bluuebunny/crossref_metadata_2025 huggingface dataset:
The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1α
Authors: Hetz Claudio , Martinon Fabio , Rodriguez Diego , Glimcher Laurie H.
Published: October 2011

Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.
The Brain Basis of Language Processing: From Structure to Function
Authors: Friederici Angela D.
Published: October 2011

Language processing is a trait of human species. The knowledge about its neurobiological basis has been increased considerably over the past decades. Different brain regions in the left and right hemisphere have been identified to support particular language functions. Networks involving the temporal cortex and the inferior frontal cortex with a clear left lateralization were shown to support syntactic processes, whereas less lateralized temporo-frontal networks subserve semantic processes. These networks have been substantiated both by functional as well as by structural connectivity data. Electrophysiological measures indicate that within these networks syntactic processes of local structure building precede the assignment of grammatical and semantic relations in a sentence. Suprasegmental prosodic information overtly available in the acoustic language input is processed predominantly in a temporo-frontal network in the right hemisphere associated with a clear electrophysiological marker. Studies with patients suffering from lesions in the corpus callosum reveal that the posterior portion of this structure plays a crucial role in the interaction of syntactic and prosodic information during language processing.
What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease
Authors: Corti Olga , Lesage Suzanne , Brice Alexis
Published: October 2011

Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.
Calcium Channels in the Development, Maturation, and Function of Spermatozoa
Authors: Darszon Alberto , Nishigaki Takuya , Beltran Carmen , Treviño Claudia L.
Published: October 2011

A proper dialogue between spermatozoa and the egg is essential for conception of a new individual in sexually reproducing animals. Ca2+is crucial in orchestrating this unique event leading to a new life. No wonder that nature has devised different Ca2+-permeable channels and located them at distinct sites in spermatozoa so that they can help fertilize the egg. New tools to study sperm ionic currents, and image intracellular Ca2+with better spatial and temporal resolution even in swimming spermatozoa, are revealing how sperm ion channels participate in fertilization. This review critically examines the involvement of Ca2+channels in multiple signaling processes needed for spermatozoa to mature, travel towards the egg, and fertilize it. Remarkably, these tiny specialized cells can express exclusive channels like CatSper for Ca2+and SLO3 for K+, which are attractive targets for contraception and for the discovery of novel signaling complexes. Learning more about fertilization is a matter of capital importance; societies face growing pressure to counteract rising male infertility rates, provide safe male gamete-based contraceptives, and preserve biodiversity through improved captive breeding and assisted conception initiatives.
Fiber Types in Mammalian Skeletal Muscles
Authors: Schiaffino Stefano , Reggiani Carlo
Published: October 2011

Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors. The relative proportion of the different fiber types varies strikingly between species, and in humans shows significant variability between individuals. Myosin heavy chain isoforms, whose complete inventory and expression pattern are now available, provide a useful marker for fiber types, both for the four major forms present in trunk and limb muscles and the minor forms present in head and neck muscles. However, muscle fiber diversity involves all functional muscle cell compartments, including membrane excitation, excitation-contraction coupling, contractile machinery, cytoskeleton scaffold, and energy supply systems. Variations within each compartment are limited by the need of matching fiber type properties between different compartments. Nerve activity is a major control mechanism of the fiber type profile, and multiple signaling pathways are implicated in activity-dependent changes of muscle fibers. The characterization of these pathways is raising increasing interest in clinical medicine, given the potentially beneficial effects of muscle fiber type switching in the prevention and treatment of metabolic diseases.
Recent Advance in Antigen-Specific Immunotherapy for Acute Myeloid Leukemia
Authors: Kadowaki Norimitsu , Kitawaki Toshio
Published: October 2011

Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML). Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML.
Prune Belly Syndrome
Authors: Tagore Koyye Ravindranath , Ramineni Asok Kumar S. , Vijaya Lakshmi A. R. , N. Bhavani
Published: October 2011

Prune belly syndrome is a rare congenital disorder of the urinary system, characterized by a triad of abnormalities. The aetiology is not known. Many infants are either stillborn or die within the first few weeks of life from severe lung or kidney problems, or a combination of congenital anomalies.
Seasonal Variation of the Aerosol Light Scattering Coefficient in Marine Air of the Northeast Atlantic
Authors: Vaishya Aditya , Jennings S. G. , O'Dowd Colin
Published: October 2011

Aerosol light scattering measurements were carried out using a TSI 3563 Nephelometer at the Mace Head Atmospheric Research Station, on the west coast of Ireland from year 2001–2010. A strong seasonal trend in the aerosol light scattering coefficient at 550 nm (), for clean marine air masses, is observed with a high value, [average (geometric mean)] of 35.3 Mm−1(29.5 Mm−1), in January and a low value of 13.7 Mm−1(10.2 Mm−1), in July. This near threefold increase in the value during the winter season is because of the large contribution of wind-speed generated sea-salt particles in the marine boundary layer. A high positive correlation coefficient of 0.82 was found between the percentage occurrence of relatively large Ångström exponent (Å) values (>1.2) and the percentage occurrence of lower values (5–15 Mm−1) in the summer season. and wind-speed have a high positive correlation coefficient of 0.88 whereas Å and wind-speed have a negative correlation coefficient of −0.89. Å values during the summer months indicate the dominance of sub-m particles thus indicating the contribution of non-sea-salt sulphate and organics towards the as these species show an enhanced concentration during the summer months.
Separation and Identification of HSP‐Associated Protein Complexes from Pancreatic Cancer Cell Lines Using 2D CN/SDS‐PAGE Coupled with Mass Spectrometry
Authors: Zhao Zhiyun , Liu Hui , Wang Xinli , Wang Xiaodong , Li Zhili
Published: October 2011

Protein complexes are a cornerstone of many biological processes and together they form various types of molecular machinery. A broad understanding of these protein complexes is crucial for revealing and building models of protein function and regulation. Pancreatic cancer is a highly lethal disease which is difficult to diagnose at early stage and even more difficult to cure. In this study, we applied a gradient clear native gel system combined with subsequent second‐dimensional SDS‐PAGE to separate protein complexes from cell lysates of SW1990 and PANC‐1 pancreatic cancer cell lines with different degrees of differentiation. Ten heat‐shock‐protein‐ (HSP‐) associated protein complexes were separated and identified, and the differentially expressed proteins related to cancers were also found, such as HSP60, protein disulfide‐isomerase A4 (ERp72), and transitional endoplasmic reticulum ATPase (TER ATPase).
Raman Spectroscopy for Clinical Oncology
Authors: Fenn Michael B. , Xanthopoulos Petros , Pyrgiotakis Georgios , Grobmyer Stephen R. , Pardalos Panos M. , Hench Larry L.
Published: October 2011

Cancer is one of the leading causes of death throughout the world. Advancements in early and improved diagnosis could help prevent a significant number of these deaths. Raman spectroscopy is a vibrational spectroscopic technique which has received considerable attention recently with regards to applications in clinical oncology. Raman spectroscopy has the potential not only to improve diagnosis of cancer but also to advance the treatment of cancer. A number of studies have investigated Raman spectroscopy for its potential to improve diagnosis and treatment of a wide variety of cancers. In this paper the most recent advances in dispersive Raman spectroscopy, which have demonstrated promising leads to real world application for clinical oncology are reviewed. The application of Raman spectroscopy to breast, brain, skin, cervical, gastrointestinal, oral, and lung cancers is reviewed as well as a special focus on the data analysis techniques, which have been employed in the studies.
Vascular Changes in Bleomycin-Induced Scleroderma
Authors: Yamamoto Toshiyuki , Katayama Ichiro
Published: October 2011

Systemic sclerosis (SSc) is characterized by vascular injury, immunological abnormalities, and fibrosis of the skin as well as various internal organs. Vascular impairment is the early manifestation and plays a fundamental role in the pathogenesis of SSc. Recent studies suggest that complex interactions among the endothelial cells, pericytes, smooth muscle cells, and fibroblasts are involved in the systemic vasculopathy in SSc, and histological feature of proliferation of vascular wall is seen in the lesional scleroderma skin at the late stage of disease. One of the most representative mouse models for scleroderma is the bleomycin-induced scleroderma; however, aspects of vascular alteration have not been described in detail so far. A number of studies have shown that bleomycin stimulates endothelial cells and fibroblasts to induce proinflammatory and fibrogenic cytokines, apoptosis, reactive oxygen species, and so on. This paper makes a focus on the vascular involvement in the bleomycin-induced murine scleroderma.
Intrauterine Contraceptive Device Migration Presenting as Abdominal Wall Swelling: A Case Report
Authors: Wani Imtiaz , Syed Adil , Maqbool Muddasir , Bakshi Iftikhar , Bhat Hilal , Andrabi Faheem Ul Hassan , Mohsin Naveed
Published: October 2011

A number of complications are reported with the use of intrauterine contraceptive devices. These may pursue asymptomatic course or present as an acute abdomen after migration into peritoneal cavity. The authors here are reporting an abdominal wall swelling caused by transuterine migration of a copper intrauterine contraceptive device in a 28-year-old female. An open approach was used, and impacted foreign body was retrieved.
Pulse Oximetry for the Detection of Obstructive Sleep Apnea Syndrome: Can the Memory Capacity of Oxygen Saturation Influence Their Diagnostic Accuracy?
Authors: Nigro Carlos A. , Dibur Eduardo , Rhodius Edgardo
Published: October 2011

Objective. To assess the diagnostic ability of WristOx 3100 using its three different recording settings in patients with suspected obstructive sleep apnea syndrome (OSAS).Methods. All participants (135) performed the oximetry (three oximeters WristOx ) and polysomnography (PSG) simultaneously in the sleep laboratory. Both recordings were interpreted blindly. Each oximeter was set to one of three different recording settings (memory capabilities 0.25, 0.5, and 1 Hz). The software (nVision 5.1) calculated the adjusted O2desaturation index-mean number of O2desaturation per hour of analyzed recording ≥2, 3, and 4% (ADI2, 3, and 4). The ADI2, 3, and 4 cutoff points that better discriminated between subjects with or without OSAS arose from the receiver-operator characteristics (ROCs) curve analysis. OSAS was defined as a respiratory disturbance index (RDI) ≥ 5.Results. 101 patients were included (77 men, mean age 52, median RDI 22.6, median BMI 27.4 kg/m2). The area under the ROCs curves (AUC-ROCs) of ADI2, 3, and 4 with different data storage rates were similar (AUC-ROCs with data storage rates of 0.25/0.5/1 Hz: ADI2: 0.958/0.948/0.965, ADI3: 0.961/0.95/0.966, and ADI4: 0.957/0.949/0.963,PNS).Conclusions. The ability of WristOx 3100 to detect patients with OSAS was not affected by the data storage rate of the oxygen saturation signal. Both memory capacity of 0.25, 0.5, or 1 Hz showed a similar performance for the diagnosis of OSAS.
Solitary Adrenal Metastasis from Esophageal Adenocarcinoma: A Case Report and Review of the Literature
Authors: Dellaportas D. , Lykoudis P. , Gkiokas G. , Polymeneas G. , Kondi-Pafiti A. , Voros D.
Published: October 2011

Introduction. In patients with extra-adrenal malignancy, an adrenal mass necessitates investigating the possibility of metastatic tumor. Curable adrenal metastasis are considered as a rare event.Case report. A 52-year-old male suffering from lower esophageal adenocarcinoma with a solitary left adrenal metastasis is presented herein, who underwent concomitant transhiatal esophagectomy and left adrenalectomy. The patient remains disease-free 18 months later.Discussion. Adrenal metastases mostly occur in patients with lung, kidney, breast, and gastrointestinal carcinomas. Primary esophageal adenocarcinoma gives adrenal metastatic deposits according to autopsy series with an incidence of about 3%–12%. When no other evidence of metastatic disease in cancer patients exists, several authors advocate adrenalectomy with curative intent. Isolated cases of long-term survival after resection of solitary adrenal metastasis from esophageal adenocarcinoma, like in our case, have been reported only as case reports.Conclusion. This study concludes that surgical resection may result in survival benefit in selected patients with solitary adrenal metastasis from esophageal adenocarcinoma.
Role of T Cells in Type 2 Diabetic Nephropathy
Authors: Wu Chia-Chao , Sytwu Huey-Kang , Lu Kuo-Cheng , Lin Yuh-Feng
Published: October 2011

Type 2 diabetic nephropathy (DN) is the most common cause of end-stage renal disease and is increasingly considered as an inflammatory disease characterized by leukocyte infiltration at every stage of renal involvement. Inflammation and activation of the immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Macrophage has been well recognized to play an important role in type 2 DN, leukocyte infiltration, and participated in process of DN, as was proposed recently. Th1, Th2, Th17, T reg, and cytotoxic T cells are involved in the development and progression of DN. The purpose of this review is to assemble current information concerning the role of T cells in the development and progression of type 2 DN. Specific emphasis is placed on the potential interaction and contribution of the T cells to renal damage. The therapeutic strategies involving T cells in the treatment of type 2 DN are also reviewed. Improving knowledge of the recognition of T cells as significant pathogenic mediators in DN reinforces the possibility of new potential therapeutic targets translated into future clinical treatments.
New Aspects in the Differential Diagnosis and Therapy of Bladder Pain Syndrome/Interstitial Cystitis
Authors: Neuhaus Jochen , Schwalenberg Thilo , Horn Lars-Christian , Alexander Henry , Stolzenburg Jens-Uwe
Published: October 2011

Diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC) is presently based on mainly clinical symptoms. BPS/IC can be considered as a worst-case scenario of bladder overactivity of unknown origin, including bladder pain. Usually, patients are partially or completely resistant to anticholinergic therapy, and therapeutical options are especially restricted in case of BPS/IC. Therefore, early detection of patients prone to develop BPS/IC symptoms is essential for successful therapy. We propose extended diagnostics including molecular markers. Differential diagnosis should be based on three diagnostical “columns”: (i) clinical diagnostics, (ii) histopathology, and (iii) molecular diagnostics. Analysis of molecular alterations of receptor expression in detrusor smooth muscle cells and urothelial integrity is necessary to develop patient-tailored therapeutical concepts. Although more research is needed to elucidate the pathomechanisms involved, extended BPS/IC diagnostics could already be integrated into routine patient care, allowing evidence-based pharmacotherapy of patients with idiopathic bladder overactivity and BPS/IC.
Renal Cell Carcinoma with Synchronous Metastasis to the Calcaneus and Metachronous Metastases to the Ovary and Gallbladder
Authors: Decoene Jasper , Ameye Filip , Lerut Evelyne , Oyen Raymond , Van Poppel Hein , Joniau Steven
Published: October 2011

Renal cell carcinomas (RCCs) are known for their unpredictable metastatic pattern. We present the case of a 63-year-old woman who initially presented in 1992 with a metastasis in the left calcaneus that led to the discovery of RCC. In 1998, a new metastasis was found in the ovary. In 2008, the diagnosis of a gallbladder metastasis was made. All metastases were surgically removed; no additional systemic therapies were used. Aggressive surgical treatment can prolong the survival of patients with resectable metastases. Patterns of metastasis are discussed, and a brief review of the literature is given regarding each localization.
Layperson-Oriented versus Clinical-Based Models for Assessing 10-Year Incidence of Coronary Heart Disease: National FINRISK Study
Authors: Qiao Qing , Laatikainen Tiina , Gao Weiguo , Pitkäniemi Janne , Vartiainen Erkki
Published: October 2011

One laboratory-based and two non-laboratory-based models with and without blood pressure measures are developed based on data of 14815 men and 16617 women aged 25–64 years. During the followup 1134 men and 566 women developed coronary heart disease (CHD). The area under the receiver operating characteristic curve (95% CI) for prediction of CHD incidence was 0.823 (0.807–0.839) for the laboratory-based model, 0.808 (0.791–0.824) and 0.803 (0.787–0.820) for the non-laboratory-based models with and without systolic blood pressure in men (P<0.01for overall comparison), and 0.878 (0.856–0.901), 0.871 (0.848–0.894), and 0.864 (0.840–0.887), respectively, in women (P<0.01). The predicted rates matched well with the observed ones (P>0.10). Compared with the model without blood pressure, the non-laboratory-based model with blood pressure tended to reclassify individuals into the higher risk categories for both event and nonevent groups in both genders. The study concludes the predictive property of the non-laboratory-based models are good.
Group CNeisseria meningitidisas a Cause of Septic Arthritis in a Native Shoulder Joint: A Case Report
Authors: Garner Amy J. , Sundram Freda , Harris Kathryn
Published: October 2011

Septic arthritis is an Orthopaedic emergency, threatening the joint within hours of onset. Up to 10% of cases of meningococcaemia have an associated septic arthritis. The aetiology of acute meningococcaemia in a variety of clinical syndromes is well documented in the literature. The pathogenNeisseria meningitidiscan cause both primary and secondary manifestations of disseminated infection. Broad-range 16S rDNA PCR is a relatively new technique, useful in identifying aetiological agents in septic patients with negative blood cultures. Here, we describe the rare clinical scenario of a 76-year-old woman with primary meningococcal septic arthritis of a native shoulder joint without associated meningococcal bloodstream infection. We discuss the role of 16s rDNA Polymerase Chain Reaction (PCR) in the identification of the infectious agent,Neisseria meningitidis, and the role of this technique in guiding subsequent management.
The Role of Nodes Distribution in Extending the Lifetime of Wireless Sensor Networks
Authors: Javadzadeh Mitra , Abbasfar Aliazam
Published: October 2011

One of the most important issues in sensor networks is prolonging the network lifetime. In this paper, we demonstrate that given a constant number of nodes, how distribution of nodes affects the lifetime. For this purpose, we first show that in a network with cluster-based routing protocol, nodes do not have equal importance, and their importance depends on their location, and we determine the most critical regions. We prove that the uniform distribution of nodes is not a good distribution. Finally, we propose a solution for the best distribution that concentrates the population of nodes on critical areas. Simulation results of our proposed distribution show a remarkable increase in network lifetime.
Inhibitory Effect ofHelicteres gardnerianaEthanol Extract on Acute Inflammation
Authors: de Melo Juliana Oliveira , de Arruda Laura Lícia Milani , Baroni Silmara , Truiti Maria da Conceição Torrado , Caparroz-Assef Silvana Martins , Cuman Roberto Kenji Nakamura , Bersani-Amado Ciomar Aparecida
Published: October 2011

The anti-inflammatory effect of an ethanol extract ofHelicteres gardneriana(Nees) Castiglioni was assayed in experimental models of pleurisy and microcirculationin situ. Treatment of animals with 500 mg/kg body weight reduced the exudate volume (35% reduction) induced by intrapleural injection of carrageenan and the migration of polymorphonuclear cells into the inflamed pleural cavity of rats (40%). Additionally, rolling and adhesion of leukocytes and the number of leukocytes that migrated toward the perivascular space in response to the carrageenan injection were decreased by the extract (500 mg/kg). These data demonstrate the anti-inflammatory effect of the ethanol extract ofHelicteres gardnerianaand imply that inhibition of leukocyte-endothelial interactions is important in the extract's mechanism of action.
Lasting Developmental Effects of Neonatal Fentanyl Exposure in Preweanling Rats
Authors: Catré Dora , Lopes Maria Francelina , Cabrita António Silvério
Published: October 2011

The present study aimed to determine whether neonatal treatment with fentanyl has lasting effects on stressed developing brain. Six-day-old rats were assigned to one of three groups (10 males/group): (1) fentanyl (incision+fentanyl), (2) saline (incision+0.9% saline), and (3) unoperated (unoperated sham). Pups with a plantar paw incision received repetitive subcutaneous injections of fentanyl or vehicle through postnatal days (PNDs) 6 to 8. A nonoperated sham group served as nonstressed control. Studies included assessment of development from PND 6 to PND 21 (growth indices and behavioral testing). Fentanyl administered twice daily for three days after surgical incision had no impact on early growth and development, as measured on PND 9, but showed a lasting impact on later growth, enhanced behavioral development, and lower anxiety, as measured through PNDs 10–21. While this does not completely support a benefit from such treatment, our findings may contribute to support the neonatal use of fentanyl, when indicated, even in premature newborns.
A Chinese Herbal Formula to Improve General Psychological Status in Posttraumatic Stress Disorder: A Randomized Placebo-Controlled Trial on Sichuan Earthquake Survivors
Authors: Meng Xian-Ze , Wu Feng , Wei Pin-Kang , Xiu Li-Juan , Shi Jun , Pang Bin , Sun Da-Zhi , Qin Zhi-Feng , Huang Yi , Lao Lixing
Published: October 2011

Introduction. Posttraumatic stress disorder (PTSD) is accompanied by poor general psychological status (GPS). In the present study, we investigated the effects of a Chinese herbal formula on GPS in earthquake survivors with PTSD.Methods. A randomized, double-blind, placebo-controlled trial compared a Chinese herbal formula,Xiao-Tan-Jie-Yu-Fang(XTJYF), to placebo in 2008 Sichuan earthquake survivors with PTSD. Patients were randomized into XTJYF (n=123) and placebo (n=122) groups. Baseline-to-end-point score changes in the three global indices of the Symptom Checklist-90-Revised (SCL-90-R) and rates of response in the SCL global severity index (GSI) were the primary endpoints. A subanalysis of the nine SCL factors and the sleep quality score were secondary endpoints.Results and Discussion. Compared to placebo, the XTJYF group was significantly improved in all three SCL global indices (P= 0.001~0.028). More patients in the XTJYF group reported “much improved” than the placebo group (P= 0.001). The XTJYF group performed significantly better than control in five out of nine SCL factors (somatization, obsessive-compulsive behavior, depression, anxiety, and hostility (P= 0.001~0.036)), and in sleep quality score (P<0.001). XTJYF produced no serious adverse events. These findings suggest that XTJYF may be an effective and safe treatment option for improving GPS in patients with PTSD.
Positive-Strand RNA Viruses Infecting the Red Imported Fire Ant,Solenopsis invicta
Authors: Valles Steven M.
Published: October 2011

The imported fire ants,Solenopsis invictaandS. richteriwere introduced into the USA between 1918 and 1945. Since that time, they have expanded their USA range to include some 138 million hectares. Their introduction has had significant economic consequences with costs associated with damage and control efforts estimated at 6 billion dollars annually in the USA. The general consensus of entomologists and myrmecologists is that permanent, sustainable control of these ants in the USA will likely depend on self-sustaining biological control agents. A metagenomics approach successfully resulted in discovery of three viruses infectingS. invicta.Solenopsis invicta virus 1(SINV-1), SINV-2, and SINV-3 are all positive, single-stranded RNA viruses and represent the first viral discoveries in any ant species. Molecular characterization, host relationships, and potential development and use of SINV-1, SINV-2, and SINV-3 as biopesticides are discussed.
Quantitative, Label-Free Detection of the Aggregation ofα-Synuclein Using Microcantilever Arrays Operated in a Liquid Environment
Authors: Jensen Jason , Farina Margherita , Zuccheri Giampaolo , Grange Wilfried , Hegner Martin
Published: October 2011

Early detection of protein aggregation is of great importance in the field of neurodegenerative diseases. The successful detection of the aggregation of the proteinα-synuclein in a quantitative, label-free manner by functionalising a microcantilever withα-synuclein monomers and operating it in dynamic mode in the presence ofα-synuclein monomers in solution is reported. A total mass of 6 ng ofα-synuclein was detected over 9 hours on the surface of the cantilever. The result is compared to conventional fluorescence measurements ofα-synuclein aggregation under similar conditions. It is found that the label-free cantilever detection method requires a concentration of protein 50 times smaller than that of the current method and indicated potential for significantly faster response times.
Pelvic Organ Prolapse Repair with and without Concomitant Burch Colposuspension in Incontinent Women: A Randomised Controlled Trial with at Least 5-Year Followup
Authors: Costantini Elisabetta , Lazzeri Massimo , Bini Vittorio , Del Zingaro Michele , Frumenzio Emanuela , Porena Massimo
Published: October 2011

The aim of this study was to reevaluate and update the followup of a previously published randomized controlled trial (RCT) on the impact of Burch Colposuspension (BC), as an anti-incontinence procedure, in patients with UI and POP, who underwent POP repair. Forty-seven women were randomly assigned to abdominal POP repair and concomitant BC (24 patients; group A) or POP repair alone without any anti-incontinence procedure (23 patients; group B). Median followup was 82 months (range 60–107); from over 47 patients, 30 reached 6-year followup. Two patients were lost at followup. In group A, 2 patients showed a stage I rectocele. In group B, 2 patients had a stage I rectocele and 1 a stage II rectocele. In group A, 13/23 (56.5%) were still incontinent after surgery compared with 9/22 patients (40.9%) in group B (P=0.298). No significant changes were observed between the first and the current followup. The update of long-term followup confirmed that BC did not improve outcome significantly in incontinent women when they undergo POP repair.
Contribution of Cytogenetics to the Debate on the Paraphyly ofPachycondylaspp. (Hymenoptera, Formicidae, Ponerinae)
Authors: Mariano Cléa dos Santos Ferreira , Pompolo Silvia das Graças , Silva Janisete Gomes , Delabie Jacques Hubert Charles
Published: October 2011

We present evidence of the paraphyly of the ant genusPachycondylaresulting from our cytogenetic studies on 29 populations in 18 species from Brazil and French Guyana. It is likely that karyotypes with a large number of chromosomes and comprising mostly small acrocentric chromosomes in species within thePachycondyla stricto sensugroup resulted from a succession of centric fission events. On the other hand, karyotypes with a small chromosome number comprising mostly metacentric chromosomes are also interpreted as little derived and tend to undergo centric fission. The karyotypes of the groupNeoponeraare more heterogeneous and probably undergo successive cycles of rearrangements tending to increase the chromosome number by centric fission. Theapicalisandverenaecomplexes form two probable sister groups that evolved independently due to centric fissions (verenae) and pericentric inversions (apicalis). Our results reveal the karyotype diversity in the genus and reinforce the hypothesis on the paraphyly ofPachycondyla.
Inflammation as an Animal Development Phenomenon
Authors: Ramos Gustavo Campos
Published: October 2011

Inflammation is a term that has been used throughout history in different contexts; it may represent a simple collection of clinical symptoms for which drugs are developed, a disease mechanism, or even a defense mechanism against microbes validating Pasteur's studies on bacteriology and Darwin's proposed struggle for survival. Thus, an explanation of this term must also consider the scientific questions addressed. In this study, I propose that several of the inflammatory events typically described in immunological, pathological, and pharmacological contexts can also be perceived as mechanisms of animal development. Thus, by recognizing that the generation of an animal form, its conservation, and its regeneration after tissue damage are phenomena of the same nature, inflammation can be addressed through the approach of developmental biology, thereby acquiring a much neglected physiological counterpart.
miR-221 Silencing Blocks Hepatocellular Carcinoma and Promotes Survival
Authors: Park Jong-Kook , Kogure Takayuki , Nuovo Gerard J. , Jiang Jinmai , He Lei , Kim Ji Hye , Phelps Mitch A. , Papenfuss Tracey L. , Croce Carlo M. , Patel Tushar , Schmittgen Thomas D.
Published: October 2011

Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis because of a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221, which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2′-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared with unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell-cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment for patients with advanced HCC. Cancer Res; 71(24); 7608–16. ©2011 AACR.
Manganese Superoxide Dismutase Is a p53-Regulated Gene That Switches Cancers between Early and Advanced Stages
Authors: Dhar Sanjit K. , Tangpong Jitbanjong , Chaiswing Luksana , Oberley Terry D. , St. Clair Daret K.
Published: October 2011

Manganese superoxide dismutase (MnSOD) plays a critical role in the survival of aerobic life, and its aberrant expression has been implicated in carcinogenesis and tumor resistance to therapy. However, despite extensive studies in MnSOD regulation and its role in cancer, when and how the alteration of MnSOD expression occurs during the process of tumor development in vivo are unknown. Here, we generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter-enhancer elements and investigated the changes of MnSOD transcription using the 7,12-dimethylbenz(α)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) multistage skin carcinogenesis model. The results show that MnSOD expression was suppressed at a very early stage but increased at late stages of skin carcinogenesis. The suppression and subsequent restoration of MnSOD expression were mediated by two transcription-factors, Sp1 and p53. Exposure to DMBA and TPA activated p53 and decreased MnSOD expression via p53-mediated suppression of Sp1 binding to the MnSOD promoter in normal-appearing skin and benign papillomas. In squamous cell carcinomas, Sp1 binding increased because of the loss of functional p53. We used chromatin immunoprecipitation, electrophoretic mobility shift assay, and both knockdown and overexpression of Sp1 and p53 to verify their roles in the expression of MnSOD at each stage of cancer development. The results identify MnSOD as a p53-regulated gene that switches between early and advanced stages of cancer. These findings also provide strong support for the development of means to reactivate p53 for the prevention of tumor progression. Cancer Res; 71(21); 6684–95. ©2011 AACR.
Economic Crises and the Elderly
Authors: Backes-Gellner Uschi , Schneider Martin R.
Published: October 2011

Economic crises in the last decades have swept elderly workers more than younger workers out of employment. But now the tide is turning. In affluent societies, elderly workers will have more opportunities of being employed in meaningful and well-paid jobs than ever before. On account of demographic changes, fewer (younger) workers will be around, and most of the reasons that in the past have induced employers to lay off older rather than younger workers will disappear. Future employment strategies will have to focus more on an optimal age mix and on benefitting from the full potential of the elderly.
Efficacy of CG3R6TAT Nanoparticles Self-Assembled from a Novel Antimicrobial Peptide for the Treatment of Candida albicans Meningitis in Rabbits
Authors: Xu Kaijin , Wang Huaying , Liu Lihong , Xu Wei , Sheng Jifang , Fan Weimin , Yang Yi-Yan , Li Lanjuan
Published: October 2011

Background: Candidal meningitis is a common clinical manifestation of invasive candidiasis in neonates. The aim of this study was to evaluate the in vivo antifungal efficacy of CG3R6TAT nanoparticles, novel core-shell structures self-assembled from cationic antimicrobial peptides, in a rabbit model of candidal meningitis. Methods: In vitro activity of CG3R6TAT nanoparticles against Candida albicans was assessed by determining the minimum inhibitory concentration and kill-time curves. In vivo, intravenous treatment with CG3R6TAT nanoparticles (n = 6; 0.25 mg/kg/day) or fluconazole (n = 6; 100 mg/kg/day) began 3 days after infection and continued for 11 consecutive days; the efficacy was assessed following 11 days of treatment by yeast counting in cerebrospinal fluid (CSF), the leukocyte concentrations in CSF and the histopathology of brain parenchyma. Results: At a concentration three times higher than the minimum inhibitory concentration (8.1 µmol/l), the nanoparticles complete- ly sterilized C. albicans after 5 h of incubation. In addition, there was a significant reduction in fungal counts and leukocyte concentrations in the CSF from rabbits treated with CG3R6TAT nanoparticles or fluconazole versus those from untreated control rabbits (p < 0.05, ANCOVA). The median number of days of treatment required to sterilize CSF cultures was 8.5 days for CG3R6TAT nanoparticle therapy (p = 0.022, vs. control) and 9.7 days for fluconazole therapy (p > 0.05, vs. control). The histopathologic severity of rabbits was significantly attenuated after CG3R6TAT treatment (p = 0.001, vs. control). Conclusion: This study suggests that CG3R6TAT nanoparticles may be a promising therapeutic agent for candidal meningitis.
Comparison of Six Statistics of Genetic Association Regarding Their Ability to Discriminate between Causal Variants and Genetically Linked Markers
Authors: Lorenzo Bermejo Justo , Garcia Perez Alfonso , Brandt Andreas , Hemminki Kari , Matthews Abigail G.
Published: October 2011

Objectives: Genome-wide association (GWA) studies still rely on the common-disease common-variant hypothesis since the assumption is associated with increased power. In GWA studies, polymorphisms are genotyped and their association with disease is investigated. Most of the identified associations are indirect and reflect a shared inheritance of the genotyped markers and genetically linked causal variants. We have compared six statistics of genetic association regarding their ability to discriminate between markers and causal susceptibility variants, including a probability value (Pval) and a Bayes Factor (BF) based on logistic regression, and the attributable familial relative risk (FRR). Methods: We carried out a simulation-based sensitivity analysis to explore several conceivable scenarios. Theoretical results were illustrated by established causal associations with age-related macular degeneration and by using imputed data based on HapMap for a case-control study of breast cancer. Results: Our data indicate that a representation of genetic association by FRRs and BFs generally facilitates the distinction of causal variants. The FRR showed the best discriminative power under most investigated scenarios, but no single statistic outperformed the others in all situations. For example, rare moderate- to low-penetrance variants (allele frequency: 1%, dominant odds ratio: ≤2.0) seem to be best discriminated by BFs. Conclusions: Present results may help to fully utilize the data generated in association studies that take advantage of next generation sequencing and/or multiple imputation based on the 1000 Genomes Project.
Calcium-Calmodulin Kinase II Mediates Digitalis-Induced Arrhythmias
Authors: Gonano Luis A. , Sepúlveda Marisa , Rico Yanina , Kaetzel Marcia , Valverde Carlos A. , Dedman John , Mattiazzi Alicia , Vila Petroff Martin
Published: October 2011

Background—

Digitalis-induced Na
+
accumulation results in an increase in Ca
2+
i
via the Na
+
/Ca
2+
exchanger, leading to enhanced sarcoplasmic reticulum (SR) Ca
2+
load, responsible for the positive inotropic and toxic arrhythmogenic effects of glycosides. A digitalis-induced increase in Ca
2+
i
could also activate calcium-calmodulin kinase II (CaMKII), which has been shown to have proarrhythmic effects. Here, we investigate whether CaMKII underlies digitalis-induced arrhythmias and the subcellular mechanisms involved.

Methods and Results—

In paced rat ventricular myocytes (0.5 Hz), 50 μmol/L ouabain increased contraction amplitude by 160±5%. In the absence of electric stimulation, ouabain promoted spontaneous contractile activity and Ca
2+
waves. Ouabain activated CaMKII (p-CaMKII), which phosphorylated its downstream targets, phospholamban (PLN) (Thr17) and ryanodine receptor (RyR) (Ser2814). Ouabain-induced spontaneous activity was prevented by inhibiting CaMKII with 2.5 μmol/L KN93 but not by 2.5 μmol/L of the inactive analog, KN92. Similar results were obtained using the CaMKII inhibitor, autocamtide-2 related inhibitory peptide (AIP) (1 to 2.5 μmol/L), and in myocytes from transgenic mice expressing SR-targeted AIP. Consistently, CaMKII overexpression exacerbated ouabain-induced spontaneous contractile activity. Ouabain was associated with an increase in SR Ca
2+
content and Ca
2+
spark frequency, indicative of enhanced SR Ca
2+
leak. KN93 suppressed the ouabain-induced increase in Ca
2+
spark frequency without affecting SR Ca
2+
content. Similar results were obtained with digoxin. In vivo, ouabain-induced arrhythmias were prevented by KN93 and absent in SR-AIP mice.

Conclusions—

These results show for the first time that CaMKII mediates ouabain-induced arrhythmic/toxic effects. We suggest that CaMKII-dependent phosphorylation of the RyR, resulting in Ca
2+
leak from the SR, is the underlying mechanism involved.
Apolipoprotein Isoform
E4
Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations
Authors: Versmissen Jorie , Oosterveer Daniëlla M. , Hoekstra Menno , Out Ruud , Berbée Jimmy F.P. , Blommesteijn-Touw Adriana C. , van Vark-van der Zee Leonie , Vongpromek Ranitha , Vanmierlo Tim , Defesche Joep C. , Mulder Monique , Kastelein John J.P. , Sijbrands Eric J.G.
Published: October 2011

Background—

In humans, the
E4
allele of the apolipoprotein
E
gene is associated with increased coronary heart disease risk. Surprisingly, in rodents, apolipoprotein
E4
only accelerates the atherosclerotic process when transgenic for the human low-density lipoprotein receptor (LDLR) protein. We therefore investigated whether the
LDLR
locus interacted with the apolipoprotein E gene genotype on coronary heart disease risk in patients clinically diagnosed with familial hypercholesterolemia with and without
LDLR
mutation. We investigated whether the presence of an
LDLR
mutation diminishing LDLR function was protective in
E4/E4
carriers.

Methods and Results—

In a cohort of 2400 patients clinically diagnosed with familial hypercholesterolemia, we found an
LDLR
gene mutation in 1383 patients, whereas in 1013 patients, such mutation was not present. In 92 patients homozygous for the apolipoprotein
E4
, the presence of an
LDLR
mutation conferred lower coronary heart disease risk (hazard ratio, 0.16; 95% CI, 0.05–0.58;
P
=0.005). Mirroring these results, the apolipoprotein
E4/E4
genotype was also associated with lower coronary heart disease risk in patients with familial hypercholesterolemia with an
LDLR
mutation (hazard ratio, 0.26; hazard ratio, 0.08–0.80;
P
=0.02).

Conclusions—

LDLR function is key to the detrimental effects of apolipoprotein
E4
in humans. Kinetic studies in humans are now required to study the consequences of our observation for prevention of both coronary heart disease and Alzheimer disease.