bluuebunny/crossref_metadata_2025 huggingface dataset:
Ovarian Cancer Spheroids Use Myosin-Generated Force to Clear the Mesothelium
Authors: Iwanicki Marcin P. , Davidowitz Rachel A. , Ng Mei Rosa , Besser Achim , Muranen Taru , Merritt Melissa , Danuser Gaudenz , Ince Tan , Brugge Joan S.
Published: June 2011

Dissemination of ovarian tumors involves the implantation of cancer spheroids into the mesothelial monolayer on the walls of peritoneal and pleural cavity organs. Biopsies of tumors attached to peritoneal organs show that mesothelial cells are not present under tumor masses. We have developed a live, image-based in vitro model in which interactions between tumor spheroids and mesothelial cells can be monitored in real time to provide spatial and temporal understanding of mesothelial clearance. In this article, we provide evidence that ovarian cancer spheroids use integrin- and talin-dependent activation of myosin and traction force to promote displacement of mesothelial cells from underneath a tumor cell spheroid. These results suggest that ovarian tumor cell clusters gain access to the submesothelial environment by exerting force on the mesothelial cells lining target organs, driving migration and clearance of the mesothelial cells.

Significance: This study uses time-lapse video microscopy to decipher cellular events associated with ovarian tumor cell intercalation of mesothelial cell layers. Ovarian cancer clusters were found to use actomyosin-generated force to physically displace mesothelial cells and gain access to the submesothelial environment. Blockade of force-conducting molecules, including α5 integrin, talin I, and nonmuscle myosin II, in cancer cells abrogated mesothelial displacement from underneath attached cancer spheroids. Cancer Discovery; 1(2); 144–57. ©2011 AACR.

Read the Commentary on this article by Kenny et al., p. 100

This article is highlighted in the In This Issue feature, p. 91
The Changing Role of Pathology in Breast Cancer Diagnosis and Treatment
Authors: Leong Anthony S.-Y. , Zhuang Zhengping
Published: June 2011

Pathological examination has been the gold standard for diagnosis in cancer and its role has also included the elucidation of etiology, pathogenesis, clinicopathological correlation, and prognostication. The advent of newer technologies and the realization that breast cancer is heterogeneous has shifted the focus to prognostication, with increased attention being paid to the identification of morphological features and immunohistochemical markers of prognostic relevance. However, despite the massive efforts invested in the identification of immunohistochemical biomarkers in breast cancer the majority have not proven to be of value in multivariate analyses and only estrogen receptor, progesterone receptor, and Her2/neu expression have remained essential components of pathological examination. These 3 markers were initially employed for prognostication but their role in treatment also rendered them of predictive value. Newer molecular methods, especially high-throughput technologies, have shown that even morphologically similar subtypes of breast cancer can show molecular heterogeneity; moreover, infiltrating ductal carcinoma can be separated into at least 4 molecular subtypes designated luminal (ER+, PR+, and Her2/neu–), Her2 overexpressing (ER–, PR–, and Her2/neu+), basal-like (ER–, PR–, Her2/neu–, and CK5/6+, EGFR+), and normal breast-like (ER–, PR–, and Her2/neu–), each with different clinical outcomes. The importance of proliferative gene expression in these subtypes has been demonstrated and surrogate immunohistochemical markers include ER, PR, Her2/neu, and Ki67 for the more expensive molecular tests. Molecular technologies, importantly, have not only provided further insights into the heterogeneity of breast cancer but have also opened new avenues for treatment through the identification of signaling molecules important in the proliferation and survival of the neoplastic cells. The treatment of cancer thus shifts from the conventional approach of ‘one size fits all’ to one of personalized treatment tailored to the specific characteristics of the tumor. Pathologists continue to play their traditional role in diagnosis but, as purveyors of the excised tissue, pathologists now have the additional role of identifying biomarkers responsive to therapeutic manipulation, thus playing an inextricable role as diagnostic oncologists in the management of breast cancer.
Changing Pathology with Changing Drugs: Skin Cancer
Authors: Karpova M.B. , Barysch M.J. , Zipser M.C. , Schönewolf N. , French L.E. , Dummer R.
Published: June 2011

Today skin cancer is mainly treated by surgical interventions. New findings concerning molecular biology and the signaling pathways in epithelial skin cancers such as basal cell carcinoma, squamous cell carcinoma or melanoma, and mesenchymal skin cancers such as angiosarcoma and dermatofibrosarcoma protuberans (DFSP) have identified new molecular targets for a systemic or local treatment approach. For DFSP there is an opportunity already today to reduce the intensity of surgical procedures by pretreatment with targeted therapy. This article highlights important aspects in several skin cancer types.
Lidocaine Does Not Reduce Pain Perception during Gel Instillation Sonography or Subsequent Office Hysteroscopy: Results of a Randomized Trial
Authors: Van den Bosch T. , Van Schoubroeck D. , Daemen A. , Domali E. , Vandenbroucke V. , De Moor B. , Deprest J. , Timmerman D.
Published: June 2011

Background: To evaluate if the addition of lidocaine to the gel used for gel infusion sonohysterography (GIS) reduces pain experienced during GIS or subsequent hysteroscopy. Methods: A total of 142 consecutive patients were randomized using computer-generated random integers. In 79 patients, GIS was performed with a gel containing lidocaine (Instillagel®) and in 63 patients the gel did not contain lidocaine (Endosgel®). Immediately after GIS, 132 patients (94%) underwent office hysteroscopy. The women were asked to fill in a questionnaire including a 100-mm visual analogue scale (VAS) score after each examination. Results: The mean age (SD) was 50.8 (12.1) years; 58.5% were premenopausal and 15.6% were nulliparous. The median (interquartile range (IR)) VAS score during GIS for all women was 6 (19.5): 8 (21) for the lidocaine group versus 5 (18.2) for those who received gel without lidocaine. The median (IR) VAS scores during hysteroscopy in the total group, the Instillagel group and the Endosgel group were 15.5 (43.2), 24 (35) and 9 (52), respectively. None of the differences were statistically significant. Conclusion: The addition of lidocaine to the gel used either for GIS or prior to office hysteroscopy does not reduce the procedure-related pain.
Amino Acid Substitutions in Matrix, Fusion and Hemagglutinin Proteins of Wild Measles Virus for Adaptation to Vero Cells
Authors: Xin Ji Yi , Ihara Toshiaki , Komase Katsuhiro , Nakayama Tetsuo
Published: June 2011

Background: Wild-type measles virus (MV) is isolated in B95a but not in Vero cells. Through an adaptation process of wild-type MV to Vero cells, several amino acid substitutions were reported. Methods: Six strains were adapted to Vero cells and membrane (M), fusion (F) and hemagglutinin (H) genes were sequenced. Cell fusion was assessed and recombinant MVs were constructed, having wild-type H or M gene with or without mutations. Results: No F gene substitution was noted. Amino-acid substitutions at positions 481 from Asn to Tyr (N481Y) and 546 from Ser to Gly (S546G) were observed in the H protein. Glu at position 89 of the M protein was substituted for Gly (E89G) and two mutations were noted at positions 62 (S62R) and 83 (S83P) in M protein. Recombinant viruses with mutation(s) detected in Vero-adapted strains induced a cytopathic effect and grew well in Vero cells, but those with the wild type did not. Recombinant viruses with mutation(s) demonstrated lower viral growth in B95a cells. Conclusions: Substitutions of E89G, S62R and S83P of the M protein were newly observed through adaptation to Vero cells, besides the mutations described in previous reports, with varying adaptation for each strain.
Maternal and Cord Blood Homocysteine and Folic Acid Levels in Smoking and Nonsmoking Pregnant Women
Authors: Coker Isil , Colak Ayfer , Gunaslan Hasturk Aybike , Yildiz Omur , Turkon Hakan , Halicioglu Oya
Published: June 2011

Introduction: The homocysteine level in blood is affected by gender, diet, smoking, folic acid and B-complex vitamins. It is known that higher than normal homocysteine levels in plasma may cause vascular endothelium dysfunction, resulting in the promotion of thrombus formation. In our study, we aimed to assess the effects of smoking during pregnancy on the homocysteine and folic acid levels of the mother and baby. Methods: The study included 58 pregnant women who had completed their 37th week of gestation: 30 women were nonsmokers (NONSM) and 28 were smokers (SM). The measurement of homocysteine and folic acid levels in all samples were performed with an Immulite 2000 analyzer, using the chemiluminescence method. Results: Maternal blood folic acid levels were significantly lower in SM (p = 0.041) than in NONSM. In SM, homocysteine levels in the umbilical cord blood were found to be significantly higher than those in NONSM (p = 0.006). Conclusion: High homocysteine levels in umbilical cord blood of smoking mothers, and the probable continuation of passive smoking for the babies after birth, make us think that the baby may have a predisposition towards vascular diseases at later periods in life.
Trophoblast Apoptosis in Placentas from Pregnancies Complicated by Preeclampsia
Authors: Tomas S.Z. , Prusac I.K. , Roje D. , Tadin I.
Published: June 2011

Aims: To assess trophoblast apoptosis separately in the cytotrophoblast, syncytiotrophoblast, total villous trophoblast, syncytial knots and syncytial knot formation, and to investigate the expression of apoptotic factors Fas ligand (FasL), Bcl-2 and proliferation marker Ki-67 in the trophoblast of placentas from preeclamptic patients. Methods: The study included placental samples from 25 preeclamptic and 25 normal pregnancies. For the detection of apoptosis and proliferation, antibody M30 and antibody against Ki-67 antigen were used. Expression of FasL and Bcl-2 was assessed using semi-quantitative HSCORE method. Syncytial knots were expressed as the number of syncytial knots per individual villus and as the total number of syncytial knots in each placental sample. Results: Trophoblast apoptosis, number of syncytial knots per individual villus and the total number of syncytial knots in each placental sample were significantly higher in preeclamptic placentas than in control group placentas. FasL expression was significantly less, and Bcl-2 expression significantly greater in the villus trophoblast among the study subjects compared with controls. There was no difference in the trophoblast proliferation between groups. Conclusion: Our findings might suggest that increased apoptosis and syncytial knot formation combined with reduced FasL expression could be involved in pathophysiological mechanisms of preeclampsia.
Interferon Alone or Combined with Ribavirin for Acute Prolonged Infection with Hepatitis C Virus in Chimpanzees
Authors: Tomoguri Tetsushi , Katayama Keiko , Tanaka Junko , Yugi Hisao , Mizui Masaaki , Miyakawa Yuzo , Yoshizawa Hiroshi
Published: June 2011

Infection with hepatitis C virus (HCV) persisted for longer than 29 weeks in 2 chimpanzees after they had been inoculated with it experimentally. One of them (C-210) received short-term subcutaneous interferon-α (IFN-α) 6 million units (MU) daily for 7 days at week 29. He cleared HCV RNA from the serum and remained negative for it during 25 weeks after the withdrawal of IFN. The other (C-224) did not respond to 2 courses of a short-term IFN monotherapy at weeks 20 and 23. Twelve weeks thereafter, he received IFN-α 3 MU daily for 2 weeks and then 3 times a week for 14 weeks combined with oral ribavirin 600 mg daily during 16 weeks. HCV RNA disappeared from the serum and stayed negative until the last follow-up 24 weeks after the completion of combination therapy.
Occurrence of Human Cytomegalovirus Glycoprotein B Genotypes in Immunocompetent and Immunosuppressed Taiwanese Patients
Authors: Wu Keh-Gong , Hung Miao-Chiu , Chang Ya-Ting , Chen Chun-Jen , Yang Su-Pen , Liu Cheng-Yi , Ho Donald Ming-Tak , Chan Yu-Jiun
Published: June 2011

Objectives: To investigate the differences of genotypic distributions among isolates between immunosuppressed and immunocompetent patients in a Taiwanese population. Methods: Human cytomegalovirus (HCMV) isolates from 76 patients with adequate chart data were analyzed. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to define gB genotypes which include gB1 to gB4. The clinical data of the 76 patients were retrospectively collected by chart review and classified into an immunosuppressed (n = 32) or immunocompetent (n = 44) group. Results: Among the 32 immunosuppressed patients, the most commonly identified HCMV genotypes were gB1 (27/32, 84.3%) and gB3 (4/32, 12.5%). 59.1% (26/44) of the immunocompetent patients were infected by gB1 while 38.6% (17/44) of them were infected by gB3. The frequency of gB1 infection in the immunosuppressed group was significantly higher than that in the immunocompetent group (p = 0.025). However, there was no statistically significant difference between gB1 and gB3 distributions by clinical diagnosis within each group. Conclusions: Only gB1 and gB3 genotypes were identified in this Taiwanese population. Although there is no significant difference between clinical diagnosis and gB genotyping, gB1 infection is significantly more predominant in immunosuppressed patients.
Basics of Systematic Reviews and Meta-Analyses for the Nephrologist
Authors: Bello Aminu K. , Wiebe Natasha , Garg Amit X. , Tonelli Marcello
Published: June 2011

Renal practitioners are expected to apply the best available evidence from rigorous scientific research to clinical decision-making and also for policy-making for those involved. Advances in information technology and unprecedented access to data have simplified the process for the search of best available evidence to guide practice. However, it is challenging to cope with the increasing volume of publications in nephrology and other areas of medicine. Accordingly, systematic reviews and meta-analysis have greatly facilitated best practice and effective clinical decision-making. Conducting a systematic review/meta-analysis involves a number of steps that start with protocol development and research question formulation, design and study selection criteria, followed by retrieval of potentially relevant studies, selection of those studies to be included and evaluation of a study’s risk of bias. Systematic reviews and meta-analyses have both strengths and weaknesses. Many of the perceived limitations of meta-analysis are not inherent in the methodology, but actually represent deficits in the conduct or reporting of individual primary studies. With the continuous proliferation of published renal clinical studies, such publications will continue to be an important resource for clinicians and researchers in nephrology. It is therefore important for nephrologists to keep abreast of developments in this field, which requires some knowledge about how these studies are conducted, reported and how to appraise them for application to clinical practice or policy-making.
Total Numbers of Undiagnosed Carriers of Hepatitis C and B Viruses in Japan Estimated by Age- and Area-Specific Prevalence on the National Scale
Authors: Tanaka Junko , Koyama Tomiko , Mizui Masaaki , Uchida Shigeru , Katayama Keiko , Matsuo Junko , Akita Tomoyuki , Nakashima Ayumu , Miyakawa Yuzo , Yoshizawa Hiroshi
Published: June 2011

Objective: To estimate total numbers of undiagnosed carriers of hepatitis C virus (HCV) and hepatitis B virus (HBV) in Japan. Methods: Area- and age-specific prevalence of HCV as well as HBV was determined in the first-time blood donors [20–39 years (n = 2,429,364)] and examinees of periodical health check-ups [40–74 years (6,204,968 for HCV and 6,228,967 for HBV)] in Japan. Prevalence in adolescents [5–19 years (79,256 for HCV and 68,792 for HBV)] was determined in a single prefecture, and that of HCV in the elderly (≧75 years) was estimated by the exponential model. HBV infection was determined by the detection of hepatitis B surface antigen, and HCV infection by either the algorithm or assuming persistent infection in 70% of the individuals with antibody to HCV. Results: Of the total population of 127,285,653 in 2005, 807,903 (95% CI 679,886–974,292) were estimated to be infected with HCV at a carrier rate of 0.63%, and 903,145 (837,189–969,572) with HBV at that of 0.71%. Conclusion: Accurate estimation of undiagnosed HCV and HBV carriers in the general population would help to predict the future burden of liver disease, and take appropriate measures for improving healthcare.
Renal TLR4 mRNA Expression Correlates with Inflammatory Marker MCP-1 and Profibrotic Molecule TGF-β1 in Patients with Chronic Kidney Disease
Authors: Lepenies Julia , Eardley Kevin S. , Kienitz Tina , Hewison Martin , Ihl Thomas , Stewart Paul M. , Cockwell Paul , Quinkler Marcus
Published: June 2011

Background: Toll-like receptor-4 (TLR4) has been implicated in the pathogenesis of different renal diseases in rodent models. However, in human kidney disease, TLR4 expression and regulation is not well understood. We hypothesized that renal TLR4 expression plays a role in chronic kidney disease (CKD) and is associated with proteinuria, kidney function, histological diagnosis, and inflammatory mediators. Methods: We quantified TLR4 mRNA as well as expression of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6) in human kidney biopsies from 70 patients with CKD. We measured kidney function, urinary MCP-1 protein excretion, and the amount of chronic damage. Macrophage load was quantified by CD68 and vascularization by CD34 immunostaining. Results: TLR4 expression correlated significantly with MCP-1 and TGF-β1 expression. High TLR4 expression was associated with high IL-6 expression. TLR4 expression was significantly upregulated in patients with severe proteinuria, and in patients with chronic ischemic renal damage and IgA nephropathy, when compared to patients with thin glomerular basement membrane disease. TLR4 expression did not correlate with creatinine clearance, renal outcome, macrophage load or chronic damage. Conclusions: We show for the first time that renal TLR4 expression was significantly associated with the pro-inflammatory marker MCP-1 and the profibrotic molecule TGF-β1 in kidney biopsies from patients with CKD, suggesting that increased expression of TLR4 is an important feature of CKD.
Drug-Induced Nephrotoxicity in Inflammatory Bowel Disease
Authors: Oikonomou Konstantinos A. , Kapsoritakis Andreas N. , Stefanidis Ioannis , Potamianos Spyros P.
Published: June 2011

Conservative management of inflammatory bowel disease (IBD) is based on a combination of drugs, including aminosalicylates (ASAs), steroids, antibiotics, immunosuppressives and biologic agents. Although various side effects have been related to treatment regimens, drug-induced nephrotoxicity is rather uncommon. Furthermore, it is often underestimated since renal function deterioration may be attributed to the underlying disease. The nephrotoxicity of ASAs and cyclosporine A seems well established, but recent data have suggested a possible role of biologic agents such as infliximab and adalimubab in renal impairment. The aim of this review is to summarize the nephrotoxic effects of medical treatment as well as to express possible caveats in the administration of novel agents in IBD.
Conditional Survival of All Primary Brain Tumor Patients by Age, Behavior, and Histology
Authors: Porter Kimberly R. , McCarthy Bridget J. , Berbaum Michael L. , Davis Faith G.
Published: June 2011

Background: Survival statistics commonly reflect survival from the time of diagnosis but do not take into account survival already achieved after a diagnosis. The objective of this study was to provide conditional survival estimates for brain tumor patients as a more accurate measure of survival for those who have already survived for a specified amount of time after diagnosis. Methods: Data on primary malignant and nonmalignant brain tumor cases diagnosed from 1985–2005 from selected SEER state cancer registries were obtained. Relative survival up to 15 years postdiagnosis and varying relative conditional survival rates were computed using the life-table method. Results: The overall 1-year relative survival estimate derived from time of diagnosis was 67.8% compared to the 6-month relative conditional survival rate of 85.7% for 6-month survivors (the probability of surviving to 1 year given survival to 6 months). The 10-year overall relative survival rate was 49.5% from time of diagnosis compared to the 8-year relative conditional survival rate of 79.2% for 2-year survivors. Conditional survival estimates and standard survival estimates varied by histology, behavior, and age at diagnosis. The 5-year relative survival estimate derived from time of diagnosis for glioblastoma was 3.6% compared to the 3-year relative conditional survival rate of 36.4% for 2-year survivors. For most nonmalignant tumors, the difference between relative survival and the corresponding conditional survival estimates were minimal. Older age groups had greater numeric gains in survival but lower conditional survival estimates than other age groups. Similar findings were seen for other conditional survival intervals. Conclusions: Conditional survival is a useful disease surveillance measure for clinicians and brain tumor survivors to provide them with better ‘real-time’ estimates and hope.
Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis: A Review
Authors: Pitsiou Georgia , Papakosta Despina , Bouros Demosthenes
Published: June 2011

Idiopathic pulmonary fibrosis (IPF) is a progressive diffuse parenchymal disease with a poor prognosis. Pulmonary hypertension (PH) often complicates the course of IPF and may even be found in patients with preserved lung function. Possible pathogenetic mechanisms of PH in IPF include vascular destruction, pulmonary hypoxic vasoconstriction and vascular remodeling due to overexpression of cytokines and growth factors. PH in IPF patients is associated with decreased exercise capacity and a worse prognosis. Due to its prognostic significance, it seems important to investigate for PH in these patients. As the symptoms of PH in IPF are nonspecific, the development of PH in a patient with known IPF can be easily overlooked. Noninvasive methods provide clues for the diagnosis, but their sensitivity is limited. Doppler echocardiography is a useful tool for the detection of PH which also provides additional information regarding associated cardiac abnormalities. However, right heart catheterization remains the gold standard diagnostic test. Therapeutic options for PH in IPF are limited. Long-term oxygen administration for the correction of hypoxemia should be recommended. The availability of new pharmacological agents in the treatment of PH has raised the possibility of therapy in patients with IPF and associated PH. Whether these PH-targeted therapies may be of benefit in this patient group, in terms of improving functional outcomes and survival, remains uncertain.
Effects of Somatostatin and Octreotide on the Interactions between Neoplastic Gastroenteropancreatic Endocrine Cells and Endothelial Cells: A Comparison between in vitro and in vivo Properties
Authors: Walter Thomas , Hommell-Fontaine Juliette , Gouysse Géraldine , Pourreyron Céline , Nejjari Mimoun , Villaume Karine , Causeret Sylvain , Hervieu Valérie , Poncet Gilles , Roche Colette , Scoazec Jean-Yves
Published: June 2011

Background/Aims: Experimental studies in vitro suggest that somatostatin and some of its analogues used in clinical practice, such as octreotide, may have potent antiangiogenic properties. However, the clinical transposition of these data is difficult. Methods: To address this issue, we designed a comparative study of the effects of somatostatin and octreotide on the interactions between neoplastic endocrine cells and endothelial cells in several in vitro and in vivo experimental models, including primary cultures of human umbilical vein endothelial cells (HUVEC), indirect cocultures between HUVEC and the somatostatin-producing endocrine cell line STC-1, and an animal model of intrahepatic dissemination of STC-1 cells. Results: 10–8M octreotide markedly inhibited both basal and VEGF-stimulated HUVEC proliferation, had no effect on endothelial cell migration, but inhibited endothelial tubule formation. HUVEC cocultured with the somatostatin- and VEGF-producing STC-1 cells presented a markedly decreased proliferation, a slightly increased motility and an increased capacity of tubule formation; in this system, the inhibition of endothelial cell proliferation was abolished by neutralizing anti-somatostatin but was restored in the presence of anti-VEGF antibodies. This suggests that somatostatin is able to antagonize the effects of VEGF on endothelial cell proliferation but not on endothelial cell sprouting. Finally, no significant effect of octreotide on tumor growth and intratumoral microvascular density was detected in an experimental model of intrahepatic dissemination of STC-1 cells. Conclusion: The in vitro antiangiogenic effects of somatostatin and its analogues are likely to be efficiently counterbalanced in the tumor microenvironment by the concomitant release of proangiogenic factors like VEGF.
Serum Vitamins and Heavy Metals in Blood and Urine, and the Correlations among Them in Parkinson’s Disease Patients in China
Authors: Fukushima Tetsuhito , Tan Xiaodong , Luo Yunwen , Kanda Hideyuki
Published: June 2011

Background: Some heavy metals are suspected to be pathogenic and some vitamins protective against Parkinson’s disease (PD), and the interaction between heavy metals and vitamins could be associated with the pathophysiology of PD. Methods: Subjects comprised PD patients and sex- and age-matched controls recruited from an outpatient clinic in China. Morning blood and urine samples were used to measure concentrations of metals and vitamins. Results: The serum iron, whole-blood manganese, urine iron and copper levels were significantly higher in the PD patients than in the controls. The correlation coefficient between serum and urine concentrations of iron in the PD patients was significant. The serum vitamin E/urine copper ratio was significantly lower in the PD patients than in the controls. Serum vitamin E was negatively correlated with serum copper and was positively correlated with urine copper in the PD patients. Serum vitamin B12 was positively correlated with serum zinc in the PD patients and was negatively correlated with urine zinc in the controls. Conclusions: Excessive intake of iron and copper, accumulation of manganese, vitamin E/copper imbalance in intake, and vitamin B12 decrease by zinc deficiency in the body might be involved in the etiology of PD.
Prevalence of Dementia among Elderly People Living in Cotonou, an Urban Area of Benin (West Africa)
Authors: Paraïso Moussiliou N. , Guerchet Maëlenn , Saizonou Jacques , Cowppli-Bony Pascale , Mouanga Alain M. , Nubukpo Philippe , Preux Pierre-Marie , Houinato Dismand S.
Published: June 2011

Background/Aims: The population of Benin is, like those of most developing countries, aging; dementia is therefore a major concern. Our goal was to estimate the prevalence of dementia in an elderly population living in urban Benin. Methods: In a cross-sectional community-based study, people aged 65 years and above were screened using the Community Screening Interview for Dementia and the Five-Word Test. Results: The prevalence of dementia was 3.7% (95% CI 2.6–4.8) overall. The figure increased with age and was higher among women than men. Conclusion: Dementia was slightly more prevalent than previously reported in a rural area of Benin, but the rate was similar to that recorded in other cities in developing countries.
West Nile Virus: The Complex Biology of an Emerging Pathogen
Authors: Ulbert Sebastian
Published: June 2011

West Nile virus (WNV) is a zoonotic virus that circulates in birds and is transmitted by mosquitoes. Incidentally, humans, horses and other mammals can also be infected. Disease symptoms caused by WNV range from fever to neurological complications, such as encephalitis or meningitis. Mortality is observed mostly in older and immunocompromised individuals. In recent years, epidemics caused by WNV in humans and horses have become more frequent in several Southern European countries, such as Italy and Greece. In 1999, WNV was introduced into the USA and spread over North America within a couple of years. The increasing number of WNV outbreaks is associated with the emergence of novel viral strains, which display higher virulence and greater epidemic potential for humans. Upon infection with WNV, the mammalian immune system counteracts the virus at several different levels. On the other side, WNV has developed elaborated escape mechanisms to avoid its elimination. This review summarizes recent findings in WNV research that help to understand the complex biology associated with this emerging pathogen.
Evolution of Leptin Structure and Function
Authors: Denver Robert J. , Bonett Ronald M. , Boorse Graham C.
Published: June 2011

Leptin, the protein product of the obese(ob or Lep) gene, is a hormone synthesized by adipocytes that signals available energy reserves to the brain, and thereby influences development, growth, metabolism and reproduction. In mammals, leptin functions as an adiposity signal: circulating leptin fluctuates in proportion to fat mass, and it acts on the hypothalamus to suppress food intake. Orthologs of mammalian Lep genes were recently isolated from several fish and two amphibian species, and here we report the identification of two Lep genes in a reptile, the lizard Anolis carolinensis. While vertebrate leptins show large divergence in their primary amino acid sequence, they form similar tertiary structures, and may have similar potencies when tested in vitro on heterologous leptin receptors (LepRs). Leptin binds to LepRs on the plasma membrane, activating several intracellular signaling pathways. Vertebrate LepRs signal via the Janus kinase (Jak) and signal transducer and activator of transcription (STAT) pathway. Three tyrosine residues located within the LepR cytoplasmic domain are phosphorylated by Jak2 and are required for activation of SH2-containing tyrosine phosphatase-2, STAT5 and STAT3 signaling. These tyrosines are conserved from fishes to mammals, demonstrating their critical role in signaling by the LepR. Leptin is anorexigenic in representatives of all vertebrate classes, suggesting that its role in energy balance is ancient and has been evolutionarily conserved. In addition to its integral role as a regulator of appetite and energy balance, leptin exerts pleiotropic actions in development, physiology and behavior.
Signaling Mechanisms That Regulate Smooth Muscle Cell Differentiation
Authors: Mack Christopher P.
Published: June 2011

Extensive studies over the last 30 years have demonstrated that vascular smooth muscle cell (SMC) differentiation and phenotypic modulation is controlled by a dynamic array of environmental cues. The identification of the signaling mechanisms by which these environmental cues regulate SMC phenotype has been more difficult because of our incomplete knowledge of the transcription mechanisms that regulate SMC-specific gene expression. However, recent advances in this area have provided significant insight, and the goal of this review is to summarize the signaling mechanisms by which extrinsic cues control SMC differentiation.
Key Transcriptional Regulators of Early Vascular Development
Authors: De Val Sarah
Published: June 2011

The formation of the vasculature depends on the precise spatial and temporal control of gene expression to define endothelial cell identity and to ensure the correct distribution and structure of the forming vessel network. This review provides an overview of the establishment of the vascular system, accompanied by a detailed discussion of the transcription factors involved in regulating endothelial gene expression during vasculogenesis and early vessel formation in both fish and mammalian systems. We also review the transcriptional pathways lying both upstream and downstream of key vascular transcription factors.
The Adventitia
Authors: Majesky Mark W. , Dong Xiu Rong , Hoglund Virginia , Mahoney William M. , Daum Guenter
Published: June 2011

Conventional views of the tunica adventitia as a poorly organized layer of vessel wall composed of fibroblasts, connective tissue, and perivascular nerves are undergoing revision. Recent studies suggest that the adventitia has properties of a stem/progenitor cell niche in the artery wall that may be poised to respond to arterial injury. It is also a major site of immune surveillance and inflammatory cell trafficking and harbors a dynamic microvasculature, the vasa vasorum, that maintains the medial layer and provides an important gateway for macrophage and leukocyte migration into the intima. In addition, the adventitia is in contact with tissue that surrounds the vessel and may actively participate in exchange of signals and cells between the vessel wall and the tissue in which it resides. This brief review highlights recent advances in our understanding of the adventitia and its resident progenitor cells and discusses progress toward an integrated view of adventitial function in vascular development, repair, and disease.
Endothelial Differentiation
Authors: Atkins G. Brandon , Jain Mukesh K. , Hamik Anne
Published: June 2011

A complex and diverse vascular system is requisite for the survival of higher organisms. The process of vascular development is highly regulated, involving the de novo formation of vessels (vasculogenesis), followed by expansion and remodeling of the primitive vasculature (angiogenesis), culminating in differentiation of endothelial phenotypes, as found in the mature vascular system. Over the last decade, significant advances have been made in understanding the molecular regulation of endothelial cell development and differentiation. Endothelial development, in particular the mechanisms in play during vasculogenesis and angiogenesis, is discussed in a sister review to this article. This review highlights the key pathways governing in endothelial differentiation, with a focus on the major molecular mechanisms of endothelial specification and heterogeneity.
Working Memory and the Hippocampus
Authors: Baddeley Alan , Jarrold Christopher , Vargha-Khadem Faraneh
Published: June 2011

A number of studies suggest an important role for the hippocampus in tasks involving visuospatial or relational working memory. We test the generality of this proposal across tasks using a battery designed to investigate the various components of working memory, studying the working memory performance of Jon, who shows a bilateral reduction in hippocampal volume of approximately 50%, comparing him to a group of 48 college students. We measure performance on four complex working memory span measures based on combining visuospatial and verbal storage with visuospatial or verbal concurrent processing as well as measuring Jon's ability to carry out the component storage and processing aspects of these tasks. Jon performed at a consistently high level across our range of tasks. Possible reasons for the apparent disparity between our own findings and earlier studies showing a hippocampal deficit are discussed in terms of both the potential differences in the demands placed on relational memory and of the proposed distinction between egocentric and allocentric visuospatial processing.
What Does Ipsilateral Delay Activity Reflect? Inferences from Slow Potentials in a Lateralized Visual Working Memory Task
Authors: Arend Anna M. , Zimmer Hubert D.
Published: June 2011

In the lateralized change detection task, two item arrays are presented, one on each side of the display. Participants have to remember the items in the relevant hemifield and ignore the items in the irrelevant hemifield. A difference wave between contralateral and ipsilateral slow potentials with respect to the relevant items, the contralateral delay activity, can be calculated. As its amplitude varies with the number of items held in working memory (WM) and reaches its asymptote with WM capacity, it is considered a pure neural correlate of visual WM load. However, in addition to this contralateral delay activity, load-dependent activity has also been observed over the hemisphere ipsilateral to the relevant hemifield, suggesting that the ipsilateral hemisphere is also involved in memory-related processes. This ipsilateral activity might either reflect a bilateral processing of relevant or else a lateralized processing of irrelevant, to-be-filtered-out items. As in the lateralized change detection task, the number of items on both sides of the display is typically identical, it was not possible to decide between these alternatives yet. To disentangle the influence of relevant and irrelevant items, we orthogonally varied the number of both types of items. Processing of relevant items caused purely contralateral load-dependent activity. Ipsilateral slow potentials were influenced by the number of irrelevant items only if visual WM load was low, but not if it was high. This suggests that whether irrelevant items are processed or filtered out depends on visual WM load.
Neural Correlates of Subsecond Time Distortion in the Middle Temporal Area of Visual Cortex
Authors: Sadeghi Navid G. , Pariyadath Vani , Apte Sameer , Eagleman David M. , Cook Erik P.
Published: June 2011

How does the brain represent the passage of time at the subsecond scale? Although different conceptual models for time perception have been proposed, its neurophysiological basis remains unknown. We took advantage of a visual duration illusion produced by stimulus novelty to link changes in cortical activity in monkeys with distortions of duration perception in humans. We found that human subjects perceived the duration of a subsecond motion pulse with a novel direction longer than a motion pulse with a repeated direction. Recording from monkeys viewing identical motion stimuli but performing a different behavioral task, we found that both the duration and amplitude of the neural response in the middle temporal area of visual cortex were positively correlated with the degree of novelty of the motion direction. In contrast to previous accounts that attribute distortions in duration perception to changes in the speed of a putative internal clock, our results suggest that the known adaptive properties of neural activity in visual cortex contributes to subsecond temporal distortions.
Activation of Fusiform Face Area by Greebles Is Related to Face Similarity but Not Expertise
Authors: Brants Marijke , Wagemans Johan , Op de Beeck Hans P.
Published: June 2011

Some of the brain areas in the ventral temporal lobe, such as the fusiform face area (FFA), are critical for face perception in humans, but what determines this specialization is a matter of debate. The face specificity hypothesis claims that faces are processed in a domain-specific way. Alternatively, the expertise hypothesis states that the FFA is specialized in processing objects of expertise. To disentangle these views, some previous experiments used an artificial class of novel objects called Greebles. These experiments combined a learning and fMRI paradigm. Given the high impact of the results in the literature, we replicated and further investigated this paradigm. In our experiment, eight participants were trained for ten 1-hr sessions at identifying Greebles. We scanned participants before and after training and examined responses in FFA and lateral occipital complex. Most importantly and in contrast to previous reports, we found a neural inversion effect for Greebles before training. This result suggests that people process the “novel” Greebles as faces, even before training. This prediction was confirmed in a postexperimental debriefing. In addition, we did not find an increase of the inversion effect for Greebles in the FFA after training. This indicates that the activity in the FFA for Greebles does not depend on the degree of expertise acquired with the objects but on the interpretation of the stimuli as face-related.
Eye Can See What You Want: Posterior Intraparietal Sulcus Encodes the Object of an Actor's Gaze
Authors: Ramsey Richard , Cross Emily S. , Hamilton Antonia F. de C.
Published: June 2011

In a social setting, seeing Sally look at a clock means something different to seeing her gaze longingly at a slice of chocolate cake. In both cases, her eyes and face might be turned rightward, but the information conveyed is markedly different, depending on the object of her gaze. Numerous studies have examined brain systems underlying the perception of gaze direction, but less is known about the neural basis of perceiving gaze shifts to specific objects. During fMRI, participants observed an actor look toward one of two objects, each occupying a distinct location. Video stimuli were sequenced to obtain repetition suppression (RS) for object identity, independent of spatial location. In a control condition, a spotlight highlighted one of the objects, but no actor was present. Observation of the human actor's gaze compared with the spotlight engaged frontal, parietal, and temporal cortices, consistent with a broad action observation network. RS for gazed object in the human condition was found in posterior intraparietal sulcus (pIPS). RS for highlighted object in the spotlight condition was found in middle occipital, inferior temporal, medial fusiform gyri, and superior parietal lobule. These results suggest that human pIPS is specifically sensitive to the type object that an observed actor looks at (tool vs. food), irrespective of the observed actor's gaze location (left vs. right). A general attention or lower-level object feature processing mechanism cannot account for the findings because a very different response pattern was seen in the spotlight control condition. Our results suggest that, in addition to spatial orienting, human pIPS has an important role in object-centered social orienting.
“She” Is Not Like “I”: The Tie between Language and Action Is in Our Imagination
Authors: Papeo Liuba , Corradi-Dell'Acqua Corrado , Rumiati Raffaella Ida
Published: June 2011

Embodied theories hold that understanding what another person is doing requires the observer to map that action directly onto his or her own motor representation and simulate it internally. The human motor system may, thus, be endowed with a “mirror matching” device through which the same motor representation is activated, when the subject is either the performer or the observer of another's action (“self-other shared representation”). It is suggested that understanding action verbs relies upon the same mechanism; this implies that motor responses to these words are automatic and independent of the subject of the verb. In the current study, participants were requested to read silently and decide on the syntactic subject of action and nonaction verbs, presented in first (1P) or third (3P) person, while TMS was applied to the left hand primary motor cortex (M1). TMS-induced motor-evoked potentials were recorded from hand muscles as a measure of cortico-spinal excitability. Motor-evoked potentials increased for 1P, but not for 3P, action verbs or 1P and 3P nonaction verbs. We provide novel demonstration that the motor simulation is triggered only when the conceptual representation of a word integrates the action with the self as the agent of that action. This questions the core principle of “mirror matching” and opens to alternative interpretations of the relationship between conceptual and sensorimotor processes.
Can We Remember Future Actions yet Forget the Last Two Minutes? Study in Transient Global Amnesia
Authors: Hainselin Mathieu , Quinette Peggy , Desgranges Béatrice , Martinaud Olivier , Hannequin Didier , de La Sayette Vincent , Viader Fausto , Eustache Francis
Published: June 2011

Transient global amnesia (TGA) is a clinical syndrome characterized by the abrupt onset of a massive episodic memory deficit that spares other cognitive functions. If the anterograde dimension is known to be impaired in TGA, researchers have yet to investigate prospective memory (PM)—which involves remembering to perform an intended action at some point in the future—in this syndrome. Furthermore, as executive functions are thought to be spared in this syndrome, TGA provides an opportunity to examine the impact of a massive “pure” memory impairment on PM. We assessed 38 patients with a newly designed protocol that distinguished between the prospective (remembering to do something at the appropriate time) and retrospective (remembering what has to be done) components of PM. Moreover, we investigated episodic memory with an anterograde memory task and assessed executive functions, anxiety and mood, as well as their links with PM. We demonstrated that PM is impaired during TGA, with a greater deficit for the retrospective component than for the prospective component. Furthermore, we highlighted a strong link between these two components. Anterograde episodic memory impairments were correlated with retrospective component deficits in TGA patients, although we were able to confirm that executive functions are globally spared. We discuss this pattern of results within the theoretical framework of PM, putting forward new arguments in favor of the idea that PM deficits can occur mainly because of a massive anterograde memory deficit. The clinical consequences of PM impairment in TGA are examined.
Behavioral Interpretations of Intrinsic Connectivity Networks
Authors: Laird Angela R. , Fox P. Mickle , Eickhoff Simon B. , Turner Jessica A. , Ray Kimberly L. , McKay D. Reese , Glahn David C. , Beckmann Christian F. , Smith Stephen M. , Fox Peter T.
Published: June 2011

An increasingly large number of neuroimaging studies have investigated functionally connected networks during rest, providing insight into human brain architecture. Assessment of the functional qualities of resting state networks has been limited by the task-independent state, which results in an inability to relate these networks to specific mental functions. However, it was recently demonstrated that similar brain networks can be extracted from resting state data and data extracted from thousands of task-based neuroimaging experiments archived in the BrainMap database. Here, we present a full functional explication of these intrinsic connectivity networks at a standard low order decomposition using a neuroinformatics approach based on the BrainMap behavioral taxonomy as well as a stratified, data-driven ordering of cognitive processes. Our results serve as a resource for functional interpretations of brain networks in resting state studies and future investigations into mental operations and the tasks that drive them.