 S. Karger AG, Basel
Mentalizing Functions Provide a Conceptual Link of Brain Function and Social Cognition in Major Mental Disorders
Authors: Schnell Knut
Published: November 2014

The review presents a research perspective that defines mentalizing functions as a very promising topic to bridge psychopathology and neurobiological foundations of mental disorders. However, the high diversity of existing observations in mentalizing research calls for a structured assessment of functional mentalizing subdomains. A notable problem is the overlap of functional systems involved in mentalizing and emotion processing. A proposed solution is to conceptualize mentalizing functions due to their content (visuospatial vs. emotional) perspective and substrates (cognitive or explicit signals). This conceptual organization is mirrored in functional imaging experiments dissociating anteromedial and posterolateral brain regions, especially the involvement of the medial prefrontal cortex in mentalizing emotions and the temporoparietal cortex in visuospatial perspective taking. The present state and perspectives of mentalizing research are demonstrated in two major fields of mental disorders, depression and schizophrenia. In depression the existent contradictory findings demand a control of cognitive impairments, which are frequently associated with depressive disorders. In schizophrenia there is already consistent evidence that defines mentalizing functions as promising endophenotype, which can possibly link psychopathology to its neurobiological foundations.
New Causes of Central Precocious Puberty: The Role of Genetic Factors
Authors: Bulcao Macedo Delanie , Nahime Brito Vinicius , Latronico Ana Claudia
Published: November 2014

A pivotal event in the onset of puberty in humans is the reemergence of the pulsatile release of the gonadotropin-releasing hormone (GnRH) from hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of kisspeptin and its cognate receptor (KISS1/KISS1R) and the inactivation of MKRN3 in the premature reactivation of GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located on the long arm of chromosome 15, encodes makorin ring finger protein 3, which is involved in ubiquitination and cell signaling. The MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explored the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing.
Neurally Adjusted Ventilatory Assist in Preterm Neonates with Acute Respiratory Failure
Authors: Longhini Federico , Ferrero Federica , De Luca Daniele , Cosi Gianluca , Alemani Moreno , Colombo Davide , Cammarota Gianmaria , Berni Paola , Conti Giorgio , Bona Gianni , Della Corte Francesco , Navalesi Paolo
Published: November 2014

Background: Neurally adjusted ventilatory assist (NAVA) is a novel mode of ventilation that has been demonstrated to improve infant-ventilator interaction, compared to the conventional modes in retrospective and short-term studies. Objectives: To prospectively evaluate the physiologic effects of NAVA in comparison with pressure-regulated volume control (PRVC) in two nonrandomized 12-hour periods. Methods: We studied 14 consecutive intubated preterm neonates receiving mechanical ventilation for acute respiratory failure. Peak airway pressure (Pawpeak), diaphragm electrical activity (EAdi), tidal volume (VT), mechanical (RRmec) and neural (RRneu) respiratory rates, neural apneas, and the capillary arterialized blood gases were measured. The RRmec-to-RRneu ratio (MNR) and the asynchrony index were also calculated. The amount of fentanyl administered was recorded. Results: Pawpeak and VT were greater in PRVC (p < 0.01). Blood gases and RRmec were not different between modes, while RRneu and the EAdi swings were greater in NAVA (p = 0.02 and p < 0.001, respectively). MNR and the asynchrony index were remarkably lower in NAVA than in PRVC (p = 0.03 and p < 0.001, respectively). 1,841 neural apneas were observed during PRVC, with none in NAVA. Less fentanyl was administered during NAVA, as opposed to PRVC (p < 0.01). Conclusions: In acutely ill preterm neonates, NAVA can be safely and efficiently applied for 12 consecutive hours. Compared to PRVC, NAVA is well tolerated with fewer sedatives.
Case Series of Bifidobacterium longum Bacteremia in Three Preterm Infants on Probiotic Therapy
Authors: Zbinden Andrea , Zbinden Reinhard , Berger Christoph , Arlettaz Romaine
Published: November 2014

Background: The use of probiotics as prophylaxis for necrotizing enterocolitis (NEC) in preterm infants is being increasingly practised. Objective: We report, for the first time, a case series of 3 preterm, very-low-birth-weight (VLBW) infants who developed bacteremia with Bifidobacterium longum on probiotic therapy with Infloran® containing viable B. longum. Methods: We retrospectively reviewed data of 3 infants (of gestational age <30 weeks and birth weight <1,230 g). They were admitted to the neonatal intensive care unit. Clinical data were retrieved from their medical records. Results: In infants 1 and 2, B. longum was isolated from the blood cultures when they were on probiotic therapy with Infloran or shortly after, respectively, and was interpreted as transient bacteremia. The clinical presentation of these infants did not require antibiotic treatment after the isolation of B. longum. Infant 3 developed an NEC despite probiotic therapy with Infloran and the blood cultures showed B. longum growth. This infant required explorative laparotomy and antibiotic treatment. The clinical isolates of B. longum and the strain of the Infloran capsule showed an identical profile on biochemical, mass-spectrometric and molecular analyses, suggesting a direct correlation between the administration of probiotics and bacteremia with B. longum in all 3 infants. Conclusions: The occurrence of bacteremia with bifidobacteria after its prophylactic administration in VLBW infants and its possible clinical consequences are a matter of concern. In the interests of safety, the use of probiotics in such a population should be indicated with caution and requires further investigation.
A Case of Vogt-Koyanagi-Harada Syndrome with Persistent Dyspnea Secondary to Laryngeal Edema
Authors: Mantopoulos Dimosthenis , deSilva Brad W. , Cebulla Colleen M.
Published: November 2014

Purpose: We report a case of laryngeal edema associated with the Vogt-Koyanagi-Harada (VKH) syndrome. Patient and Methods: A 32-year-old African-American female presented with a 12-day prodrome, including headache, tinnitus and shortness of breath, which preceded sudden photophobia and bilateral visual loss. Examination and clinical testing were most consistent with VKH, and the patient improved with intravenous methylprednisolone therapy. Results: The patient had persistent dyspnea, which was out of proportion to chest CT findings and which was exacerbated during a recurrence of VKH. Flexible fiberoptic laryngoscopy with stroboscopy revealed diffuse laryngeal edema. Symptoms were alleviated with breathing exercises. Conclusions: Several autoimmune diseases may cause diffuse laryngeal edema. In this case, VKH was associated with the patient's glottic edema and dyspnea. We recommend that laryngeal edema be considered in the differential diagnosis for patients with dyspnea and VKH.
Idiopathic Accelerated Idioventricular Rhythm or Ventricular Tachycardia Originating From the Right Bundle Branch
Authors: Chen Minglong , Gu Kai , Yang Bing , Chen Hongwu , Ju Weizhu , Zhang Fengxiang , Yang Gang , Li Mingfang , Lu Xinzheng , Cao Kejiang , Ouyang Feifan
Published: November 2014

Background—

Accelerated idioventricular rhythm (AIVR) or ventricular tachycardia (VT) originating from the right bundle branch (RBB) is rare and published clinical data on such arrhythmia are scarce. In this study, we will describe the clinical manifestations, diagnosis, and management of a cohort of patients with this novel arrhythmia.

Methods and Results—

Eight patients (5 men; median age, 25 years) with RBB-AIVR/VT were consecutively enrolled in the study. Pharmacological testing, exercise treadmill testing, electrophysiological study, and catheter ablation were performed in the study patients, and ECG features were characterized. All RBB-AIVR/VTs were of typical left bundle-branch block morphology with atrioventricular dissociation. The arrhythmias, which demonstrated chronotropic variability, were often isorhythmic with sinus rhythm and were accelerated by physical exercise, stress, and intravenous isoprenaline infusion. The rate of RBB-AIVR/VT varied from 45 to 200 beats per minute. Two patients experienced syncope, and 3 had impaired left ventricular function. Metoprolol was proven to be the most effective drug to decelerate the arrhythmia rate and relieve symptoms. Electrophysiology study was performed in 5 patients and the earliest activation with a sharp RBB potential was localized in the mid or distal RBB area. Catheter ablation terminated the arrhythmia with subsequent RBB block morphology during sinus rhythm. During follow-up, patients’ symptoms were controlled with normalization of left ventricular function either on metoprolol or by catheter ablation.

Conclusions—

RBB-AIVR/VT is an unusual type of ventricular arrhythmia. It can result in significant symptoms and depressed ventricular function and can be successfully treated with catheter ablation.
Gut Microbiota-Dependent Trimethylamine
N
-Oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease
Authors: Tang W.H. Wilson , Wang Zeneng , Kennedy David J. , Wu Yuping , Buffa Jennifer A. , Agatisa-Boyle Brendan , Li Xinmin S. , Levison Bruce S. , Hazen Stanley L.
Published: November 2014

Rationale:

Trimethylamine-
N
-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and
l
-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis.

Objective:

To both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction.

Methods and Results:

We first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, <60 mL/min per 1.73 m
2
). Median TMAO level among CKD subjects was 7.9 μmol/L (interquartile range, 5.2–12.4 μmol/L), which was markedly higher (
P
<0.001) than in non-CKD subjects (n=3166). Within CKD subjects, higher (fourth versus first quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. After adjustments for traditional risk factors, high-sensitivity C-reactive protein, estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio, 1.93; 95% confidence interval, 1.13–3.29;
P
<0.05). TMAO provided significant incremental prognostic value (net reclassification index, 17.26%;
P
<0.001 and differences in area under receiver operator characteristic curve, 63.26% versus 65.95%;
P
=0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction.

Conclusions:

Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.
Embolic Strokes of Undetermined Source in the Athens Stroke Registry
Authors: Ntaios George , Papavasileiou Vasileios , Milionis Haralambos , Makaritsis Konstantinos , Manios Efstathios , Spengos Konstantinos , Michel Patrik , Vemmos Konstantinos
Published: November 2014

Background and Purpose—

A new clinical construct termed embolic stroke of undetermined source (ESUS) was recently introduced, but no such population has been described yet. Our aim is to provide a detailed descriptive analysis of an ESUS population derived from a large prospective ischemic stroke registry using the proposed diagnostic criteria.

Methods—

The criteria proposed by the Cryptogenic Stroke/ESUS International Working Group were applied to the Athens Stroke Registry to identify all ESUS patients. ESUS was defined as a radiologically confirmed nonlacunar brain infarct in the absence of (a) extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the ischemic area, (b) major-risk cardioembolic source, and (c) any other specific cause of stroke.

Results—

Among 2735 patients admitted between 1992 and 2011, 275 (10.0%) were classified as ESUS. In the majority of ESUS (74.2%), symptoms were maximal at onset. ESUS were of moderate severity (median National Institute Health Stroke Scale score, 5). The most prevalent risk factor was arterial hypertension (64.7%), and 50.9% of patients were dyslipidemic. Among potential causes of the ESUS, covert atrial fibrillation (AF) was the most prevalent: in 30 (10.9%) patients, AF was diagnosed during hospitalization for stroke recurrence, whereas in 50 (18.2%) patients AF was detected after repeated ECG monitoring during follow-up. Also, covert AF was strongly suggested in 38 patients (13.8%) but never recorded.

Conclusions—

About 10% of patients with first-ever ischemic stroke met criteria for ESUS; covert paroxysmal AF seems to be a frequent cause of ESUS.
Conditional Density Estimation with Dimensionality Reduction via Squared-Loss Conditional Entropy Minimization
Authors: Tangkaratt Voot , Xie Ning , Sugiyama Masashi
Published: November 2014

Regression aims at estimating the conditional mean of output given input. However, regression is not informative enough if the conditional density is multimodal, heteroskedastic, and asymmetric. In such a case, estimating the conditional density itself is preferable, but conditional density estimation (CDE) is challenging in high-dimensional space. A naive approach to coping with high dimensionality is to first perform dimensionality reduction (DR) and then execute CDE. However, a two-step process does not perform well in practice because the error incurred in the first DR step can be magnified in the second CDE step. In this letter, we propose a novel single-shot procedure that performs CDE and DR simultaneously in an integrated way. Our key idea is to formulate DR as the problem of minimizing a squared-loss variant of conditional entropy, and this is solved using CDE. Thus, an additional CDE step is not needed after DR. We demonstrate the usefulness of the proposed method through extensive experiments on various data sets, including humanoid robot transition and computer art.