bluuebunny/crossref_metadata_2025 huggingface dataset:
Bile Acids and Stellate Cells
Authors: Kordes Claus , Sawitza Iris , Götze Silke , Häussinger Dieter
Published: June 2015

Hepatic stellate cells are mainly known for their contribution to fibrogenesis in chronic liver diseases, but their identity and function in normal liver remain unclear. They were recently identified as liver-resident mesenchymal stem cells (MSCs), which can differentiate not only into adipocytes and osteocytes, but also into liver epithelial cells such as hepatocytes and bile duct cells as investigated in vitro and in vivo. During hepatic differentiation, stellate cells and other MSCs transiently develop into liver progenitor cells with epithelial characteristics before hepatocytes are established. Transplanted stellate cells from the liver and pancreas are able to contribute to liver regeneration in stem cell-based liver injury models and can also home into the bone marrow, which is in line with their classification as MSCs. There is experimental evidence that bile acids support liver regeneration and are able to activate signaling pathways in hepatic stellate cells. For this reason, it is important to analyze the influence of bile acids on developmental fate decisions of hepatic stellate cells and other MSC populations.
Relationship between Obesity, Gut Microbiome and Hepatocellular Carcinoma Development
Authors: Hara Eiji
Published: June 2015

During the past several decades, the percentage of excess bodyweight and obese adults and children has increased dramatically, and is becoming one of the most serious public health problems worldwide. Extensive epidemiological studies have revealed that there is a strong link between obesity and some common cancers. However, the exact molecular mechanisms linking obesity and cancer are not fully understood yet. Recently, we have reported that dietary or genetic obesity provokes alterations of gut microbiota profile, thereby increasing the levels of deoxycholic acid (DCA), a secondary bile acid produced solely by the 7α-dehydroxylation of primary bile acids carried out by gut bacteria. The enterohepatic circulation of DCA provokes DNA damage and consequent cellular senescence in hepatic stellate cells (HSCs) which, in turn, secrete various inflammatory and tumor-promoting factors in the liver, thus facilitating hepatocellular carcinoma (HCC) development in mice. Interestingly, signs of senescence-associated secretory phenotypes were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis, implying that a similar pathway is likely to contribute to at least certain aspects of obesity-associated HCC development in humans as well. In this review, I will provide an overview of our recent work and discuss the next steps, focusing on the potential clinical implications of our findings.
Changes on the Modulation of the Startle Reflex in Alcohol-Dependent Patients after 12 Weeks of a Cognitive-Behavioral Intervention
Authors: Jurado-Barba Rosa , Rubio Valladolid Gabriel , Martínez-Gras Isabel , Alvarez-Alonso María José , Ponce Alfaro Guillermo , Fernández Alberto , Moratti Stephan , Heinz Andreas , Jimenez-Arriero Miguel Ángel
Published: June 2015

Aims: Little is known about changes in the modulation of the startle reflex when patients go through an alcohol-dependence treatment in an outpatient facility. In the current study, the affective modulation of the cue-related startle reflex has been used to evaluate changes in the emotional processing of alcohol-related stimuli that occurred after a standard cognitive-behavioral intervention, and to assess the outcome of this intervention. We hypothesized a ‘normalization' of the startle inhibition for the alcohol-related cues during the period of treatment. We also assumed that higher startle inhibition at baseline elicited by alcohol cues would predict the relapse on alcohol consumption during treatment. Participants: A total of 98 alcohol-dependent subjects were included who fulfilled DSM-IV criteria for alcohol dependence. A control group of 72 subjects was selected to match demographic characteristics. Measurements: All patients received a standard cognitive-behavioral therapy once a week throughout the study period. Findings: Results show that the startle response differed significantly after 12 weeks of treatment for alcohol-related, neutral and aversive stimuli between alcohol-dependent patients and controls. Low startle responses at baseline to alcohol cues predicted relapse. Conclusions: These results may indicate that the startle reflex is referred to enduring and permanent processes of cue reactivity, and that the emotional processing of alcohol-associated cues assessed with the affect-modulated startle reflex is less altered by interventions attempting to influence explicit cognitions. Furthermore, lower values of the baseline startle reflex elicited by alcohol-associated stimuli were associated with higher probability of relapse on alcohol use.
Risk Factors for Borderline Personality Disorder in Treatment Seeking Patients with a Substance Use Disorder: An International Multicenter Study
Authors: Wapp Manuela , van de Glind Geurt , van Emmerik-van Oortmerssen Katelijne , Dom Geert , Verspreet Sofie , Carpentier Pieter Jan , Ramos-Quiroga Josep Antoni , Skutle Arvid , Bu Eli-Torlid , Franck Johan , Konstenius Maija , Kaye Sharlene , Demetrovics Zsolt , Barta Csaba , Fatséas Melina , Auriacombe Marc , Johnson Brian , Faraone Stephen V. , Levin Frances R. , Allsop Steve , Carruthers Susan , Schoevers Robert A. , Koeter Maarten W.J. , van den Brink Wim , Moggi Franz ,   IASP Research Group
Published: June 2015

Borderline personality disorder (BPD) and substance use disorders (SUDs) often co-occur, partly because they share risk factors. In this international multicenter study, risk factors for BPD were examined for SUD patients. In total, 1,205 patients were comprehensively examined by standardized interviews and questionnaires on psychiatric diagnosis and risk factors, and it was found that 1,033 (85.7%) had SUDs without BPD (SUD) and 172 (14.3%) had SUD with BPD (SUD + BPD). SUD + BPD patients were significantly younger, more often females and more often diagnosed with comorbid adult attention deficit/hyperactivity disorder. SUD + BPD patients did not differ from SUD patients on most risk factors typical for SUD such as maternal use of drugs during pregnancy or parents having any SUD. However, SUD + BPD patients did have a higher risk of having experienced emotional and physical abuse, neglect, or family violence in childhood compared to SUD patients, suggesting that child abuse and family violence are BPD-specific risk factors in patients with SUDs.
Review of the Bethesda System for Reporting Thyroid Cytopathology: A Local Study in Bohol Island, Philippines
Authors: Salillas Annette L. , Sun Faye Candice S. , Almocera Emelisa G.
Published: June 2015

Objectives: The aim of this study was to evaluate the adaptability and reproducibility of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) in a local setting and to determine the risk of malignancy for each category. Materials and Methods: A retrospective cross-sectional study of 80 thyroid fine-needle aspiration cytology cases using the BSRTC with corresponding histopathology was done between September 2009 and December 2012. Agreement scores were calculated using kappa statistics. Results: Consensus among two readers was attained for 73 cases (91.25%). No disagreement was noted for the malignant cases. The strength of agreement was very good, with a kappa statistic of 0.90. The risk of malignancy observed histologically was as follows: benign 3%, atypia of undetermined significance (AUS) 50%, suspicious for follicular/Hürthle cell neoplasm 50%, suspicious for malignancy 78%, and malignant 100%. Conclusion: In this study, there is an outstanding reproducibility for the classification scheme. The application of the BSRTC as the standardized reporting is readily adaptable and therefore its application in larger medical centers is highly recommended. Our findings of a higher risk of malignancy seen in AUS (50%) and malignant (100%) categories in those who underwent surgical resection corroborated other published studies. Conveying this risk to clinical colleagues is important and will facilitate optimal patient care.
Thickness of the Bony Otic Capsule: Etiopathogenetic Perspectives on Superior Canal Dehiscence Syndrome
Authors: Park Joo Hyun , Kang Seong Il , Choi Hyun Seok , Lee Sang Yeon , Kim Ji-Soo , Koo Ja-Won
Published: June 2015

The etiology of superior canal dehiscence (SCD) is controversial. An embryological perspective suggests that SCD may occur through the failure of postnatal bone formation over the superior semicircular canal (SC), whereas an acquired theory suggests that trauma or pressure from the overlying temporal lobe could break or gradually thin the SC. We infer the etiology of SCD by comparing the thickness of the bony otic capsule of the unaffected side of SCD patients with that of non-SCD participants. Twelve SCD patients (13 SCD ears and 11 normal ears) and 34 age-matched controls (68 ears) were included. The control group was subdivided into an aerated group (49 ears) and a nonaerated group (19 ears), as defined by the presence of air cells above the SC. A high-resolution temporal bone CT was performed in all participants. The thicknesses of the SC, horizontal canal (HC) and posterior canal (PC) of the unaffected ears of SCD patients were compared with those of the controls. The SC of the unaffected side in the SCD group (n = 11, 0.41 ± 0.23 mm) was significantly thinner than the one in the control group (n = 68, 0.64 ± 0.21 mm, p = 0.002). The HC and PC were also thinner in the SCD group (n = 24, 0.58 ± 0.11 and 1.39 ± 0.31 mm, respectively) than in the controls (0.70 ± 0.08 and 1.61 ± 0.32 mm; p < 0.0001 and p = 0.005, respectively). The SC, HC and PC thicknesses were also compared between the aerated and nonaerated ears within the control group. The SC was significantly thicker in the aerated group (0.73 ± 0.14 mm) than in the nonaerated group (0.60 ± 0.23 mm; p = 0.046); however, no significant difference was observed for the HC and PC thickness (aerated group, n = 49, 0.72 ± 0.07 and 1.67 ± 0.34 mm; nonaerated group, n = 19, 0.70 ± 0.09 and 1.59 ± 0.34 mm; p = 0.350 and p = 0.428, respectively). The bony otic capsule was significantly thinner in the SCD patients than in the controls. However, even within unaffected individuals, SCs lacking overlying air cells were also thinner than those with overlying air cells. These results suggest that both embryological and acquired factors affect the occurrence of SCD.
Modest Decrease in Pgc1α Results in TAG Accumulation but not in Insulin Resistance in L6 Myotubes
Authors: Lukaszuk Bartlomiej , Miklosz Agnieszka , Chabowski Adrian , Górski Jan
Published: June 2015

Background/Aims: PGC-1α is an important cellular protein (coactivator) regulating myocyte mitochondria number and function, and therefore whole cellular energy status. The aim of this work was to investigate the effects of modest, temporary PGC-1α knock-down on L6 myotubes insulin resistance in a light of cellular lipid metabolism. Methods: Gas liquid chromatography was applied for assessing FAs content and composition. For the expression of mitochondrial enzymes, as well as FA and glucose transporters, Western Blot technique was adopted. Additionally, radiolabelled glucose and palmitic acid uptake was performed to estimate the nutrients cellular influx. Results: Modest (-24%) PGC-1α protein ablation resulted in decreased mitochondrial activity in general (reduced Cyt C content) and FAs oxidation in particular (diminished β-HAD expression) without increased FAs cellular influx. The aforementioned intervention led to significantly increased TAG cellular level, but not DAG nor CER. Consequently, no changes in cellular insulin responsiveness were noticed. Conclusions: Modest (-24%) PGC-1α protein depletion results in lipid accumulation, without causing insulin resistance. Importantly, it seems that this TAG loading is a result of decreased mitochondrial oxidative capacity and/or possibly increased lipid biosynthesis but not fatty acid cellular influx.
Down-Regulation of Homer1b/c Protects Against Chemically Induced Seizures Through Inhibition of mTOR Signaling
Authors: Cao Lei , Tian Ye , Jiang Yi , Zhang Ge-Juan , Lei Hui , Di Zheng-Li
Published: June 2015

Background: Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. Reducing Homer1b/c expression has been shown in previous studies to be protective against excitotoxic insults, implicating Homer1b/c in the physiological regulation of aberrant neuronal excitability. Methods: To test the efficacy of a Homer1b/c reducing therapy for disorders with a detrimental hyperexcitability profile in mice, we used small interfere RNA (siRNA) to decrease endogenous Homer1b/c expression in mouse hippocampus. The baseline motor and cognitive behavior was measured by sensorimotor tests, Morris water maze and elevated plus maze tasks. The anti-epileptic effects of Homer1b/c knockdown were determined in two chemically induced seizure models induced by Picrotoxin (PTX) or pentylenetetrazole (PTZ) administration. Results: The results of sensorimotor tests, Morris water maze and elevated plus maze tasks showed that Homer1b/c reduction had no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced Homerb/c protein had less severe seizures than control mice. Total Homer1b/c protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of Homer1b/c. In addition, the phosphorylation of mammalian target of rapamycin (mTOR) and its target protein S6 was significantly inhibited in Homer1b/c down-regulated mice. Homer1b/c knockdown-induced inhibition of mTOR pathway was partially ablated by the metabotropic glutamate receptor 5 (mGluR5) agonist CHPG. Conclusion: Our results demonstrate that endogenous Homer1b/c is integral for regulating neuronal hyperexcitability in adult animals and suggest that reduction of Homer1b/c could protect against chemically induced seizures through inhibition mTOR pathway.
Activation of PAR-1/NADPH Oxidase/ROS Signaling Pathways is Crucial for the Thrombin-Induced sFlt-1 Production in Extravillous Trophoblasts: Possible Involvement in the Pathogenesis of Preeclampsia
Authors: Huang Qi-tao , Chen Jian-hong , Hang Li-lin , Liu Shi-san , Zhong Mei
Published: June 2015

Backgrounds/Aims: Preeclampsia was characterized by excessive thrombin generation in placentas and previous researches showed that thrombin could enhance soluble Fms-like tyrosine kinase 1 (sFlt-1) expression in first trimester trophoblasts. However, the detailed mechanism for the sFlt-1 over-production induced by thrombin was largely unknown. The purpose of this study was to explore the possible signaling pathway of thrombin-induced sFlt-1 production in extravillous trophoblasts (EVT). Methods: An EVT cell line (HRT-8/SVneo) was treated with various concentrations of thrombin. The mRNA expression and protein secretion of sFlt-1 in EVT were detected with real-time polymerase chain reaction and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production were determined by DCFH-DA. Results: Exposure of EVT to thrombin induced increased intracellular ROS generation and overexpression of sFlt-1 at both mRNA and protein levels in a dose dependent manner. Short interfering RNA (siRNA) directed against PAR-1 or apocynin (an inhibitor of NADPH oxidase) could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. Conclusions: Our results suggested that thrombin increased sFlt-1 production in EVT via the PAR-1 /NADPH oxidase /ROS signaling pathway. This also highlights the PAR-1 / NADPH oxidase / ROS pathway might be a potential therapeutic target for the prevention of preeclampsia in the future.
Quantitative Proteomic Analysis of the Metastasis-Inhibitory Mechanism of miR-193a-3p in Non-Small Cell Lung Cancer
Authors: Deng Wei , Yan Mingxia , Yu Tao , Ge Haiyan , Lin Hechun , Li Jing , Liu Ying , Geng Qin , Zhu Miaoxin , Liu Lei , He Xianghuo , Yao Ming
Published: June 2015

Background: microRNAs can repress the expression of target genes by destabilizing their mRNAs or by inhibiting their translation. Our previous findings suggested that miR-193a-3p inhibited the progression of NSCLC both in vitro and in vivo. However, the biological processes and molecular pathways through which this miRNA exerts its positive effects are unknown. Methods: To explore the molecular mechanisms by which miR-193a-3p inhibited NSCLC metastasis, we investigated the changes in the protein profile of SPC-A-1sci (highly metastatic) cells in response to the up-regulation of miR-193a-3p expression using a proteomics approach (iTRAQ combined with NanoLC-MS/MS). Changes in the profiles of the expressed proteins were verified using western blotting and were analyzed using the DAVID and STRING programs. Results: In the two replicated experiments, 4962/4946 proteins were identified, and the levels of expression of 4923/4902 proteins were quantified. In total, 112 of these proteins were differentially expressed. Among them, the up-regulated levels of expression of two of the 62 proteins with up-regulated expression (PPP2R2A and GSN) and the down-regulated levels of expression four of the 50 proteins with down-regulated expression (LMNB2, UHRF1, G3BP1, and HNRNPU) were verified using western blotting. The bioinformatics analysis revealed the interactions and signaling networks of these differentially expressed proteins. Conclusion: miR-193a-3p inhibited the metastasis of lung cancer cells by deregulating the expression of tumor-related proteins. These findings may improve the understanding of the molecular mechanisms underlying the metastatic-inhibitory effect of miR-193a-3p on lung cancer cells.
Roundabout4 Suppresses Glioma-Induced Endothelial Cell Proliferation, Migration and Tube Formation in Vitro by Inhibiting VEGR2-Mediated PI3K/AKT and FAK Signaling Pathways
Authors: Cai Heng , Xue Yixue , Li Zhen , Hu Yi , Wang Zhenhua , Liu Wenjing , Li Zhiqing , Liu Yunhui
Published: June 2015

Background and Aims: Endothelial cell (EC) proliferation, migration, and tube formation are the critical steps for tumor angiogenesis, which is involved in the formation of new tumor blood vessels. Roundabout4 (Robo4), a new member of Robo proteins family, is specifically expressed in endothelial cells. This study aimed to investigate the effects of Robo4 on glioma-induced endothelial cell proliferation, migration and tube formation in vitro. Methods and Results: We found that Robo4 was endogenously expressed in Human Brain Microvascular Endothelial Cells (HBMECs), while Robo4 was significantly down-regulated in endothelial cells cultured in glioma conditioned medium. Robo4 over-expression remarkably suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro. In addition, Robo4 influenced the glioma-induced angiogenesis via binding to its ligand Slit2. Further studies demonstrated that the knockdown of Robo4 up-regulated the phosphorylation of VEGFR2, PI3K, AKT and FAK in EC cultured in glioma conditioned medium. VEGFR2 inhibitor SU-1498, AKT inhibitor LY294002 and FAK inhibitor 14 (FAK inhibitor) blocked the Robo4 knockdown-mediated alteration in glioma angiogenesis in vitro. Conclusion: Our results proved that Robo4 suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated activation of PI3K/AKT and FAK signaling pathways.
Inhibition of Ocular Neovascularization by Co-Inhibition of VEGF-A and PLGF
Authors: Huo Xiaochuan , Li Youxiang , Jiang Yuhua , Sun Xiaoyun , Gu Lixue , Guo Wenshi , Sun Dapeng
Published: June 2015

Background/Aims: Age-related macular degeneration (AMD) appears to be a disease with increasing incidence in Western countries and may develop into acquired blindness. Choroidal neovascularization (CNV) is the most frequent cause for AMD, and is commonly induced by regional inflammation. Past studies have highlighted vascular endothelial growth factor A (VEGF-A) as a major trigger for CNV. However, studies on the associated angiogenic factors other than VEGF-A are lacking. Methods: Here, we used a well-established laser burn (LB)-induced experimental CNV mouse model to study the molecular mechanisms underlying the development of CNV after ocular injury. We analyzed vessel density by lectin labeling. We isolated macrophages, endothelial cells and other cell types by flow cytometry, and analyzed levels of different angiogenic factors in these populations. We used antisera against VEGF-A (aVEGF) and/or antisera against placental growth factor (PLGF; aPLGF) to antagonize CNV. We used an antibody-driven toxin to selectively eliminate macrophages to evaluate the role of macrophages in CNV. We also examined expression of PLGF in macrophage subtypes. Results: The choroidal vessel density increased significantly 7 days after LB. LB increased significantly the levels of VEGF-A and PLGF in mouse eyes. Treatment with aVEGF significantly blunted increases in vessel density by LB. Treatment with aPLGF alone did not significantly reduce increases in vessel density. However, aPLGF significantly increased the inhibitory effects of aVEGF on vessel density increases. While VEGF-A was produced by endothelial cells, macrophages and other types at similar levels, PLGF seemed to be predominantly produced by macrophages. Selective macrophage depletion significantly reduced CNV. M2, but M1 macrophages produced high levels of PLGF. Conclusions: Together, our data suggest a previously unappreciated role of PLGF in coordination with VEGF-A to regulate CNV during ocular injury. Our study highlights macrophages and their production of PLGF as novel targets for CNV therapy.
Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus
Authors: Bing Dan , Lee Sze Chim , Campanelli Dario , Xiong Hao , Matsumoto Masahiro , Panford-Walsh Rama , Wolpert Stephan , Praetorius Mark , Zimmermann Ulrike , Chu Hanqi , Knipper Marlies , Rüttiger Lukas , Singer Wibke
Published: June 2015

Background: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. Methods: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. Results: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. Conclusion: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.
The Pyridone-Annelated Isoindigo (5‘-Cl) Induces Apoptosis, Dysregulation of Mitochondria and Formation of ROS in Leukemic HL-60 Cells
Authors: Saleh Ayman M. , Aljada Ahmad , El-Abadelah Mustafa M. , Sabri Salim S. , Zahra Jalal A. , Nasr Amre , Aziz Mohammad A.
Published: June 2015

Background/Aims: In our quest to develop an isoindigo with improved efficacy and bioavailability, we recently synthesized a series of novel substituted pyridone-annelated isoindigo and evaluated their antiproliferative effects. We identified the compound [(E)-1-(5'-Chloro-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f] quinoline-8-carboxylic acid], abbreviated as 5'-Cl, which shows selective antiproliferative activities against various cancer cell lines mediated through apoptosis. Here we have investigated the molecular mechanisms underlying the apoptotic activity of 5'-Cl in the human promyelocytic leukemia HL-60 cells. Methods: We employed different methods to determine the apoptotic pathways triggered by 5'-Cl in HL-60 cells, using flow cytometry, nuclear staining, caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and Western blotting techniques. Results: Low concentrations (1-8 µM) of 5'-Cl inhibited the growth of HL-60 cells in a dose and time-dependent manner. Cytotoxicity of this compound is found to be mediated by a caspase-dependent apoptosis. Also, there were indications of caspase independent apoptosis as z-VAD-FMK failed to fully rescue the cells from 5‘-Cl-induced apoptosis. In addition, the compound triggered generation of Reactive Oxygen Species (ROS), caused depolarization of the mitochondrial inner membrane, decreased the level of cellular ATP, modulated the expression and phosphorylation of Bcl-2 leading to loss of its association with Bax and increased the release of cytochrome c to the cytosol of treated cells. The effects of 5‘-Cl on mitochondria and apoptosis were substantially blocked in the presence of a combination between z-VAD-FMK and either of the ROS scavenger N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC). Conclusion: We demonstrated that the growth inhibitory effects of 5'-Cl in HL-60 cells involve multiple pathways of apoptosis and dysregulation of mitochondrial functions.
Model-Based Deep Brain Stimulation Programming for Parkinson's Disease: The GUIDE Pilot Study
Authors: Pourfar Michael H. , Mogilner Alon Y. , Farris Sierra , Giroux Monique , Gillego Maria , Zhao Yufan , Blum David , Bokil Hemant , Pierre Mark C.
Published: June 2015

Background: Achieving optimal results following deep brain stimulation (DBS) typically involves several months of programming sessions. The Graphical User Interface for DBS Evaluation (GUIDE) study explored whether a visual programming system could help clinicians accurately predetermine ideal stimulation settings in DBS patients with Parkinson's disease. Methods: A multicenter prospective, observational study was designed that utilized a blinded Unified Parkinson's Disease Rating Scale (UPDRS)-III examination to prospectively assess whether DBS settings derived using a neuroanatomically based computer model (Model) could provide comparable efficacy to those determined through traditional, monopolar review-based programming (Clinical). We retrospectively compared the neuroanatomical regions of stimulation, power consumption and time spent on programming using both methods. Results: The average improvement in UPDRS-III scores was 10.4 ± 7.8 for the Model settings and 11.7 ± 8.7 for the Clinical settings. The difference between the mean UPDRS-III scores with the Model versus the Clinical settings was 0.26 and not statistically significant (p = 0.9866). Power consumption for the Model settings was 48.7 ± 22 μW versus 76.1 ± 46.5 μW for the Clinical settings. The mean time spent programming using the Model approach was 31 ± 16 s versus 41.4 ± 29.1 min using the Clinical approach. Conclusion: The Model-based DBS settings provided similar benefit to the Clinical settings based on UPDRS-III scores and were often arrived at in less time and required less power than the Clinical settings.
Evaluation of Femoral Ultrasonography as a Tool for Promoting Cessation of Groin-Injecting Behaviour
Authors: Senbanjo Richard , Strang John
Published: June 2015

Aim: To assess the impact of femoral ultrasonography accompanied by explanation of the findings (UFV) on groin-injecting behaviour. Methods: 348 heroin-addicted groin injectors (GIs) on opioid substitution treatment (OST) were included in the study: 174 received UFV (cases), 174 did not (controls). Injecting behaviour among cases and matched controls were compared for both ‘persistent GIs' (patients who had injected via the femoral vein in the 28-day period preceding the baseline) and ‘former GIs' (patients with a history of previous groin injecting). Findings: There were no significant between-group differences in gender, mean age, time in treatment, substitute medication and mean dose at baseline or injecting behaviour prior to baseline. After baseline, reduction by a third in the proportion still groin injecting was immediately evident among UFV cases versus controls (number needed to treat: 3, 95% CI: 2, 8; p < 0.001). Marked reduction in groin-injecting behaviour among UFV cases was maintained over 12 months, including fewer relapses among ‘former GIs' (number needed to treat: 5, 95% CI: 4, 9; p < 0.001). Conclusion: Single-session UFV may promote cessation of groin-injecting behaviour among patients receiving OST. This benefit appears to be evident 12 months later. Further evaluation of this novel approach to the management of groin injecting, a particularly harmful behaviour, is now warranted.
The Effect of Trimetazidine Added to Pharmacological Treatment on All-Cause Mortality in Patients with Systolic Heart Failure
Authors: Grajek Stefan , Michalak Michał
Published: June 2015

The anti-ischemic agent trimetazidine (TMZ) added to pharmacological treatment appears to have positive effects on cardiac parameters of patients with heart failure (HF) as a result of specific antioxidant properties. Objectives: We aimed to verify whether the marked improvement provided by TMZ in echocardiographic and clinical parameters was likely to translate into reduced all-cause mortality in systolic HF patients. Methods: Meta-analysis of available published prospective randomized controlled trial (RCT) data (1967-2014) retrieved from PubMed, Web of Science and Cochrane Collaboration. Results: A total of 326 patients from 3 RCTs were analyzed: 164 who received TMZ on top of pharmacological HF therapy and 162 controls. Study durations ranged from 12 to 48 months. The analysis had no publication bias and the studies were homogeneous (p = 0.442, I2 = 0). The results show a significant effect of TMZ on the reduction of all-cause mortality (RR = 0.283, p < 0.0001). The rate of events attributable to the drug was lower with TMZ than it was among control patients. Conclusion: This meta-analysis suggests that in patients with HF, TMZ given as an add-on therapy is likely to provide a protective effect, reduce all-cause mortality and increase event-free survival, and could be an effective and useful adjunct to our armamentarium for the treatment of HF patients.
Effectiveness of Rapid Intake into Methadone Treatment: A Natural Experiment in Israel
Authors: Lawental Maayan
Published: June 2015

The effect of intake procedures on treatment entry and retention was examined in a natural experiment, in which a methadone maintenance clinic in Israel admitted 127 clients by employing a rapid intake procedure (maximum of 3 days before the initiation of treatment was offered). Using information gathered from patient files, these clients were retrospectively compared to a control group (n = 121) who underwent the clinic's regular intake procedure (between 3 weeks and 3 months). Outcome measures included entry into treatment and subsequent retention in treatment (at 3, 6 and 12 months). Results show that 81% of clients from the rapid intake group entered treatment compared to only 57% from the regular intake group. Treatment retention was similar for both groups. In addition, Jewish clients were more likely to enter treatment via the rapid intake procedure than clients from other religions, and women were retained in treatment longer than men, regardless of the type of intake procedure. Results of this single-site study lend support to the effectiveness of rapid intake procedures as a way to engage clients in treatment and carry significant implications for improving access into treatment.
Hyperthermia Is Now Included in the NCCN Clinical Practice Guidelines for Breast Cancer Recurrences: An Analysis of Existing Data
Authors: Kouloulias Vassilis , Triantopoulou Sotiria , Uzunoglou Nikolaos , Pistevou-Gompaki Kyriaki , Barich Alfred , Zygogianni Anna , Kyrgias George , Kardamakis Dimitris , Pectasidis Dimitris , Kouvaris John ,   on behalf of the Greek Society of Hyperthermic Oncology
Published: June 2015

Background: Hyperthermia has been included in the 2013 National Comprehensive Cancer Network (NCCN) guidelines as an option for the treatment of breast recurrences. The purpose of this article is to demonstrate the important role of hyperthermia as a therapeutic modality by presenting clinical trials on this subject carried out in the last decades. Materials and Methods: All relevant trials published since 1987 were retrieved from Medline and reviewed. Results: Results show that the addition of hyperthermia to radiotherapy and/or chemotherapy for the treatment of breast cancer enhances treatment response and can increase local control. Conclusion: Further studies are required to evaluate potential benefits of hyperthermia in the treatment of other kinds of superficial tumors.
Altered Neural Activity in the Anterior and Posterior Insula in Individuals with Problematic Internet Use
Authors: Yoon HeungSik , Kim Shin Ah , Ahn Hyeon Min , Kim Sang Hee
Published: June 2015

Background: Individuals with problematic Internet use (PIU) are known to experience increased craving for immediate monetary reward despite long-term negative consequences. What remains unclear is whether their sensitivity to monetary loss is altered. We investigated neural alterations in brain regions involved in the anticipation of a monetary reward and loss avoidance in order to advance our understanding of the characteristics of PIU. Methods: A total of 11 adults with PIU and 22 age-matched controls participated in this functional magnetic resonance imaging study. Inside the scanner, participants performed a monetary incentive learning task during which they chose one of two fractal stimuli associated with monetary gain (reward trials) or avoidance of monetary loss (avoidance trials). Results: We found that, relative to controls, activity in the posterior insula during reward anticipation was greater in participants with PIU, whereas its activity during avoidance anticipation was reduced. No group differences in activation were found during reception phases. Conclusions: Given the roles of the posterior insula in the cortical representation of somatosensory arousal, our results suggest that individuals with PIU may experience more elaborate somatosensory arousal during the anticipation of monetary reward and yet experience less elaborate somatosensory arousal during the anticipation of loss avoidance compared with typical controls.
Fetal Kidney Programming by Maternal Smoking Exposure: Effects on Kidney Structure, Blood Pressure and Urinary Sodium Excretion in Adult Offspring
Authors: Block Daniel B. , Mesquita Flávia F. , de Lima Ize P. , Boer Patricia A. , Gontijo José A.R.
Published: June 2015

Introduction: Fetal programming by different insults results in low birth weight and reduction in nephron number increasing the risk for adult development of cardiovascular and renal diseases. Maternal smoking is an important modifiable adverse fetal exposure worldwide and leads to a decrease in the offspring's birth weight. Thus far, the specific adverse fetal smoking exposures and mechanisms underlying these associations on renal development and functional disorder are unclear. Methods: The present study investigates, in adult male rats, the effect of smoking exposure (Sk) in uteri on blood pressure (BP) by an indirect tail-cuff method using an electrosphygmomanometer, and its association with nephron structure by stereological estimation, immunohistochemical and histological techniques, in parallel with kidney function creatinine and lithium clearance. Results: The current study showed in a 16-week old Sk offspring enhanced arterial blood pressure associated with, reduced urinary sodium excretion and higher TGF-β1 glomerular expression. Sk glomeruli also presented an upregulated collagen and fibronectin deposition intrinsically related to fibrotic process as compared to age-matched control group. Conclusion: Here, we demonstrate that fetal-programmed Sk offspring present pronounced glomerular TGF-β1 and fibrotic marker expression that may, subsequently, promote a glomerular epithelial-mesenchymal transition activated process in an Sk offspring. Although the precise mechanism responsible for the subsequently renal morphological and functional response in Sk offspring is incompletely known, the current data suggest that changes in renal function are conducive to excess sodium tubule reabsorption that is associated with enhanced TGF-β1, fibronectin and collagen deposition, intrinsically related to fibrotic process, might potentiate the programming of adult hypertension.
Delays in Manual Reaching Are Associated with Impaired Functional Abilities in Early Dementia Patients
Authors: de Boer Casper , Pel Johan J.M. , van der Steen Johannes , Mattace-Raso Francesco
Published: June 2015

Background/Aims: Recent evidence shows that early dementia patients have deficits in manual reaching tasks. It is important to understand the impact of these functional disabilities on their quality of life. The aim of this study was to investigate if there is an association between manual reaching and measures of (instrumental) activities of daily living (IADL) in a group of patients with cognitive complaints. Methods: The manual reaching performance of 27 patients was assessed in detail with eye and hand tracking devices. Patients were divided into three groups based on self-reported loss of IADL function. Parameters describing hand response and movement times were compared between groups. Results: Patients with loss of IADL function in ≥1 domain had delayed hand response and hand movement times towards visible targets compared to patients with no loss of IADL function. Conclusion: Delays in manual reaching movements are related to the degree of loss of IADL function in early dementia patients.
Ein Fall von Fremdkörpergranulom der Glabella infolge eines Polyacrylamid-Fillers und von therapierefraktärem Ulkus nach einer Hautbiopsie: Immunhistochemische Untersuchung der entzündlichen Veränderungen
Authors: Park Kio , Nishiwaki Fuyuko , Kabashima Kenji , Miyachi Yoshiki
Published: June 2015

Einleitung: Polyacrylamid-Hydrogel gilt als sicheres und biokompatibles Füllmaterial für Weichteilgewebe und findet breite Anwendung in der kosmetischen Chirurgie. Aktuelle Studien haben jedoch einige Komplikationen nach Polyacrylamid-Filler-Injektionen offengelegt.Fallbericht: Wir stellen einen Fall von Fremdkörpergranulomen der Glabella vor, aus denen sich nachfolgend - 3 Jahre nach einer Polyacrylamid-Injektion - ein infektiöses Ulkus entwickelte. Eine immunhistochemische Auswertung der Fremdkörpergranulome wurde vorgenommen, um den Zusammenhang zwischen Fremdkörpergranulomen und Immunreaktion zu untersuchen.Schlussfolgerung: Wir sind der Ansicht, dass unsere Analyse von Fremdkörpergranulomen 1 und 3 Jahre nach einer Filler-Injektion dazu beitragen könnte, die Mechanismen chronischer und therapierefraktärer Infektionen nach Filler-Injektionen zu ergründen.
Anti-Amoxicillin Immunoglobulin E, Histamine-2 Receptor Antagonist Therapy and Mast Cell Activation Syndrome Are Risk Factors for Amoxicillin Anaphylaxis
Authors: Pastorello Elide Anna , Stafylaraki Chrysi , Mirone Corrado , Preziosi Donatella , Aversano Maria Gloria , Mascheri Ambra , Losappio Laura Michelina , Ortolani Valeria , Nichelatti Michele , Farioli Laura
Published: June 2015

Background: β-Lactam antibiotics (mainly amoxicillin, AX) are the drugs that most frequently induce systemic drug allergy reactions. Objective: We attempted to identify the risk factors associated with systemic reactions to AX. Methods: All patients who were referred to our department for suspected hypersensitivity reactions to AX over a 6-month period were evaluated for anti-AX immunoglobulin E (IgE) levels and skin-test positivity for β-lactams. Age, sex, concomitant diseases, therapies, total IgE, serum tryptase levels and signs and symptoms suggesting mast cell activation syndrome (MCAS) were analyzed in relation to the severity of the reaction in accordance with the Mueller classification. Results: Sixty-seven patients were selected: 39 with mild reactions such as cutaneous or gastrointestinal symptoms (grades I and II) and 28 with severe systemic reactions (grades III and IV). Anti-AX IgE levels and total IgE were significantly higher in severe reactions than in mild ones (p < 0.00005, p = 0.0037). Treatment with histamine-2 receptor antagonists (anti-H2) was significantly related to severe reactions (p = 0.007). No significant correlations were found between the severity of the reactions and dyslipidemia or levels of angiotensin-converting enzyme and tryptase. Conclusion: Anti-AX IgE levels were the most significant immunological parameter distinguishing patients who presented with severe reactions to AX and those with mild reactions. Higher values of total IgE, the use of gastroprotective drugs and signs and symptoms suggesting an MCAS significantly increased the odds ratio of having a severe reaction. The risk of serious adverse reactions to AX increased in older patients and in males, but this trend was not significant.
Effects of Intranasal Oxytocin on Steroid Hormones in Men and Women
Authors: Wirth Michelle M. , Gaffey Allison E. , Martinez Brandy S.
Published: June 2015

Background: Recent interest in the social and cognitive effects of intranasal oxytocin prompts a need for understanding its physiological effects in humans. Few studies have examined the effects of intranasal oxytocin on steroid hormones. Filling this gap is especially important given the evidence that steroid hormones participate in some of the same behavioral functions as oxytocin, e.g. in stress, processing of emotional stimuli, aggression, trust, empathy, and parental care. Methods: In randomized, double-blind experiments, we administered oxytocin (24 IU) or saline placebo to 97 healthy participants. Saliva samples were collected before and at several time points after the oxytocin/placebo administration to assess the levels of cortisol, progesterone, and testosterone. Results: Oxytocin had no effects on testosterone, progesterone, or cortisol in women or men. Conclusion: Acute intranasal oxytocin does not affect the levels of cortisol, testosterone or progesterone in humans, at least in the absence of a stressful context. These data suggest that acute oxytocin does not have a direct impact on the human hypothalamic-pituitary-adrenal or hypothalamic-pituitary-gonadal axes under nonstressful circumstances. This knowledge helps rule out potential mechanisms for some of the effects of oxytocin in humans and adds to the generally limited body of knowledge on the basic physiological or psychological effects of intranasal oxytocin in human beings.
Comparability of Computer-Supported Concurrent Voice Analysis
Authors: Hanschmann Holger , Gärtner Sebastian , Berger Roswitha
Published: June 2015

Objective: The assessment of vocal ability parameters can be made easier and more objective by computer-supported analysis systems. For this, multiple commercially available systems exist. But how strongly do the measured results of one method differ from the results of another and is the evaluation result of one method replaceable by or directly comparable with another? Patients and Methods: 15 women aged 20-55 years and 15 men aged 18-56 years took part in this prospective study. The programs lingWAVES and rpSzene® were compared for the results of jitter, shimmer and glottal-to-noise excitation ratio. Correlation coefficients, Youden plots and Bland-Altman plots were calculated to make the comparison. Results: For both systems, none of the values were in accordance with a normal distribution. The results of the two programs did not produce satisfactory consistency. Conclusions: In this study, absolute equivalency in the recording was ensured by the simultaneous recording of the voice signal and subsequent analysis with two different voice analysis methods. Nevertheless, the results varied so much that they cannot be compared properly. To reach a comparability of voice analyses, it is necessary to develop perturbation measurements which guarantee good clinical applicability and comparability between different analysis systems.
Ethics of Birth at the Limits of Viability: The Risky Business of Prediction
Authors: Shinwell Eric S.
Published: June 2015

Infants born at the limits of viability present neonatologists in particular and society in general with difficult challenges. Ethical and legal considerations establish a framework for action, although this varies between countries, departments and individuals and shows dynamic changes over time. This brief review includes a vignette telling a familiar story. In this case, the parents ask searching questions and the caring, knowledgeable neonatologist uses up-to-date information to offer empathic and thoughtful guidance - a challenge for all.
Lungs, Microbes and the Developing Neonate
Authors: Warner Barbara B. , Hamvas Aaron
Published: June 2015

Microbes are ubiquitous on the human body and comprise approximately 90% of the cells and 99% of the genes of the human supraorganism. High-throughput sequencing technology has permitted the development of culture-independent means to identify the microbiota that are unique to the various microenvironments of the body and probably contribute some function. Although the respiratory tract interfaces with the environment, the lungs were always thought to be a sterile environment - until recently, when these techniques were applied to healthy and disease states. Further, there appears to be a complex interplay between the development of the gastrointestinal and respiratory microbiota and the regulation of immune function. The contribution of this dynamic metabolic mass to respiratory disease in the newborn is unknown. This article will review emerging data from recent human and murine studies that suggest there is a microbial influence on the development of respiratory disease, but it will also highlight many of the gaps that remain in understanding the function of the respiratory microbiome.
Diffuse Liver Metastasis of Small-Cell Lung Cancer Presenting as Acute Liver Failure and Diagnosed by Transjugular Liver Biopsy: A Rare Case in Whom Nodular Lesions Were Detected by Enhanced CT Examination
Authors: Mishima S. , Nozaki Y. , Mikami S. , Kihira E. , Iikura M. , Koketsu R. , Sugiyama H. , Masuda T. , Kaname H. , Egami Y. , Nakayama T. , Hasuo K. , Nakamura H. , Igari T. , Watanabe K. , Nagata N. , Sakurai T. , Yokoi C. , Kobayakawa M. , Kojima Y. , Akiyama J. , Imamura M. , Masaki N. , Yanase M.
Published: June 2015

Small-cell lung cancer (SCLC) is a subgroup of lung cancer with a high frequency of liver metastasis, which is a predictor of poor prognosis. Diffuse liver metastases of SCLC with no visible nodular lesions in the liver when examined using computed tomography (CT) are relatively rare; however, a few cases with rapid progression to acute liver failure that were diagnosed after death have been reported. In this paper, we report a 63-year-old man with diffuse liver metastases of SCLC that were histologically diagnosed using a transjugular liver biopsy while the patient was alive, even though no lesions were visible during a contrast-enhanced CT examination.