bluuebunny/crossref_metadata_2025 huggingface dataset:
Weighted Estimates for Bilinear Operators
Authors: Zhu Hua , Liu Heping
Published: February 2014

We study the boundedness of weighted multilinear operators given by products of finite vectors of Calderón-Zygmund operators. We also investigate weighted estimates for bilinear operators related to Schrödinger operator.
Flow Cytometric Evaluation of T Cell Activation Markers after Cardiopulmonary Bypass
Authors: Dieterlen Maja-Theresa , Bittner Hartmuth B. , Tarnok Attila , Garbade Jens , Dhein Stefan , Mohr Friedrich W. , Barten Markus J.
Published: February 2014

Background. Cardiopulmonary bypass surgery (CPBS) is associated with an increased risk for infections or with subsequent organ dysfunction. As T cell activation is a central mechanism during inflammatory processes, we developed an assay to evaluate T cell activation pathways in patients undergoing CPBS.Methods. Blood was obtained from eleven patients undergoing CPBS preoperatively, on postoperative day (POD)-3, and on POD-7 and was stimulated with different concentrations of Concanavalin A (ConA). Cyclosporine and sirolimus, inhibiting different pathways of the T cell cycle, were added to blood ex vivo. Expression of T cell activation markers CD25 and CD95 was analyzed by flow cytometry.Results. In untreated blood, expression of CD25 and CD95 significantly increased with higher ConA concentrations(P<0.05)and decreased for all ConA concentrations for both antigens over the study time(P<0.05). Independently from the ConA concentration, inhibition of CD25 and CD95 expression was highest preoperatively for sirolimus and on POD-3 for cyclosporine. At all time points, inhibition of CD25 and CD95 expression was significantly higher after cyclosporine compared to sirolimus treatment(P<0.001).Conclusion. Our results showed that different pathways of T cell activation are impaired after CPBS. Such knowledge may offer the opportunity to identify patients at risk for postoperative complications.
“Almost Bleeding to Death”: The Conundrum of Acquired Amegakaryocytic Thrombocytopenia
Authors: Brown Gabrielle Elena , Babiker Hani M. , Cantu Carlos L. , Yeager Andrew M. , Krishnadasan Ravitharan
Published: February 2014

Acquired amegakaryocytic thrombocytopenia (AAT) is a rare hematological disorder causing severe thrombocytopenia and bleeding. Previous in vitro studies postulated both cell-mediated suppression of megakaryocytopoiesis in early megakaryocytic progenitor cells and humoral-mediated suppression by anti-thrombopoietin antibodies as possible etiologies of AAT. Patients with AAT usually present with severe bleeding and thrombocytopenia that is unresponsive to steroids and intravenous immunoglobulin (IVIG). Although standard guidelines have not been established for management of AAT, a few case reports have indicated a response to immunosuppressive treatment. The prompt recognition of this disease entity is essential in view of the substantial risk of morbidity and mortality from excessive bleeding. We report a case of AAT successfully treated with equine antithymocyte globulin (ATG) and cyclosporine (CSP).
Supporting Preemptive Multitasking in Wireless Sensor Networks
Authors: Lattanzi Emanuele , Freschi Valerio , Bogliolo Alessandro
Published: February 2014

Supporting the concurrent execution of multiple tasks on lightweight sensor nodes could enable the deployment of independent applications on a shared wireless sensor network, thus saving cost and time by exploiting infrastructures which are typically underutilized if dedicated to a single task. Existing approaches to wireless sensor network programming provide limited support to concurrency at the cost of reducing the generality and the expressiveness of the language adopted. This paper presents a java-compatible platform for wireless sensor networks which provides a thorough support to preemptive multitasking while allowing the programmers to write their applications in java. The proposed approach has been implemented and tested on top of VirtualSense, an ultra-low-power wireless sensor mote providing a java-compatible runtime environment. Performance and scalability of the solution are discussed in light of extensive experiments performed on representative benchmarks.
Sign of Leser-Trélat Associated with Esophageal Squamous Cell Cancer
Authors: Gaduputi Vinaya , Chandrala Chaitanya , Tariq Hassan , Kanneganti Kalyan
Published: February 2014

The sign of Leser-Trélat is a rare paraneoplastic phenomenon marked by accelerated onset of multiple seborrheic keratoses. The occurrence of the sign often points towards underlying visceral malignancies which in a majority are adenocarcinomas of the gastrointestinal tract. We report this case of a 65-year-old man who presented with sign of Leser-Trélat and was diagnosed with poorly differentiated squamous cell cancer of the esophagus. To our knowledge this is only the second such reported association of Leser-Trélat sign with squamous cell cancer of esophagus.
Hilbert Transforms along Convex Curves for lq-Valued Functions
Authors: Liu Honghai
Published: February 2014

We show that Hilbert transforms along a large class of convex curves are bounded on Lp(ℝ2,lq), where 5/3<p, q<5/2.
Chemodynamics of Methyl Parathion and Ethyl Parathion: Adsorption Models for Sustainable Agriculture
Authors: Tabassum Noshabah , Rafique Uzaira , Balkhair Khaled S. , Ashraf Muhammad Aqeel
Published: February 2014

The toxicity of organophosphate insecticides for nontarget organism has been the subject of extensive research for sustainable agriculture. Pakistan has banned the use of methyl/ethyl parathions, but they are still illegally used. The present study is an attempt to estimate the residual concentration and to suggest remedial solution of adsorption by different types of soils collected and characterized for physicochemical parameters. Sorption of pesticides in soil or other porous media is an important process regulating pesticide transport and degradation. The percentage removal of methyl parathion and ethyl parathion was determined through UV-Visible spectrophotometer at 276 nm and 277 nm, respectively. The results indicate that agricultural soil as compared to barren soil is more efficient adsorbent for both insecticides, at optimum batch condition of pH 7. The equilibrium between adsorbate and adsorbent was attained in 12 hours. Methyl parathion is removed more efficiently (by seven orders of magnitude) than ethyl parathion. It may be attributed to more available binding sites and less steric hindrance of methyl parathion. Adsorption kinetics indicates that a good correlation exists between distribution coefficient (Kd) and soil organic carbon. A general increase in Kd is noted with increase in induced concentration due to the formation of bound or aged residue.
Role of Ink4a/Arf Locus in Beta Cell Mass Expansion under Physiological and Pathological Conditions
Authors: Salas Elisabet , Rabhi Nabil , Froguel Philippe , Annicotte Jean-Sébastien
Published: February 2014

The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin.
Properties of Vulcanized Polyisoprene Rubber Composites Filled with Opalized White Tuff and Precipitated Silica
Authors: Samaržija-Jovanović Suzana , Jovanović Vojislav , Marković Gordana , Zeković Ivana , Marinović-Cincović Milena
Published: February 2014

Opalized white tuff (OWT) with 40 μm average particle size and 39.3 m2/g specific surface area has been introduced into polyisoprene rubber (NR). Their reinforcing effects were evaluated by comparisons with those from precipitated silica (PSi). The cure characteristic, apparent activation energy of cross-link (Eac) and reversion (Ear), and mechanical properties of a variety of composites based on these rubbers were studied. This was done using vulcanization techniques, mechanical testing, and scanning electron microscopy (SEM). The results showed that OWT can greatly improve the vulcanizing process by shortening the time of optimum cure (tc90) and the scorch time (ts2) of cross-linked rubber composites, which improves production efficiency and operational security. The rubber composites filled with 50 phr of OWT were found to have good mechanical and elastomeric properties. The tensile strengths of the NR/OWT composites are close to those of NR/PSi composites, but the tear strength and modulus are not as good as the corresponding properties of those containing precipitated silica. Morphology results revealed that the OWT is poorly dispersed in the rubber matrix. According to that, the lower interactions between OWT and polyisoprene rubber macromolecules are obtained, but similar mechanical properties of NR/OWT (100/50) rubber composites compared with NR/PSi (100/50) rubber composites are resulted.
The First Fifty ABO Blood Group Incompatible Kidney Transplantations: The Rotterdam Experience
Authors: van Agteren Madelon , Weimar Willem , de Weerd Annelies E. , te Boekhorst Peter A. W. , Ijzermans Jan N. M. , van de Wetering Jaqueline , Betjes Michiel G. H.
Published: February 2014

This study describes the single center experience and long-term results of ABOi kidney transplantation using a pretransplantation protocol involving immunoadsorption combined with rituximab, intravenous immunoglobulins, and triple immune suppression. Fifty patients received an ABOi kidney transplant in the period from 2006 to 2012 with a follow-up of at least one year. Eleven antibody mediated rejections were noted of which 5 were mixed antibody and cellular mediated rejections. Nine cellular mediated rejections were recorded. Two grafts were lost due to rejection in the first year. One-year graft survival of the ABOi grafts was comparable to 100 matched ABO compatible renal grafts, 96% versus 99%. At 5-year follow-up, the graft survival was 90% in the ABOi versus 97% in the control group. Posttransplantation immunoadsorption was not an essential part of the protocol and no association was found between antibody titers and subsequent graft rejection. Steroids could be withdrawn safely 3 months after transplantation. Adverse events specifically related to the ABOi protocol were not observed. The currently used ABOi protocol shows good short and midterm results despite a high rate of antibody mediated rejections in the first years after the start of the program.
Composition, In Vitro Antioxidant and Antimicrobial Activities of Essential Oil and Oleoresins Obtained from Black Cumin Seeds (Nigella sativaL.)
Authors: Singh Sunita , Das S. S. , Singh G. , Schuff Carola , de Lampasona Marina P. , Catalán César A. N.
Published: February 2014

Gas chromatography-mass spectrometry (GC-MS) analysis revealed the major components in black cumin essential oils which were thymoquinone (37.6%) followed by p-cymene (31.2%),α-thujene (5.6%), thymohydroquinone (3.4%), and longifolene (2.0%), whereas the oleoresins extracted in different solvents contain linoleic acid as a major component. The antioxidant activity of essential oil and oleoresins was evaluated against linseed oil system at 200 ppm concentration by peroxide value, thiobarbituric acid value, ferric thiocyanate, ferrous ion chelating activity, and 1,1-diphenyl-2-picrylhydrazyl radical scavenging methods. The essential oil and ethyl acetate oleoresin were found to be better than synthetic antioxidants. The total phenol contents (gallic acid equivalents, mg GAE per g) in black cumin essential oil, ethyl acetate, ethanol, and n-hexane oleoresins were calculated as11.47±0.05,10.88±0.9,9.68±0.06, and8.33±0.01, respectively, by Folin-Ciocalteau method. The essential oil showed up to 90% zone inhibition againstFusarium moniliformein inverted petri plate method. Using agar well diffusion method for evaluating antibacterial activity, the essential oil was found to be highly effective against Gram-positive bacteria.
Examination of the Ovarian Reserve after Generation of Unilateral Rudimentary Uterine Horns in Rats
Authors: Toyganözü Hasan , Nazik Hakan , Narin Raziye , Satar Deniz , Narin Mehmet Ali , Büyüknacar Sinem , Api Murat , Aytan Hakan
Published: February 2014

Objective. The purpose of this experimental rat model study is to evaluate the changes in the ovarian environment after excision of the rudimentary horn.Methods. Ten female Wistar albino rats were used in this study. One cm of right uterine horn length was excised in the first operation. Two months after the first operation, all animals were sacrificed to obtain ovaries for histological examination. Mann-WhitneyUtest and Student'st-test were used for statistical analysis purposes. Statistical significance was defined asP<0.005.Results. The number of primordial follicles (P=0.415), primary follicles (P=0.959), preantral follicles (P=0.645), antral follicles (P=0.328), and Graafian follicles (P=0.721) was decreased and the number of atretic follicles (P=0.374) increased in the right ovarian side. Howeve,r this difference was not found to be statistically significant.Conclusion. The results of this experimental rat model study suggest that the excision of rudimentary horn could have negative effects on ipsilateral ovarian functions.
Anti-Inflammatory Effect of Recreational Exercise in TNBS-Induced Colitis in Rats: Role of NOS/HO/MPO System
Authors: Szalai Zita , Szász András , Nagy István , Puskás László G. , Kupai Krisztina , Király Adél , Berkó Anikó Magyariné , Pósa Anikó , Strifler Gerda , Baráth Zoltán , Nagy Lajos I. , Szabó Renáta , Pávó Imre , Murlasits Zsolt , Gyöngyösi Mariann , Varga Csaba
Published: February 2014

There are opposite views in the available literature: Whether physical exercise has a protective effect or not on the onset of inflammatory bowel disease (IBD). Therefore, we investigated the effects of recreational physical exercise before the induction of colitis. After 6 weeks of voluntary physical activity (running wheel), male Wistar rats were treated with TNBS (10 mg). 72 hrs after trinitrobenzene sulphonic acid (TNBS) challenge we measured colonic gene (TNF-α, IL-1β, CXCL1 and IL-10) and protein (TNF-α) expressions of various inflammatory mediators and enzyme activities of heme oxygenase (HO), nitric oxide synthase (NOS), and myeloperoxidase (MPO) enzymes. Wheel running significantly increased the activities of HO, constitutive NOS (cNOS) isoform. Furthermore, 6 weeks of running significantly decreased TNBS-induced inflammatory markers, including extent of lesions, severity of mucosal damage, and gene expression of IL-1β, CXCL1, and MPO activity, while IL-10 gene expression and cNOS activity were increased. iNOS activity decreased and the activity of HO enzyme increased, but not significantly, compared to the sedentary TNBS-treated group. In conclusion, recreational physical exercise can play an anti-inflammatory role by downregulating the gene expression of proinflammatory mediators, inducing anti-inflammatory mediators, and modulating the activities of HO and NOS enzymes in a rat model of colitis.
Exercise-Induced Biological and Psychological Changes in Overweight and Obese Individuals: A Review of Recent Evidence
Authors: Dinas Petros C. , Markati Aleksandra S. , Carrillo Andres E.
Published: February 2014

On a global scale, the most recent evidence indicates that over 400 million adults are obese while ~20 million children and 1.6 billion adults are overweight. The World Health Organization reveals that, by the year 2015, ~2.3 billion adults will be overweight and more than 700 million will be obese. In this review paper we summarized the current evidence to elucidate the impact of exercise training on biological and psychological health indices in overweight and obese individuals. Endocrine function indices that are discussed herein include leptin, adiponectin, growth hormone, and ghrelin levels. Psychological factors include anxiety and depression, body image, and motivation for exercise. Overall, exercise promotes physical and psychological health in overweight and obese individuals particularly because exercise-induced adaptations occur across a multitude of systems within the active human. The impact of exercise on specific biological and psychological health indices contributes to overall health in overweight and obese individuals.
Low Dose of Valproate Improves Motor Function after Traumatic Brain Injury
Authors: Tai Yu-Ting , Lee Wen-Yuan , Lee Fei-Peng , Lin Tien-Jen , Shih Chia-Lin , Wang Jia-Yi , Chiu Wen-Ta , Hung Kuo-Sheng
Published: February 2014

Background.Traumatic brain injuries (TBIs) are a major health care problem worldwide. Approximately 1.5 million new TBI cases occur annually in the United States, with mortality rates ranging between 35% and 40% in severe patients. Despite the incidence of these injuries and their substantial socioeconomic implications, no specific pharmacological intervention is available for clinical use. Several studies have indicated that 300 mg/kg or 400 mg/kg of valproate (VPA) exhibits neuroprotective effects in animal models. However, humans cannot tolerate high doses of VPA. This study aims to investigate whether 30 mg/kg of VPA administered to rats affects TBIs.Methods.We used a rat model to test the effects of 30 mg/kg of VPA on TBIs. Molecular identifications for histone acetylation and phosphorylation of cAMP response element-binding protein (CREB) and phosphorylated extracellular signal regulated kinase (ERK) were performed.Results.The results indicated that treating adult rats with VPA after TBIs significantly decreased the contusion volume and recovery of contusion-related skilled forelimb reaching deficits. Applying VPA also increased histone acetylation, p-ERK, and p-CREB expression in the brain. Furthermore, applying VPA reduced inflammation, glial fibrillary acidic protein activation, and apoptosis.Conclusion.This study found that 30 mg/kg of VPA assists in treating TBIs in rat models.
Getting More Out of Survival Data by Using the Hazard Function
Authors: Hess Kenneth R. , Levin Victor A.
Published: February 2014

Information about the survival experience for a group of patients is almost exclusively conveyed using plots of the survival function. However, the hazard function provides information about the survival experience that is not readily evident from inspection of the survival function. The hazard function tracks the instantaneous failure rate over time among the surviving patients and can be readily estimated with available software. We illustrate how these estimates can be used in conjunction with estimates of the survival function to glean clinically relevant information from survival data. Clin Cancer Res; 20(6); 1404–9. ©2014 AACR.
Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors
Authors: Chen Fuyi , Becker Albert J. , LoTurco Joseph J.
Published: February 2014

The etiology of central nervous system (CNS) tumor heterogeneity is unclear. To clarify this issue, a novel animal model was developed of glioma and atypical teratoid/rhabdoid-like tumor (ATRT) produced in rats by nonviral cellular transgenesis initiated in utero. This model system affords the opportunity for directed oncogene expression, clonal labeling, and addition of tumor-modifying transgenes. By directing HRasV12 and AKT transgene expression in different cell populations with promoters that are active ubiquitously (CAG promoter), astrocyte-selective (glial fibrillary acidic protein promoter), or oligodendrocyte-selective (myelin basic protein promoter) we generated glioblastoma multiforme and anaplastic oligoastrocytoma, respectively. Importantly, the glioblastoma multiforme and anaplastic oligoastrocytoma tumors were distinguishable at both the cellular and molecular level. Furthermore, proneural basic helix-loop-helix (bHLH) transcription factors, Ngn2 (NEUROG2) or NeuroD1, were expressed along with HRasV12 and AKT in neocortical radial glia, leading to the formation of highly lethal ATRT like tumors. This study establishes a unique model in which determinants of CNS tumor diversity can be parsed out and reveals that both mutation and expression of neurogenic bHLH transcription factors contribute to CNS tumor diversity.

Implications: A novel CNS tumor model reveals that oncogenic events occurring in disparate cell types and/or molecular contexts lead to different tumor types; these findings shed light on the sources of brain tumor heterogeneity. Mol Cancer Res; 12(5); 742–53. ©2014 AACR.
Curcumin Implants, Not Curcumin Diet, Inhibit Estrogen-Induced Mammary Carcinogenesis in ACI Rats
Authors: Bansal Shyam S. , Kausar Hina , Vadhanam Manicka V. , Ravoori Srivani , Pan Jianmin , Rai Shesh N. , Gupta Ramesh C.
Published: February 2014

Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17β-estradiol (E2)–mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached >80% (∼6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm3 vs. 280 ± 141 mm3; P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered. Cancer Prev Res; 7(4); 456–65. ©2014 AACR.
Safety and Chemopreventive Effect of Polyphenon E in Preventing Early and Metastatic Progression of Prostate Cancer in TRAMP Mice
Authors: Kim Seung Joon , Amankwah Ernest , Connors Shahnjayla , Park Hyun Y. , Rincon Maria , Cornnell Heather , Chornokur Ganna , Hashim Arig Ibrahim , Choi Junsung , Tsai Ya-Yu , Engelman Robert W. , Kumar Nagi , Park Jong Y.
Published: February 2014

Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer. Cancer Prev Res; 7(4); 435–44. ©2014 AACR.
Long-term Complete Remission Following Radiosurgery and Immunotherapy in a Melanoma Patient with Brain Metastasis: Immunologic Correlates
Authors: Karbach Julia , Gnjatic Sacha , Biskamp Melina , Atmaca Akin , Weidmann Eckhart , Brandt Kathrin , Wahle Claudia , Bernhard Helga , Knuth Alexander , Jäger Elke
Published: February 2014

A melanoma patient with brain metastases was treated by gamma-knife radiosurgery and immunotherapy with autologous tumor-lysate–loaded dendritic cells (DC). Ten years after the combined treatment, the patient remains in complete remission. Remarkable immunologic correlates to the clinical development were the transient induction of NY-ESO-1 antibody and the durable expansion of MAGE-A1p161–169 EADPTGHSY–specific CD8+ T cells. Although the induction of NY-ESO-1 antibody most likely resulted from gamma-knife–mediated “auto-vaccination,” the persistence of circulating MAGE-A1–specific T cells, which are still detectable ex vivo in the absence of any tumor manifestation, coincides with DC-based vaccination administered monthly until today. Cancer Immunol Res; 2(5); 404–9. ©2014 AACR.
Deep Brain Stimulation for Psychiatric Diseases: A Pooled Analysis of Published Studies Employing Disease-Specific Standardized Outcome Scales
Authors: Nangunoori Raj , Tomycz Nestor D. , Quigley Matthew , Oh Michael Y. , Whiting Donald M.
Published: February 2014

Background: Deep brain stimulation (DBS) has emerged in recent years as a novel therapy in the treatment of refractory psychiatric disease, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). Standardized outcome scales were crucial in establishing that DBS was an effective therapy for movement disorders. Objective: In order to better characterize the evidence supporting DBS for various psychiatric diseases, we performed a pooled analysis of those studies which incorporated specific standardized rating scales. Methods: A Medline search was conducted to identify all studies reporting DBS for MDD, OCD, and TS. The search yielded a total of 49 articles, of which 24 were included: 4 related to MDD (n = 48), 10 to OCD (n = 64), and 10 to TS (n = 46). Results: A meta-analysis of DBS for MDD, OCD, and TS in studies employing disease-specific standardized outcome scales showed that the outcome scales all improved in a statistically significant fashion for these psychiatric diseases. Our pooled analysis suggests that DBS for TS has the highest efficacy amongst the psychiatric diseases currently being treated with DBS, followed by OCD and MDD. Conclusion: DBS for psychiatric diseases remains investigational; however, even when studies failing to incorporate standardized outcome scales are excluded, there is statistically significant evidence that DBS can improve symptoms in MDD, OCD, and TS. Standardized disease-specific outcome scales facilitate pooled analysis and should be a required metric in future studies of DBS for psychiatric disease.
Efficacy and Tolerability of Benzodiazepines versus Antidepressants in Anxiety Disorders: A Systematic Review and Meta-Analysis
Authors: Offidani Emanuela , Guidi Jenny , Tomba Elena , Fava Giovanni Andrea
Published: February 2014

Background: Placebo-controlled trials showed that both benzodiazepines (BDZ) and antidepressant drugs (AD) are effective in treating anxiety disorders. However, in the last years a progressive shift in the prescribing pattern from BDZ to newer AD has taken place. The aim of this systematic review and meta-analysis is to analyze whether controlled comparisons support such a shift. Methods: CINHAL, the Cochrane Library, MEDLINE, PubMed and Web of Science were searched from inception up to December 2012. A total of 22 studies met the criteria for inclusion. They were mostly concerned with tricyclic antidepressants (TCA; 18/22) and involved different anxiety disorders. In order to reduce clinical heterogeneity, only the 10 investigations that dealt with the comparison between TCA and BDZ in panic disorder were submitted to meta-analysis, whereas the remaining papers were individually summarized and critically examined. Results: According to the systematic review, no consistent evidence emerged supporting the advantage of using TCA over BDZ in treating generalized anxiety disorder (GAD), complex phobias and mixed anxiety-depressive disorders. Indeed, BDZ showed fewer treatment withdrawals and adverse events than AD. In panic disorder with and without agoraphobia our meta-analysis found BDZ treatments more effective in reducing the number of panic attacks than TCA (risk ratio, RR = 1.13; 95% CI = 1.01-1.27). Furthermore, BDZ medications were significantly better tolerated than TCA drugs, causing less discontinuation (RR = 0.40; 95% CI = 0.20-0.57) and side effects (RR = 0.41; 95% CI = 0.34-0.50). As to newer AD, BDZ trials resulted in comparable or greater improvements and fewer adverse events in patients suffering from GAD or panic disorder. Conclusions: The change in the prescribing pattern favoring newer AD over BDZ in the treatment of anxiety disorders has occurred without supporting evidence. Indeed, the role and usefulness of BDZ need to be reappraised.
Low-Dose Tissue Plasminogen Activator and Standard-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke in Asian Populations: A Review
Authors: Ramaiah Siva Seeta , Yan Bernard
Published: February 2014

Background: The burden of stroke is becoming an important issue in Asian countries, where half of the world's population lives. In Western populations, standard-dose intravenous tissue plasminogen activator (tPA) at a dose of 0.9 mg/kg administered up to 4.5 h following acute ischaemic stroke has been shown to improve clinical outcomes. However, the dosage of tPA in Asian populations varies, partly influenced by treatment costs in developing countries and the perceived racial differences in treatment response. Furthermore, no randomized controlled trial of intravenous tPA thrombolysis has been carried out in Asia with the exceptions of observational and multicentre registries in Japan. Summary of the Review: This review aims to examine the current use of low-dose tPA in Asian populations with particular emphasis on its clinical benefits. Historically, the findings of 2-chain tPA (duteplase) trials in the early 1990s were the basis of low-dose tPA in Japan, and standard-dose tPA was chosen taking into account a pilot dose escalation study. Most of the trials incorporating low-dose tPA suggested that low-dose tPA has clinical efficacy comparable with the standard dose and that it is associated with a lower incidence of symptomatic haemorrhage. It follows that consensus regarding the dosage of tPA is wanting. Conclusions: Standard-dose tPA would be a reasonable choice in Asian populations until the results are available from randomized controlled studies comparing low-dose with standard-dose tPA.
Neuroinflammation and β Amyloid Deposition in Alzheimer's Disease: In vivo Quantification with Molecular Imaging
Authors: Hommet C. , Mondon K. , Camus V. , Ribeiro M.J. , Beaufils E. , Arlicot N. , Corcia P. , Paccalin M. , Minier F. , Gosselin T. , Page G. , Guilloteau D. , Chalon S.
Published: February 2014

Background/Aims: Neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Its relationship with underlying β amyloid deposition remains unclear. In vivo visualization of microglial activation has become possible with the development of molecular imaging ligands when used with positron emission tomography (PET). The translocator protein (TSPO) is upregulated during neuroinflammation. Consequently, targeting TSPO with radiolabeled ligands for PET is an attractive biomarker for neuroinflammation. Methods: A review of the research literature on PET imaging which studied in vivo neuroinflammation in AD subjects and its relationship with amyloid load was performed, including papers published between 2001 and 2012. Results: Six studies were included using either [11C]PK-11195 or another non-TSPO radioligand that binds to the monoaminooxidase B. All the studies evaluated amyloid load with [11C]PIB. Microglial activation and astrocytosis are potentially early phenomena in AD. However, the individual levels of amyloid deposition and microglial activation were not correlated. Conclusion: Noninvasive in vivo molecular imaging to visualize neuroinflammation in AD may contribute to our understanding of the kinetics of neuroinflammation and its relationship to the hallmarks of the disease. Both are important for the development of future therapeutic modalities and for quantifying the efficacy of future disease-modifying treatments.
The Journey Towards Lung Protective Respiratory Support in Preterm Neonates
Authors: Berger Thomas M. , Fontana Matteo , Stocker Martin
Published: February 2014

The aim of this conceptual review is to provide the reader with a broad perspective on progress made in respiratory support of preterm infants over the past five decades. Landmark discoveries are described in their historical context and underlying theories of lung protection are discussed. The review finishes by integrating different approaches and perspectives into a state-of-the-art concept for lung-protective ventilation in this fragile patient population. Improvements in neonatal respiratory support in the 1970s and 1980s have contributed to dramatic improvements of mortality and morbidity rates among neonates with respiratory failure. Continuous positive airway pressure, antenatal corticosteroids and surfactant replacement therapy revolutionized the care of preterm infants. With the recognition that atelectrauma, volutrauma and oxygen toxicity are the main factors contributing to ventilator-induced lung injury, lung-protective strategies, including noninvasive respiratory support, tidal volume targeting during conventional mechanical ventilation and high frequency ventilation were developed in the 1990s. Given the fact that progress made in the last decade has only resulted in minor improvements in mortality and morbidity rates of neonates with respiratory failure, it seems unlikely that further refinements of current technologies will produce giant leaps forward in high-resource countries. It appears that entirely new approaches would be required. In contrast, knowledge and technology transfer of basic respiratory support strategies (e.g. use of oxygen, simple systems to provide continuous positive airway pressure), could have an enormous impact on the prognosis of neonates with respiratory failure in low-resource countries.
Is It Time to Rethink How Neuropsychological Tests Are Used to Diagnose Mild Forms of HIV-Associated Neurocognitive Disorders? Impact of False-Positive Rates on Prevalence and Power
Authors: Meyer Ana-Claire L. , Boscardin W. John , Kwasa Judith K. , Price Richard W.
Published: February 2014

Background: Between 0 and 48% of normal HIV-uninfected individuals score below threshold neuropsychological test scores for HIV-associated neurocognitive disorders (HAND) or are false positives. There has been little effort to understand the effect of varied interpretations of research criteria for HAND on false-positive frequencies, prevalence and analytic estimates. Methods: The proportion of normal individuals scoring below Z score thresholds drawn from research criteria for HAND, or false-positive frequencies, was estimated in a normal Kenyan population and a simulated normal population using varied interpretations of research criteria for HAND. We calculated the impact of false-positive frequencies on prevalence estimates and statistical power. Results: False-positive frequencies of 2-74% were observed for asymptomatic neurocognitive impairment/mild neurocognitive disorder and 0-8% for HIV-associated dementia. False-positive frequencies depended on the definition of an abnormal cognitive domain, Z score thresholds and neuropsychological battery size. Misclassification led to clinically important overestimation of prevalence and dramatic decreases in power. Conclusions: Minimizing false-positive frequencies is critical to decrease bias in prevalence estimates and minimize reductions in power in studies of association, particularly for mild forms of HAND. We recommend changing the Z score threshold to ≤-1.5 for mild impairment, limiting analysis to 3-5 cognitive domains and using the average Z score to define an abnormal domain.
Transcriptional and Epigenetic Regulation of Neural Crest Induction during Neurulation
Authors: Mayanil Chandra S.
Published: February 2014

Neurulation is one of the many important events in mammalian development. It is the stage of organogenesis in vertebrate embryos during which the neural tube is transformed into the primitive structures that will later develop into the central nervous system. Recent transcriptome analysis during neurulation and early organogenesis in humans and mice has identified the global dynamics of gene expression changes across developmental time. This has revealed a richer understanding of gene regulation and provides hints at the transcriptional regulatory networks that underlie these processes. Similarly, epigenome analysis, which collectively constitutes histone modifications, transcription factor binding, and other structural features associated with gene regulation, has given a renewed appreciation to the subtle mechanisms involving the process of neurulation. More specifically, the histone demethylases KDM4A and KDM6B have recently been shown to be key histone H3K4 and H3K27 modifiers that regulate neural crest specification and neural tube closure. Additionally, miRNAs have recently been shown to influence transcription of genes directly or by altering the levels of epigenetic modifiers and thus regulate gene expression. This mini review briefly summarizes the literature, highlighting the transcriptional and epigenetic regulation of key genes involved in neural crest induction and neural crest specification by transcription factors and miRNAs. Understanding how these mechanisms work individually and in clusters will shed light on pathways in the context of diseases associated with neural crest cell derivatives such as melanoma, cardiovascular defects and neuronal craniofacial defects.
Postadolescent Acne in Females
Authors: Holzmann R. , Shakery K.
Published: February 2014

Acne in the adult female often presents as a chronic condition that can have a considerable negative psychological, social and emotional impact on the affected individual. Estimated prevalence rates of adult female acne vary widely according to study type. Case reports and clinical examinations estimate the prevalence of clinical acne at 10-12%, while survey estimates of physiological disease states are as high as 54%. Two subtypes of adult female acne may be defined according to time of onset: ‘persistent' and ‘late-onset', accounting for approximately 80 and 20% of cases, respectively. Postadolescent acne is generally mild-to-moderate in severity and presents with more inflammatory lesions and fewer comedones compared to adolescent acne. Furthermore, the impact of acne on the quality of life is often greater in adult females than in younger individuals. Despite these important differences, the key principles of acne treatment in the adult female do not differ significantly from those of other age groups. However, specific characteristics relating to the adult female should be considered when selecting a treatment regimen.
Probiotics for Preterm Neonates: What Will It Take to Change Clinical Practice?
Authors: Ofek Shlomai N. , Deshpande G. , Rao S. , Patole S.
Published: February 2014

Necrotizing enterocolitis (NEC) is a major cause of mortality (25%) and morbidity including recurrent sepsis, dependence on parenteral nutrition, need for surgery, and survival with short bowel syndrome in preterm very low birth weight infants. Mortality (45-100%) and morbidity including the risk of long-term neurodevelopmental impairment are higher in extremely preterm infants needing surgery for NEC. Systematic reviews of randomized controlled trials (RCT) indicate that probiotics significantly reduce the risk of NEC (RR 0.39; 95% CI 0.29-0.52; p < 0.00001) and all-cause mortality (RR 0.52; 95% CI 0.40-0.69; p < 0.00001) while facilitating enteral feeds in preterm infants. At present, data from 25 RCT (∼5,000 neonates) and reports on routine use (∼3,000 neonates) indicates that significant adverse effects of probiotics are rare. Despite the robust evidence, there is still reluctance in incorporating routine probiotic prophylaxis in clinical practice. If the goal is to have zero tolerance for NEC, then probiotic prophylaxis must be adopted as soon as possible. Current gaps in knowledge can be addressed by continued research while providing routine probiotic supplementation. We believe that the concept of evidence-based practice of medicine has been stretched too far in this case. Trial sequential analysis has already shown that the evidence for probiotic supplementation was conclusive after 10 trials. Results of the ongoing trials are unlikely to change the conclusions of the systematic reviews significantly. Currently we are at trial number 25; how many more trials do we need? What will it take to change clinical practice?
Posttraumatic Stress Disorder and Cardiometabolic Disease
Authors: Levine Arlene Bradley , Levine Lionel M. , Levine T. Barry
Published: February 2014

The need for addressing posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing public health concern. Current PTSD management addresses psychiatric parameters of this condition. However, PTSD is not simply a psychiatric disorder. Traumatic stress increases the risk for inflammation-related somatic diseases and early mortality. The metabolic syndrome reflects the increased health risk associated with combat stress and PTSD. Obesity, dyslipidemia, hypertension, diabetes mellitus, and cardiovascular disease are prevalent among PTSD patients. However, there has been little appreciation for the need to address these somatic PTSD comorbidities. Medical professionals treating this vulnerable population should screen patients for cardiometabolic risk factors and avail themselves of existing preventive diet, exercise, and pharmacologic modalities that will reduce such risk factors and improve overall long-term health outcomes and quality of life. There is the promise that cardiometabolic preventive therapy complementing psychiatric intervention may, in turn, help improve the posttraumatic stress system dysregulation and favorably impact psychiatric and neurologic function.
Current Perspective on the Pathogenesis of Small Intestinal Neuroendocrine Tumors: Progress in Biomarkers and Molecular Events
Authors: Chen Ying-Xuan , Fang Jing-Yuan
Published: February 2014

Background: Neuroendocrine tumors of the gastrointestinal tract differ in their histopathologic and clinical presentation. Small intestinal neuroendocrine tumors (SI-NETs), representing only a small portion within gastrointestinal malignancies, are often associated with a delayed diagnosis due to their non-specific symptoms. The increased incidence of SI-NETs during the last decades demands earlier diagnosis and more effective treatment, which both rely on a better understanding on the underlying molecular mechanisms. Summary: The purpose of this review is to discuss the biomolecular changes responsible for the pathogenesis of SI-NETs, and potential biomarkers in the diagnostic and prognostic evaluation. Key Message A greater understanding of the molecular mechanisms that underpin the pathogenesis of small intestinal neuroendocrine tumors (SI-NETs) facilitates the classification, diagnosis and treatment of these relatively rare gastrointestinal malignancies. Practical Implications Currently, SI-NETs are diagnosed using histological examination and staining for various neuroendocrine markers. Genetically, SI-NETs are characterized by an absence of alterations to K-ras, p53 and DNA mismatch repair genes. Loss of chromosome 18, deletion of Smad2 and Smad4, and amplification of SRC, EGFR and PDGFR have been reported. Abnormal DNA methylation status, reflected by overexpression of DNA methyltransferase, higher methylation of the RASSF1A promoter and overexpression of histone H1x are also associated with SI-NETs. These tumors are also associated with fibrosis, possibly due to the high levels of serotonin and other fibrotic factors produced. Genetic studies have pinpointed genes that can differentiate SI-NETs from other neuroendocrine tumors (oxytocin receptor, G protein-coupled receptor 113, VMAT-1, CDX-2), enabling more accurate diagnosis. Paraneoplastic antigen Ma2, neurokinin A and the CART peptide are under investigation as prognostic biomarkers. There is, however, still an unmet need for more sensitive biomarkers for earlier diagnosis and for a more specific classification system that encompasses tumor histology and reliable predictors of clinical response.