bluuebunny/crossref_metadata_2025 huggingface dataset:
AngiotensinII Preconditioning Promotes AngiogenesisIn Vitrovia ERKs Phosphorylation
Authors: Guan Aili , Zou Yunzeng , Gong Hui , Niu Yuhong , Ye Yong , Jia Jianguo , Li Bingyu , Zhang Guoping , Qian Sanli , Ge Junbo
Published: February 2012

AngiotensinII (AngII) is involved in not only the formation of cardiac hypertrophy but also the development of cardiac remodeling both of which are associated with myocardial angiogenesis. This study was therefore performed to clarify the effects of AngII on the formation of vasculatures by cultured cardiac microvascular endothelial cells (CMVECs) after a long-period stimulation with or without the AngII preconditioning. Incubation with AngII for 18 hrs significantly impaired the formation of capillary-like tubes comparing to that without AngII. CMVECs with AngII pretreatment for 5 and 10 min formed more capillary-like tubes than those without AngII pretreatment, suggesting that preconditioning with AngII at a lower dose for a short period could prevent the further damage of CMVECs by a higher concentration of AngII. Moreover, AngII (10-7 M) stimulation for 5 and 10 min significantly induced the increase in extracellular signal-regulated protein kinases (ERKs) phosphorylation, and an ERKs inhibitor, PD98059, abrogated the increase in the formation of capillary-like tubes induced by the AngII-pretreatment. In conclusion, preconditioning with a lower concentration of AngII for a short period prevents the subsequent impairment of CMVECs by a higher dose of AngII, at least in part, through the increase in ERKs phosphorylation.
Cellular-Based Immunotherapies for Patients with Glioblastoma Multiforme
Authors: Xu Xun , Stockhammer Florian , Schmitt Michael
Published: February 2012

Treatment of patients with glioblastoma multiforme (GBM) remains to be a challenge with a median survival of 14.6 months following diagnosis. Standard treatment options include surgery, radiation therapy, and systemic chemotherapy with temozolomide. Despite the fact that the brain constitutes an immunoprivileged site, recent observations after immunotherapies with lysate from autologous tumor cells pulsed on dendritic cells (DCs), peptides, protein, messenger RNA, and cytokines suggest an immunological and even clinical response from immunotherapies. Given this plethora of immunomodulatory therapies, this paper gives a structure overview of the state-of-the art in the field. Particular emphasis was also put on immunogenic antigens as potential targets for a more specific stimulation of the immune system against GBM.
Porous Hydroxyapatite and Aluminium-Oxide Ceramic Orbital Implant Evaluation Using CBCT Scanning: A Method forIn VivoPorous Structure Evaluation and Monitoring
Authors: Lukáts Olga , Bujtár Péter , Sándor George K. , Barabás József
Published: February 2012

Objective. This study aimed to define CBCT as a technique for postimplantationin vivoexamination of porous hydroxyapatite and aluminium-oxide orbital implant shape, volume and density changes.Methods and Materials. CBCT was used to evaluate 30 enucleated patients treated with spherical polyglactin 910 wrapped hydroxyapatite and aluminum-oxide orbital implants. The mean duration of patient followup was 3.2 years or 1338 days with a range of 0.2 to 7.2 years or 79 to 2636 days in a population with an average age of 40.8 years.Results. The resolution of currently clinically used CBCT equipment allowed detailed structural observation of the orbital hydroxyapatite implants with some modifications. Volume and shape estimations were possible while density evaluation was more complicated compared to medical source computed tomography. The mean densities of the orbital implants were followed and a consistent gradual decrease identified from the beginning of implantation which was better defined after the applied correction procedure.Conclusion. CBCT with lower dosages of radiation exposure can be used to follow changes in implanted high-density porous structures. The density evaluation is possible with calibration modifications. Changes in orbital implant densities identified in this study may correspond to healing and maturation of soft tissues surrounding and penetrating the implants.
Tipping the Proteome with Gene-Based Vaccines: Weighing in on the Role of Nanomaterials
Authors: Flores Kristin J. , Craig Michael , Wanekaya Adam , Dong Lifeng , Ghosh Kartik , Smith Joshua J. , DeLong Robert K.
Published: February 2012

Since the first generation of DNA vaccines was introduced in 1988, remarkable improvements have been made to improve their efficacy and immunogenicity. Although human clinical trials have shown that delivery of DNA vaccines is well tolerated and safe, the potency of these vaccines in humans is somewhat less than optimal. The development of a gene-based vaccine that was effective enough to be approved for clinical use in humans would be one of, if not the most important, advance in vaccines to date. This paper highlights the literature relating to gene-based vaccines, specifically DNA vaccines, and suggests possible approaches to boost their performance. In addition, we explore the idea that combining RNA and nanomaterials may hold the key to successful gene-based vaccines for prevention and treatment of disease.
Parkinson's Disease and Mesenchymal Stem Cells: Potential for Cell-Based Therapy
Authors: Kitada Masaaki , Dezawa Mari
Published: February 2012

Cell transplantation is a strategy with great potential for the treatment of Parkinson's disease, and many types of stem cells, including neural stem cells and embryonic stem cells, are considered candidates for transplantation therapy. Mesenchymal stem cells are a great therapeutic cell source because they are easy accessible and can be expanded from patients or donor mesenchymal tissues without posing serious ethical and technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson's disease. This paper focuses mainly on the potential of mesenchymal stem cells as a therapeutic cell source and discusses their potential clinical application in Parkinson's disease.
The Effects of Hypertension on Cognitive Function in Children and Adolescents
Authors: Cha Stephen D. , Patel Hiren P. , Hains David S. , Mahan John D.
Published: February 2012

Hypertension (HTN) is found in about 3-4% of the pediatric population with long-term risks of end organ damage if untreated or poorly controlled. Although children with HTN are being more frequently screened for end organ damage (i.e., LVH), the cognitive effects of HTN and methods to screen for cognitive dysfunction have not been extensively explored. In recent years, there have been a small number of studies that have provided important insights that can guide future research in this area. These studies show that HTN can be associated with headaches, restlessness, sleep disturbance, anxiety, depression, decreased attention, and also poor executive functioning. By increasing the utilization of cognitive tests in hypertensive children and adolescents, important cognitive defects secondary to HTN may be detected. More research is needed in the area, and the results of future studies could have far reaching implications for long-term outcomes in hypertensive children and adolescents.
The Natural History and Treatment Options for Unruptured Intracranial Aneurysms
Authors: Loewenstein Joshua E. , Gayle Shaneze C. , Duffis E. Jesus , Prestigiacomo Charles J. , Gandhi Chirag D.
Published: February 2012

Recent advances in angiographic technique have raised our awareness of the presence of unruptured intracranial aneurysms (UIAs). However, the appropriate management for these lesions remains controversial. To optimize patient outcomes, the physician must weigh aneurysmal rupture risk associated with observation against the complication risks associated with intervention. In the case that treatment is chosen, the two available options are surgical clipping and endovascular coiling. Our paper summarizes the current body of literature in regards to the natural history of UIAs, the evolution of the lesion if it progresses uninterrupted, as well as the safety and efficacy of both treatment options. The risks and benefits of treatment and conservative management need to be evaluated on an individual basis and are greatly effected by both patient-specific and aneurysm-specific factors, which are presented in this paper. Ultimately, this body of data has led to multiple sets of treatment guidelines, which we have summated and presented in this paper.
Room Temperature Direct Band Gap Emission from Ge p-i-n Heterojunction Photodiodes
Authors: Kasper E. , Oehme M. , Arguirov T. , Werner J. , Kittler M. , Schulze J.
Published: February 2012

Room temperature direct band gap emission is observed for Si-substrate-based Ge p-i-n heterojunction photodiode structures operated under forward bias. Comparisons of electroluminescence with photoluminescence spectra allow separating emission from intrinsic Ge (0.8 eV) and highly doped Ge (0.73 eV). Electroluminescence stems from carrier injection into the intrinsic layer, whereas photoluminescence originates from the highly n-doped top layer because the exciting visible laser wavelength is strongly absorbed in Ge. High doping levels led to an apparent band gap narrowing from carrier-impurity interaction. The emission shifts to higher wavelengths with increasing current level which is explained by device heating. The heterostructure layer sequence and the light emitting device are similar to earlier presented photodetectors. This is an important aspect for monolithic integration of silicon microelectronics and silicon photonics.
Modified Chebyshev‐Picard Iteration Methods for Station‐Keeping of Translunar Halo Orbits
Authors: Bai Xiaoli , Junkins John L.
Published: February 2012

The halo orbits around the Earth‐Moon L2 libration point provide a great candidate orbit for a lunar communication
satellite, where the satellite remains above the horizon on the far side of the Moon being visible from the Earth at all
times. Such orbits are generally unstable, and station‐keeping strategies are required to control the satellite to remain
close to the reference orbit. A recently developed Modified Chebyshev‐Picard Iteration method is used to compute
corrective maneuvers at discrete time intervals for station‐keeping of halo orbit satellite, and several key parameters
affecting the mission performance are analyzed through numerical simulations. Compared with previously published
results, the presented method provides a computationally efficient station‐keeping approach which has a simple control
structure that does not require weight turning and, most importantly, does not need state transition matrix or gradient
information computation. The performance of the presented approach is shown to be comparable with published
methods.
Advanced Asymptomatic Carotid Disease and Cognitive Impairment: An Understated Link?
Authors: Martinić-Popović Irena , Lovrenčić-Huzjan Arijana , Demarin Vida
Published: February 2012

Advanced carotid disease is known to be associated with symptomatic cerebrovascular diseases, such as stroke or transient ischemic attack (TIA), as well as with poststroke cognitive impairment. However, cognitive decline often occurs in patients with advanced carotid stenosis without clinically evident stroke or TIA, so it is also suspected to be an independent risk factor for dementia. Neurosonological methods enable simple and noninvasive assessment of carotid stenosis in patients at risk of advanced atherosclerosis. Cognitive status in patients diagnosed with advanced carotid stenosis is routinely not taken into consideration, although if cognitive impairment is present, such patients should probably be called symptomatic. In this paper, we discuss results of some most important studies that investigated cognitive status of patients with asymptomatic advanced carotid disease and possible mechanisms involved in the causal relationship between asymptomatic advanced carotid disease and cognitive decline.
A Fuzzy Simulation‐Based Optimization Approach for Groundwater Remediation Design at Contaminated Aquifers
Authors: Yang A. L. , Huang G. H. , Fan Y. R. , Zhang X. D.
Published: February 2012

A fuzzy simulation‐based optimization approach (FSOA) is developed for identifying optimal design of a benzene‐contaminated groundwater remediation system under uncertainty. FSOA integrates remediation processes (i.e., biodegradation and pump‐and‐treat), fuzzy simulation, and fuzzy‐mean‐value‐based optimization technique into a general management framework. This approach offers the advantages of (1) considering an integrated remediation alternative, (2) handling simulation and optimization problems under uncertainty, and (3) providing a direct linkage between remediation strategies and remediation performance through proxy models. The results demonstrate that optimal remediation alternatives can be obtained to mitigate benzene concentration to satisfy environmental standards with a minimum system cost.
A Phase I Combination Study of Olaparib with Cisplatin and Gemcitabine in Adults with Solid Tumors
Authors: Rajan Arun , Carter Corey A. , Kelly Ronan J. , Gutierrez Martin , Kummar Shivaani , Szabo Eva , Yancey Mary Ann , Ji Jiuping , Mannargudi Baskar , Woo Sukyung , Spencer Shawn , Figg William Douglas , Giaccone Giuseppe
Published: February 2012

Purpose: To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination.

Experimental Design: We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m2 on days 3 and 10, and cisplatin 60 mg/m2 on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC).

Results: Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DL−1). No DLTs were seen in six patients at DL−1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration.

Conclusions: Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy. Clin Cancer Res; 18(8); 2344–51. ©2012 AACR.
A Phase II Study of Lapatinib in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck
Authors: de Souza Jonas A. , Davis Darren W. , Zhang Yujian , Khattri Arun , Seiwert Tanguy Y. , Aktolga Serdal , Wong Stuart J. , Kozloff Mark F. , Nattam Sreenivasa , Lingen Mark W. , Kunnavakkam Rangesh , Stenson Kerstin M. , Blair Elizabeth A. , Bozeman Jeffrey , Dancey Janet E. , Vokes Everett E. , Cohen Ezra E.W.
Published: February 2012

Purpose: This study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).

Experimental Design: This phase II multiinstitutional study enrolled patients with recurrent/metastatic SCCHN into two cohorts: those without (arm A) and those with (arm B) before exposure to an epidermal growth factor receptor (EGFR) inhibitor. All subjects were treated with lapatinib 1,500 mg daily. Primary endpoints were response rate (arm A) and progression-free survival (PFS; arm B). The biologic effects of lapatinib on tumor growth and survival pathways were assessed in paired tumor biopsies obtained before and after therapy.

Results: Forty-five patients were enrolled, 27 in arm A and 18 in arm B. Diarrhea was the most frequent toxicity occurring in 49% of patients. Seven patients experienced related grade 3 toxicity (3 fatigue, 2 hyponatremia, 1 vomiting, and 1 diarrhea). In an intent-to-treat analysis, no complete or partial responses were observed, and stable disease was the best response observed in 41% of arm A (median duration, 50 days, range, 34–159) and 17% of arm B subjects (median, 163 days, range, 135–195). Median PFS was 52 days in both arms. Median OS was 288 (95% CI, 62–374) and 155 (95% CI, 75–242) days for arms A and B, respectively. Correlative analyses revealed an absence of EGFR inhibition in tumor tissue.

Conclusion: Lapatinib as a single agent in recurrent/metastatic SCCHN, although well tolerated, appears to be inactive in either EGFR inhibitor naive or refractory subjects. Clin Cancer Res; 18(8); 2336–43. ©2012 AACR.
Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo
Authors: Rajendran Peramaiyan , Li Feng , Shanmugam Muthu K. , Kannaiyan Radhamani , Goh Jen Nee , Wong Kwong Fai , Wang Wei , Khin Ester , Tergaonkar Vinay , Kumar Alan Prem , Luk John M. , Sethi Gautam
Published: February 2012

Cumulative evidences(s) have established that the constitutive activation of STAT3 plays a pivotal role in the proliferation, survival, metastasis, and angiogenesis and thus can contribute directly to the pathogenesis of hepatocellular carcinoma (HCC). Thus, novel agents that can inhibit STAT3 activation have potential for both prevention and treatment of HCCs. The effect of celastrol on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was investigated. The in vivo effect of celastrol on the growth of human HCC xenograft tumors in athymic nu/nu mice was also examined. We observed that celastrol inhibited both constitutive and inducible STAT3 activation, and the suppression was mediated through the inhibition of activation of upstream kinases c-Src, as well as Janus-activated kinase-1 and -2. Vanadate treatment reversed the celastrol-induced modulation of STAT3, suggesting the involvement of a tyrosine phosphatase. The inhibition of STAT3 activation by celastrol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Celastrol also inhibited the proliferation and induced apoptosis in HCC cells. Finally, when administered intraperitoneally, celastrol inhibited STAT3 activation in tumor tissues and the growth of human HCC xenograft tumors in athymic nu/nu mice without any side effects. Overall, our results suggest for the first time that celastrol exerts its antiproliferative and proapoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo. Cancer Prev Res; 5(4); 631–43. ©2012 AACR.
Is Neuregulin 1 Involved in Determining Cerebral Volumes in Schizophrenia? Preliminary Results Showing a Decrease in Superior Temporal Gyrus Volume
Authors: Tosato Sarah , Bellani Marcella , Bonetto Chiara , Ruggeri Mirella , Perlini Cinzia , Lasalvia Antonio , Marinelli Veronica , Rambaldelli Gianluca , Cristofalo Doriana , Bertani Mariaelena , Zanoni Martina , Lazzarotto Lorenza , Cerini Roberto , Pozzi Mucelli Roberto , Tansella Michele , Dazzan Paola , Di Forti Marta , Murray Robin M. , Collier David A. , Brambilla Paolo
Published: February 2012

Background/Aims: Reduced left superior temporal gyrus (STG) volume is one of the most replicated imaging findings in schizophrenia. However, it remains unclear whether genes play any role in our understanding of such structural alteration. It has been proposed that Neuregulin 1 (NRG1) might be a promising gene involved in schizophrenia, because of its role in neurodevelopment and neuroplasticity. In this study, the association between NRG1 and STG anatomy in patients with schizophrenia was explored for the first time. Methods: We investigated a 1-year treated prevalence cohort of patients with schizophrenia in contact with the South Verona Community-Based Mental Health Service. A blood sample was collected for DNA extraction and brain structure was assessed with an MRI scan. A total of 27 subjects with schizophrenia underwent both assessments and were included in the study. Results: We investigated the association between the polymorphism SNP8NRG222662 (rs4623364) of NRG1 and volume of the STG. We found that patients homozygous for the C allele had reduced left STG gray and white matter volumes in comparison to those homozygous for the G allele (p < 0.01 and p < 0.001, respectively). Conclusions: This exploratory study suggests that NRG1 may be involved in determining STG size in schizophrenia, and may play a role in the neurogenetic basis of the language disturbances seen in this disorder. However, due to our small sample size, the results should be regarded as preliminary and replicated in a larger sample.
Psychiatric Side Effects and Fluctuations in Serotonergic Parameters in the Treatment of Chronic Hepatitis C Infection
Authors: Bezemer G. , Van Gool A.R. , Fekkes D. , Vrolijk J.M. , Hansen B.E. , Janssen H.L.A. , de Knegt R.J.
Published: February 2012

Introduction: Treatment of hepatitis C with peginterferon induces psychiatric side effects. These might include changes in serotonergic function. Methods: Twenty-two hepatitis C patients were treated with peginterferon. At different time points, psychometric assessment was performed using the Profile of Mood States. Plasma samples were taken to study serotonergic parameters. Results: Anger and depression increased compared to baseline, starting with anger (from week 3 onwards), followed by depression (from week 7 onwards). Other scores did not show consistent changes. No consistent changes were observed in tryptophan, tryptophan/large neutral amino acids ratio, biopterin and 5-hydroxyindoleacetic acid. The tyrosine/large neutral amino acids ratio, neopterin, phenylalanine/tyrosine ratio, and prolactin concentrations increased compared to baseline. Prolactin levels were associated with the occurrence of depression and anger. Discussion: Particularly anger and depression increased during treatment. Neither a decrease in tryptophan and tryptophan availability was seen, nor a relationship between these parameters and the development of psychopathology. Therefore, other mechanisms in the induction of psychopathology should be considered. The observed increases in neopterin and phenylalanine/tyrosine ratio are indicative of changes in tetrahydrobiopterin, which is involved in the metabolism of serotonin, noradrenaline and dopamine, and possibly mediating the increase in prolactin. The increase in prolactin levels and its relationship with depression and anger needs further exploration.
Pranlukast, a Cysteinyl Leukotriene Type 1 Receptor Antagonist, Attenuates the Progression but Not the Onset of Silica-Induced Pulmonary Fibrosis in Mice
Authors: Shimbori Chiko , Shiota Naotaka , Okunishi Hideki
Published: February 2012

Background: Although cysteinyl leukotrienes (CysLTs) have been implicated in the etiology of acute inflammatory diseases, recent studies have suggested that they also directly stimulate fibroblasts. However, their precise role in the pathogenesis of pulmonary fibrosis is unclear. Methods: In this study, we evaluated the effect of both short- and long-term treatment with pranlukast, a CysLT type 1 (CysLT1) receptor antagonist, on silica-induced pulmonary fibrosis in mice, which is characterized by persistent progression of fibrosis in the chronic phase. Pranlukast (30 mg/kg/day) was administered orally to mice for 2 or 10 weeks after intratracheal silica instillation. Results: Pranlukast treatment for 10 weeks significantly attenuated the progression of pulmonary fibrosis, and decreased the content of CysLTs and LTB4, which were markedly increased in the bronchoalveolar lavage fluid (BALF) and lung tissues of silica-instilled mice in the chronic phase. However, pranlukast treatment for 2 weeks neither affected the acute inflammatory response induced by silica instillation nor inhibited the onset of fibrosis. The expression of TGF-β1 and TNF-α was not affected by pranlukast treatment for either 2 or 10 weeks. Conclusions: Pranlukast attenuates the progression of pulmonary fibrosis in the chronic phase but has no effect on the acute inflammatory response or on the onset of pulmonary fibrosis. The antifibrotic effect of pranlukast may be exhibited by antagonizing the direct profibrotic effect of CysLTs, without affecting the expression of other profibrotic cytokines such as TGF-β1 and TNF-α, and also by decreasing the production of CysLTs and LTB4.
Evidence for a Double Dissociation of Articulatory Rehearsal and Non-Articulatory Maintenance of Phonological Information in Human Verbal Working Memory
Authors: Trost Sarah , Gruber Oliver
Published: February 2012

Objective: Recent functional neuroimaging studies have provided evidence that human verbal working memory is represented by two complementary neural systems, a left lateralized premotor-parietal network implementing articulatory rehearsal and a presumably phylogenetically older bilateral anterior-prefrontal/inferior-parietal network subserving non-articulatory maintenance of phonological information. In order to corroborate these findings from functional neuroimaging, we performed a targeted behavioural study in patients with very selective and circumscribed brain lesions to key regions suggested to support these different subcomponents of human verbal working memory. Methods: Within a sample of over 500 neurological patients assessed with high-resolution structural magnetic resonance imaging, we identified 2 patients with corresponding brain lesions, one with an isolated lesion to Broca’s area and the other with a selective lesion bilaterally to the anterior middle frontal gyrus. These 2 patients as well as groups of age-matched healthy controls performed two circuit-specific verbal working memory tasks. In this way, we systematically assessed the hypothesized selective behavioural effects of these brain lesions on the different subcomponents of verbal working memory in terms of a double dissociation. Results: Confirming prior findings, the lesion to Broca’s area led to reduced performance under articulatory rehearsal, whereas the non-articulatory maintenance of phonological information was unimpaired. Conversely, the bifrontopolar brain lesion was associated with impaired non-articulatory phonological working memory, whereas performance under articulatory rehearsal was unaffected. Conclusion: The present experimental neuropsychological study in patients with specific and circumscribed brain lesions confirms the hypothesized double dissociation of two complementary brain systems underlying verbal working memory in humans. In particular, the results demonstrate the functional relevance of the anterior prefrontal cortex for non-articulatory maintenance of phonological information and, in this way, provide further support for the evolutionary-based functional-neuroanatomical model of human working memory.
Altered Cerebral Vasoregulation Predicts the Outcome of Patients with Partial Anterior Circulation Stroke
Authors: Troisi Elio , Matteis Maria , Silvestrini Mauro , Paolucci Stefano , Grasso Maria Grazia , Pasqualetti Patrizio , Vernieri Fabrizio , Caltagirone Carlo
Published: February 2012

Background and Purpose: The aim of this study was to investigate the correlation between cerebral hemodynamic changes and the evolution of neurological deficit after stroke. Methods: We included 65 patients with non-lacunar stroke admitted to a rehabilitation hospital within 4 weeks from the event. An evaluation of cerebrovascular reactivity to hypercapnia was performed with transcranial Doppler ultrasonography using the breath-holding index (BHI). Activities of daily living status was measured by the Barthel Index (BI) and impairment of mobility was assessed by means of the Rivermead Mobility Index (RMI). Multivariate analyses were performed using effectiveness of treatment, evaluated on BI and RMI as dependent variables. Independent variables were BHI values, age, sex, length of stay, hypertension, smoking habit, presence of aphasia and neglect, poststroke depression, and the degree of severity of stroke. Results: The effectiveness on BI was associated positively with normal BHI values and with neurological severity at admission, measured by the Canadian Neurological Scale. The regression coefficients for effectiveness on RMI showed that the most relevant predictor was ipsilateral BHI (the slope resulted equal to 5.8), followed by age (a 10-year age difference is expected to diminish the effectiveness by about 4.3%) and by depression (depressed patients have almost 11% less effectiveness than non-depressed patients). Conclusion: These findings suggest that a satisfactory recovery from neurologic deficits requires a preserved cerebrovascular reactivity in the lesioned hemisphere despite the presence of an anatomic lesion.
Transcranial Focused Ultrasound to the Thalamus Is Associated with Reduced Extracellular GABA Levels in Rats
Authors: Yang Po Song , Kim Hyungmin , Lee Wonhye , Bohlke Mark , Park Shinsuk , Maher Timothy J. , Yoo Seung-Schik
Published: February 2012

Objective: Transcranial focused ultrasound (FUS), with its ability to non-invasively modulate the excitability of region-specific brain areas, is gaining attention as a potential neurotherapeutic modality. The aim of this study was to examine whether or not FUS administered to the brain could alter the extracellular levels of glutamate and γ-aminobutyric acid (GABA), which are representative excitatory and inhibitory amino acid neurotransmitters, respectively. Methods: FUS, delivered in the form of a train of pulses, was applied to the thalamus of Sprague-Dawley rats transcranially. Glutamate and GABA were directly sampled from the frontal lobe of the rat brain via a direct microdialysis technique before, during, and after the sonication. The dialysate concentrations were determined by high-performance liquid chromatography. Results: The individual levels of the neurotransmitters sampled were normalized to the baseline level for each rat. In terms of the changes in extracellular glutamate levels, there was no difference between the FUS-treated group and the unsonicated control group. However, extracellular GABA levels started to decrease upon sonication and remained reduced (approximately 20% below baseline; repeated-measures ANOVA, p < 0.05, adjusted for multiple comparisons) compared to the control group. Conclusion: The ability to modulate region-specific brain activity, along with the present evidence of the ability to modulate neurotransmission, demonstrates the potential utility of FUS as a completely new non-invasive therapeutic modality.
Vascular Risk Factors, White Matter Hyperintensities and Hippocampal Volume in Normal Elderly Individuals
Authors: Gattringer Thomas , Enzinger Christian , Ropele Stefan , Gorani Faton , Petrovic Katja Elisabeth , Schmidt Reinhold , Fazekas Franz
Published: February 2012

Background/Aims: Hippocampal atrophy has been identified as marker for the development of Alzheimer’s dementia (AD). To what extent vascular risk factors and white matter hyperintensities (WMH) affect hippocampal volume (HV) in asymptomatic elderly subjects and thus may impact such a predictive capacity is controversial. Methods: We analysed 287 participants of the Austrian Stroke Prevention Study (mean age 66.6 ± 6.6 years) with a Mini Mental State Examination score ≧27 who were free of neuropsychiatric disease and had undergone MRI including coronal T1-weighted sequences allowing for semi-automatic assessment of HV. Global brain volume (BV) was measured using SIENAX. WMH were rated according to the Fazekas scale and segmented to obtain WMH volumes. Results: Higher age was associated with lower absolute and normalized HV, a lower BV and higher WMH volume. None of the vascular risk factors had an impact on HV except for high-density lipoprotein. This effect disappeared after normalization of HV. WMH severity and volume did not affect HV either. Conclusion: Our data indicate HV loss in parallel with the whole brain and suggest no specific vulnerability towards vascular risk factors or age-related WMH in a cognitively intact normal elderly population. This also supports the utility of HV measurements to identify impending AD.
Perinatal Outcomes following the Ultrasound Diagnosis of Echogenic Bowel: An Australian Perspective
Authors: Ameratunga D.M. , Said J.M. , Reidy K. , Palma-Dias R.
Published: February 2012

Introduction: The aim of this study was to describe the association between fetal echogenic bowel (FEB) diagnosed during the second trimester and adverse perinatal outcomes in an Australian antenatal population. Methods: A retrospective analysis of ultrasound scans was performed between March 1, 2004 and March 1, 2009 at The Royal Women’s Hospital, Melbourne, Vic., Australia. Cases reported as having FEB on second trimester ultrasound were included. Medical records of each case were reviewed and information concerning additional investigations and perinatal outcomes were extracted. Results: A total of 66 cases were identified in our database. Three patients (5%) were excluded from further analysis as they were lost to follow-up, leaving 63 (95%) cases in this series. Thirty-two fetuses (52%) underwent karyotyping via amniocentesis, 5 (16%) of which were found to have chromosomal defects. Maternal serology for cytomegalovirus (CMV) was performed in 49 (78%) cases. Investigations indicated a total of 5 women who had CMV infection during their pregnancy. Thirty-three pregnancies (53%) were tested for cystic fibrosis (CF) and 1 baby was confirmed to have CF postnatally. Among the 50 liveborn infants, 3 cases of fetal growth restriction were apparent. Overall, 42 of the 50 liveborn infants (84%) and 67% of the entire cohort of 63 patients with a midtrimester diagnosis of FEB had a normal short-term neonatal outcome. Conclusion: This study reiterates the increased prevalence of aneuploidy, CMV, CF and fetal growth restriction in pregnancies complicated by the midtrimester sonographic finding of FEB. However, reassuringly, 67% of cases with ultrasound-detected echogenic bowel in the second trimester had a normal short-term neonatal outcome in this multiethnic Australian population.
Elevated Proportion of Small, Dense Low-Density Lipoprotein Particles and Lower Adiponectin Blood Levels Predict Early Structural Valve Degeneration of Bioprostheses
Authors: Shetty Rahul , Girerd Nicolas , Côté Nancy , Arsenault Benoit , Després Jean-Pierre , Pibarot Philippe , Mathieu Patrick
Published: February 2012

Objectives: Long-term durability of bioprosthetic heart valves (BPs) are limited by structural valve degeneration (SVD) leading to stenosis and/or regurgitation. In this study, we sought to determine the metabolic markers associated with SVD. Methods: In a cohort of 220 patients with an aortic BP (mean follow-up of 2.5 ± 1.2 years), we compared the metabolic and blood lipid profile including the levels of adiponectin and the proportion of small, dense low-density lipoprotein (LDL) particles (%LDL<255Å) in individuals developing echocardiographic evidence of early BP hemodynamic dysfunction with subjects having no features of BP dysfunction. Results: Patients developing BP dysfunction (n = 69; 31.3%) had a tendency of higher triglyceride levels. Moreover, patients with BP dysfunction had an increased proportion of %LDL<255Å. In multivariate linear regression analysis, after adjustment for age, gender, BP size and hypertension, the %LDL<255Å (p = 0.04) was significantly associated with BP dysfunction. In addition, patients with an elevated level of %LDL<255Å along with a decreased plasma adiponectin level were at a very high risk of developing early BP hemodynamic dysfunction (OR = 2.54, p = 0.04). Conclusion: BP dysfunction is significantly associated with an increased proportion of small, dense LDL.
Climatic Conditions and the Onset of Primary Spontaneous Pneumothorax: An Investigation of the Influence of Solar Terms
Authors: Zhang Guang-Jian , Gao Rui , Fu Jun-Ke , Jin Xin , Zhang Yong , Wang Zhe
Published: February 2012

Objective: To study the correlation between climatic changes and the development of primary spontaneous pneumothorax (PSP). Subjects and Methods: We retrospectively studied the relationship between 337 patients with conservatively treated PSP and meteorological conditions during a 3-year period in the urban area of Xi’an, China. The comparison was made depending on solar terms and on different aspects of atmospheric pressure, outdoor temperature, relative humidity, and wind speed. Results: Significant differences were found between PSP and non-PSP days depending on daily mean values of outdoor temperature and atmospheric pressure (p = 0.001 and p < 0.001, respectively). However, no obvious differences of meteorological factor variations between the ‘PSP day’ and the ‘pre-PSP day’ on days with and without PSP were found. The occurrence of PSP was associated with the solar terms Spring Equinox (p < 0.05) and End of Heat (p < 0.01). Conclusion: Among the factors examined in our study, daily mean outdoor temperature and atmospheric pressure showed a strong correlation with the occurrence of PSP. The solar terms Spring Equinox and End of Heat were found to be closely related with PSP development, which shed light on a new way for PSP incidence evaluation.
Temporal Effect of Afro-Caribbean Race on Serum Pregnancy-Associated Plasma Protein-A at 9–13 Weeks’ Gestation in Screening for Aneuploidies
Authors: Ball Susan , Wright David , Sodre Danielle , Lachmann Robert , Nicolaides Kypros H.
Published: February 2012

Objective: It was the aim of this study to investigate the pregnancy characteristics that influence the measured concentrations of maternal serum-free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 9+0–13+6 weeks’ gestation. Methods: In singleton pregnancies attending for routine care, serum-free β-hCG and PAPP-A were measured at 9+0–13+6 weeks’ gestation and fetal nuchal translucency was measured at 11+0–13+6 weeks. The population included 27,908 chromosomally normal and 104 trisomy 21 pregnancies. Multiple regression analysis was used to examine the pregnancy characteristics that have a significant effect on the measured concentrations of free β-hCG and PAPP-A. We also examined the impact of incorporating temporal effects on performance of screening for trisomy 21. Results: Serum-free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, preexisting diabetes mellitus type 2, smoking and conception by in vitro fertilization. There was a significant gestational age-dependent effect of Afro-Caribbean race on PAPP-A levels (p = 0.0005), with a weekly increase of 4.9% (95% CI 2.1–7.8). Conclusions: Serum-free β-hCG and PAPP-A concentrations at 9+0–13+6 weeks’ gestation are affected by several pregnancy characteristics and the effect of Afro-Caribbean race on PAPP-A increases with gestational age.
Renal Adaptation to Gentamicin-Induced Mineral Loss
Authors: Lee Chien-Te , Chen Hung Chun , Ng Hwee-Yeong , Lai Li-Wen , Lien Yeong-Hau H.
Published: February 2012

Background: Gentamicin, a well-known nephrotoxic drug, affects calcium and magnesium homeostasis. Although gentamicin induces urinary calcium and magnesium wasting immediately, it rarely causes significant hypocalcemia or hypomagnesemia clinically. Methods: We conducted an animal study to investigate the renal adaptation in calcium and magnesium handling after gentamicin treatment and effects on the expression of calcium and magnesium transport molecules in distal tubule. Gentamicin (40 mg/kg) was injected daily in male Sprague-Dawley rats (220–250 g) for up to 7 days. Results: This treatment did not affect serum creatinine, calcium, or magnesium levels. Gentamicin induced significant hypercalciuria (14-fold) and hypermagnesiuria (10-fold) in 6 h, which was associated with upregulation of TRPV5 (175 ± 3%), TRPV6 (170 ± 4%), TRPM6 (156 ± 4%) and calbindin-D28k (174 ± 3%; all p < 0.05 vs. control). This gene upregulation was maintained with daily injection of gentamicin for 7 days. The gentamicin-induced urinary calcium loss was reduced by 80% at days 3 and 7, while magnesium loss was reduced by 52 and 57% at days 3 and 7, respectively. On the other hand, urinary loss of potassium became worse on day 7 (2-fold), and phosphorus loss worse from day 3 to day 7 (3-fold). Conclusion: There is a rapid adaptation to gentamicin-induced hypercalciuria and hypermagnesiuria. The upregulation of distal tubule transport molecules, TRPV5, TRPV6, TRPM6 and calbindin-D28k occurs within 6 h of gentamicin treatment. This renal adaptation prevents further mineral loss due to gentamicin treatment.
Reduction of thrombus size in murine models of thrombosis following administration of recombinant α1-proteinase inhibitor mutant proteins
Authors: Eltringham-Smith Louise J. , Bhakta Varsha , Gataiance Sharon , Sheffield William P.
Published: February 2012

The variant serpin α1-PI M358R inhibits thrombin and other proteases such as activated protein C (APC) and factor XIa. We previously described recombinant proteins HAPI M358R (α1-PI M358R containing an N-terminal extension corresponding to residues 1–75 of heparin cofactor II) and HAPI RCL5 (HAPI M358R with F352-I356 and I360 substituted for the corresponding residues of antithrombin), with enhanced selectivity for thrombin over APC inhibition. We tested the hypotheses that these recombinant proteins would limit thrombosis in three mouse models, and that the HAPI chimeric proteins would be more effective than α1-PI M358R. Recombinant serpins were purified from Escherichia coli by nickel chelate and ion exchange affinity chromatography, and administered to mice intravenously. HAPI RCL5 reduced incorporation of radiolabelled fibrin(ogen) into thrombi in the ferric chloride-injured vena cava in a dose-dependent manner; HAPI M358R was less effective and α1-PI M358R was without effect. In a model of murine endotoxaemia, HAPI RCL5 was more effective than α1-PI M358R in reducing radiolabelled fibrin(ogen) deposition in heart and kidneys; immunohis-tochemistry of tissue sections showed lesser staining with anti-fibrin(ogen) antibodies with both treatments. In the ferric chloride-injured murine carotid artery, administration of both recombinant serpins was equally effective in lengthening the vessel’s time to occlusion. Our results show that the antithrombotic efficacy of the recombinant serpins correlates with their potency as thrombin inhibitors, since HAPI RCL5 inhibits thrombin, but not factors Xa, XIa, XIIa, or neutrophil elastase, more rapidly than α1-PI M358R.
Micro-array profiling exhibits remarkable intra-individual stability of human platelet micro-RNA
Authors: Stratz Christian , Nührenberg Thomas G. , Binder Harald , Valina Christian M. , Trenk Dietmar , Hochholzer Willibald , Neumann Franz , Fiebich Bernd L.
Published: February 2012

Platelets play an important role in haemostasis and thrombus formation. Latest research identified platelets harbouring so called microRNAs (miRNA). MiRNAs are short single-stranded RNAs modulating gene expression by targeting mRNAs. Limited data exist on inter-individual variability of platelet miRNA profile while no data are available on intra-individual variability. We assessed platelet miRNA profile in five volunteers at five time points over a time course of 10 days; 24 hours prior to the last blood sampling, subjects took 500 mg acetylsali-cylic acid (ASA). Platelet miRNA was isolated from leucocyte-depleted platelet-rich plasma, and miRNA array-analysis was performed. Temporal patterns and ASA effect were explored by a linear mixed effects model for each miRNA. For the 20 most abundantly expressed platelet miRNAs, target gene search was performed and an annotation network was created. MiRNA expression profiling of 1,281 human miRNAs revealed relevant expression of 221 miRNAs consistently expressed in all samples at all time points. Correlation of platelet miRNA ranks was highly significant to other studies. Global distribution of miRNA expression was relatively similar in all subjects. No miRNA exhibited a significant effect of time at level 0.05. After 24 hours, no significant effect of ASA was found. Concerning functional implications of the 20 most abundantly expressed miRNAs, we found six functional themes. In conclusion, platelet miRNA profile is remarkably stable over the time period studied. Single-point analysis of platelet miRNA profile is reasonable when inter-individual differences are studied. The functional annotation network points toward extra-platelet effects of platelet miRNAs.
The role of microRNAs in arterial remodelling
Authors: Nazari-Jahantigh Maliheh , Wei Yuanyuan , Schober Andreas
Published: February 2012

Adaptive alterations of the vessel wall architecture, called vascular remodelling, can be found in arterial hypertension, during the formation of aneurysms, in restenosis after vascular interventions, and in atherosclerosis. MicroRNAs (miR) critically affect the main cellular players in arterial remodelling and may either promote or inhibit the structural changes in the vessel wall. They regulate the phenotype of smooth muscle cells (SMCs) and control the inflammatory response in endothelial cells and macrophages. In SMCs, different sets of miRs induce either a synthetic or contractile phenotype, respectively. The conversion into a synthetic SMC phenotype is a crucial event in arterial remodelling. Therefore, reprogramming of the SMC phenotype by miR targeting can modulate the remodelling process. Furthermore, the effects of stimuli that induce remodelling, such as shear stress, angiotensin II, oxidised low-density lipoprotein, or apoptosis, on endothelial cells are mediated by miRs. The endothelial cell-specific miR-126, for example, is transferred in microvesicles from apoptotic endothelial cells and plays a protective role in atherogenesis. The inflammatory response of the innate immune system, especially through macrophages, promotes arterial remodelling. miR-155 induces the expression of inflammatory cytokines, whereas miR-146a and miR-147 are involved in the resolution phase of inflammation. However, in vivo data on the role of miRs in vascular remodelling are still scarce, which are required to test the therapeutic potential of the available, highly effective miR inhibitors.
The Revolutionary Worlds of Lexington and Concord Compared
Authors: Fuhrer Mary Babson
Published: February 2012

Since 19 April 1775, Lexington and Concord have been fused in Americans’ cultural memory. Yet Lexington was no Concord. The towns’ social, demographic, political, religious, and ideological differences shed light on their radically different responses to imperial crises as well as on the shared motivations that prompted both—ultimately—to take up arms.
Two Documents Detailing the Oneida Community’s Practice of Complex Marriage
Authors: La Moy William T.
Published: February 2012

In 1915, Dr. George E. Cragin delivered a candid (and heretofore unpublished) lecture to the Oneida Medical Club on male continence, or coitus reservatus, a practice supporting the Oneida Community’s concept of complex marriage, or free love. A portion of a published article to which Cragin alludes, containing an account by one disaffected woman member, is offered in counterpoint.